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Differential roles of serotonin receptor subtypes in the modulation of lordosis behaviour in the female… Mendelson, Scott Douglas 1988

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DIFFERENTIAL ROLES OF SEROTONIN RECEPTOR SUBTYPES IN THE MODULATION OF LORDOSIS BEHAVIOUR IN THE FEMALE RAT. By SCOTT DOUGLAS MENDELSON M.A. The University of B r i t i s h Columbia, 1985 B.A. Sonoma State University, 1981 A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY in THE FACULTY OF GRADUATE STUDIES Department of Psychology We accept th i s thesis as conforming to the required standard THE UNIVERSITY OF BRITISH COLUMBIA A p r i l 1988 © Scott Douglas Mendelson, 1988 In presenting this thesis in partial fulfilment of the requirements for an advanced degree at the University of British Columbia, I agree that the Library shall make it freely available for reference and study. I further agree that permission for extensive copying of this thesis for scholarly purposes may be granted by the head of my department or by his or her representatives. It is understood that copying or publication of this thesis for financial gain shall not be allowed without my written permission. Department of P s y c h o l o g y The University of British Columbia 1956 Main Mall Vancouver, Canada V6T 1Y3 D a t e A p r i l 25, 1988 DF-fifVfm i i ABSTRACT In 1985, Mendelson and Gorzalka proposed the dual role hypothesis of serotonergic modulation of lordosis behaviour. In this hypothesis i t was proposed that serotonergic a c t i v i t y can either i n h i b i t or f a c i l i t a t e lordosis behaviour. S p e c i f i c a l l y i t was suggested that the l o r d o s i s - i n h i b i t i n g e f f e c t s of serotonin are mediated by a c t i v i t y at 5-HT, receptors, whereas lordosis-f a c i l i t a t i n g effects of serotonin are mediated by a c t i v i t y at 5-HT2 receptors. The purpose of the following series of studies was both to confirm and to extend the dual role hypothesis. The intraperitoneal administration of the 5-HT2 antagonists p i z o t e f i n (1 mg/kg), cyproheptadine (1 mg/kg), metitepine (1 mg/kg), and ketanserin (1 mg/kg) were found to i n h i b i t lordosis behavior in ovariectomized rats that had been primed with e s t r a d i o l benzoate (EB) and progesterone (P). Pipamperone was i n e f f e c t i v e . The 5-HT2 agonist guipazine (3 mg/kg) was in e f f e c t i v e alone, but i t reversed the inh i b i t o r y e f fects of p i z o t e f i n , cyproheptadine, and ketanserin. It did not reverse the e f f e c t s of metitepine. The highly selective 5-HT2 antagonist LY53857 (0.3 mg/kg) was also found to i n h i b i t lordosis behaviour in female rats that had been primed with EB and P. The lor d o s i s -i n h i b i t i n g effect of LY53857 (1 mg/kg) in females primed with EB and P was reversed by quipazine (3 mg/kg). The nonselective 5-HT antagonist methysergide (7 mg/kg) was found to i n h i b i t lordosis behavior 30 min after intraperitoneal administration to females treated chronically with EB, or with EB and P. However, methysergide was found to f a c i l i t a t e lordosis behavior 200 and 300 min after administration to female rats treated acutely with E B . In an analysis of dose response i t was found that methysergide (0.02 - 7 mg/kg) administered 30 min prior to behavioural testing produced no f a c i l i t a t i o n of lordosis in females primed with E B . However, when administered 200 min prior to testing, methysergide (1 mg/kg) produced a s i g n i f i c a n t f a c i l i t a t i o n of lordosis. The administration of the 5 - H T,A agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH DPAT) inhibited lordosis behavior in ovariectomized rats primed with E B . 8-OH DPAT was in e f f e c t i v e at 0.01 mg/kg, whereas i n h i b i t i o n occurred at the 0.03, 0.1, 0.3, 1.0, and 3.0 mg/kg doses. In an evaluation of the eff e c t s of 8-OH DPAT on the expression of male sexual behaviour by females treated chronically with testosterone, 8-OH DPAT ( 1 mg/kg) increased the number of females mounting and s i g n i f i c a n t l y increased mount frequency. The 5 - H T,A agonists ipsapirone (0.1 mg/kg) and gepirone (0.3 mg/kg) f a c i l i t a t e d lordosis in females treated with E B . When administered at higher doses, ipsapirone (3.0 mg/kg) and buspirone (3.0 mg/kg) inhibited lordosis in rats treated with E B . In females treated with E B and P, ipsapirone (> 1.0 mg/kg), gepirone (> 0.3), and buspirone (> 0.3) inhibited lordosis behaviour. The newly developed 5 - H T,A antagonist B M Y 7378 (0.2 mg/kg) f a c i l i t a t e d lordosis behaviour in females treated with E B . However, th i s f a c i l i t a t i o n was no longer apparent at the 5 mg/kg dose. B M Y 7378 (0.04 - 5 mg/kg) was ine f f e c t i v e in females primed with E B and P. The 5 -H T T B agonist 1 -(3-trifluoromethylphenyl)piperazine (TFMPP, 0.2 -5 mg/kg) was found to f a c i l i t a t e lordosis in females treated with E B . In females primed with E B and P, TFMPP (5 mg/kg) produced a i v s i g n i f i c a n t i n h i b i t i o n of l o r d o s i s . The 5-HT,B a g o n i s t m-c h l o r o p h e n y l p i p e r a z i n e (MCPP, 0.04 - 5 mg/kg) was i n e f f e c t i v e i n females primed e i t h e r w i t h EB or w i t h EB and P. The 5 - H T 3 A n t a g o n i s t ICS 205-930 (5 mg/kg) was found t o f a c i l i t a t e l o r d o s i s b e h a v i o u r , whereas the 5-HT3 A n t a g o n i s t MDL 72222 (0.05 - 5 mg/kg ) was found t o be i n e f f e c t i v e i n females primed w i t h EB. The r e s u l t s of thes e s t u d i e s tend t o c o n f i r m t h a t s e r o t o n e r g i c a c t i v i t y can e i t h e r i n h i b i t or f a c i l i t a t e l o r d o s i s b e h a v i o u r . I t i s suggested t h a t the l o r d o s i s - i n h i b i t i n g e f f e c t s of s e r o t o n i n a r e mediated by a c t i v i t y a t p o s t s y n a p t i c 5 - H T T A and p o s s i b l y 5 - H T 3 R e c e p t o r s . The l o r d o s i s - f a c i l i t a t i n g e f f e c t s of s e r o t o n i n a r e mediated by a c t i v i t y a t 5 - H T 2 and p o s s i b l y p r e s y n a p t i c 5 - H T , B r e c e p t o r s . F i n a l l y , i t i s suggested t h a t a c t i v i t y a t s o m a t o - d e n d r i t i c 5 - H T , A a u t o r e c e p t o r s may mediate f a c i l i t a t o r y e f f e c t s of low doses of 5 - H T , A a g o n i s t s . In c l o s i n g , t h e r e i s a d i s c u s s i o n of the i m p l i c a t i o n s t h e s e r e s u l t s might h o l d f o r the u n d e r s t a n d i n g of the e f f e c t s of s e r o t o n e r g i c drugs on human b e h a v i o u r . TABLE OF CONTENTS ABSTRACT i i LIST OF TABLES v i LIST OF FIGURES v i i ACKNOWLEDGMENTS ix INTRODUCTION 1 GENERAL METHODS 12 EXPERIMENTS Experiment 1 16 Experiment 2 28 Experiment 3 38 Experiment 4 62 Experiment 5 70 Experiment 6 83 Experiment 7 90 Experiment 8 96 Experiment 9 105 GENERAL DISCUSSION 112 Effects of 5-HT antagonists on lordosis 115 Effects of 5-HT agonists on lordosis 121 Conclusions 130 IMPLICATIONS FOR UNDERSTANDING EFFECTS OF SEROTONERGIC DRUGS ON HUMAN BEHAVIOUR 133 SUMMARY 141 REFERENCES 141 v i LIST OF TABLES 1. The e f f e c t of 8-hydroxy - 2 -(di-n-propylamino)tetralin on the expression male sexual behaviour in the female rat 79 v i i LIST OF FIGURES 1. Effects of 5-HT2 antagonists on lordosis behaviour that was induced by the administration of es t r a d i o l benzoate and progesterone 20 2. Effects of 5-HT2 antagonists and quipazine on on lordosis behaviour that was induced by the administration of es t r a d i o l benzoate and progesterone 23 3. Effects of LY 53857 on lordosis behaviour that was induced by the administration of e s t r a d i o l benzoate 32 4. Effects of LY 53857 on lordosis behaviour that was induced by the administration of es t r a d i o l benzoate and progesterone 34 5. Effect of LY 53857 and quipazine on lordosis behaviour that was induced by the administration- of e s t r a d i o l benzoate and progesterone 36 6. Time-dependent effects of methysergide on lordosis behaviour that was induced by the administration of 10 Mg es t r a d i o l benzoate and 150 jug progesterone 45 7. Time-dependent effects of methysergide on lordosis behaviour that was induced by chronic administration of 10 Mg e s t r a d i o l benzoate 48 8. Time dependent effects of methysergide on lordosis behaviour that was induced by the administration of 5 Mg e s t r a d i o l benzoate and 150 Mg progesterone 51 9. Time-dependent effects of methysergide on lordosis behaviour induced by chronic administration of 5 Mg e s t r a d i o l benzoate..54 10. Time-dependent effects of methysergide on lordosis behaviour induced by the administration of 2 Mg es t r a d i o l benzoate 57 11. Dose-dependent effects of methysergide 30 min prior to testing on lordosis behaviour induced by the administration of est r a d i o l benzoate 66 12. Dose-dependent ef f e c t s of methysergide 200 min prior to testing on lordosis behaviour induced by the administration of est r a d i o l benzoate ..68 13. Ef f e c t s of 8-hydroxy-2-(di-n-propylamino)tetralin on lordosis behaviour induced by the administration of e s t r a d i o l benzoate 75 14. Effects of buspirone, ipsapirone and gepirone on lordosis behaviour induced by the administration of e s t r a d i o l benzoate or est r a d i o l benzoate and progesterone 87 v i i i 15. E f f e c t s of BMY 7378 on lordosis behaviour induced by the administration of e s t r a d i o l benzoate or es t r a d i o l benzoate and progesterone 94 16. E f f e c t s of 1-(3-trifluoromethylphenyl)piperazine on lordosis behaviour induced by the administration of es t r a d i o l benzoate or es t r a d i o l benzoate and progesterone 100 17. E f f e c t s of m-chlorophenlypiperazine on lordosis behaviour induced by the administration of e s t r a d i o l benzoate or e s t r a d i o l benzoate and progesterone 102 18. E f f e c t s of ICS 205-930 on lordosis behaviour induced by the administration of e s t r a d i o l benzoate 108 19. E f f e c t s of MDL 72222 on lordosis behaviour induced by the administration of e s t r a d i o l benzoate 110 1 INTRODUCTION Recent evidence indicates that the neurotransmitter serotonin plays a role in the modulation of a variety of human and animal behaviours. Among the behaviours that are thought to be at least p a r t i a l l y under serotonergic control are feeding, sleeping, aggression, anxiety, depression and sexual behaviour. The ways in which certain serotonergically modulated behaviours are expressed may d i f f e r considerably in humans and animals. Nonetheless, i t must be emphasized that the serotonin molecule i t s e l f i s i d e n t i c a l in humans and animals, and the effects produced by serotonergic drugs are often found to be quite s i m i l a r . Indeed, in some cases i t has been possible to develop animal models of serotonergic control of human behaviour. These models have proved quite useful in screening substances for psychotherapeutic value. In view of the fact that very l i t t l e i s known about the neuropharmacology of human sexual behaviour, an animal model of serotonergic modulation of sexual behaviour might prove to be extremely valuable. The role played by serotonin in the modulation of the sexual behaviour of the female rat was f i r s t evaluated by Meyerson in the early 1960's. As has frequently been the case in the study of female sexual behaviour, Meyerson primarily investigated the effect of serotonergic drugs on the expression of l o r d o s i s . Lordosis i s the downward flex i o n of the back and l i f t i n g of the rump and t a i l that may be displayed by a female rat in response to the mounting and pelvic thrusting of a male. The display of lordosis behaviour is generally regarded as an 2 i n d i c a t o r of s e x u a l r e c e p t i v i t y i n the female r a t . The a b i l i t y of a female r a t t o produce the l o r d o s i s response i s e n t i r e l y e s t r o g e n dependent. O v a r i e c t o m i z e d females d e p r i v e d of e s t r o g e n replacement do not d i s p l a y l o r d o s i s . However, c h r o n i c a d m i n i s t r a t i o n of low doses of e s t r o g e n r e s t o r e s l o r d o s i s b e h a v i o u r i n o v a r i e c t o m i z e d r a t s . A l t h o u g h the a d m i n i s t r a t i o n of p r o g e s t e r o n e i s not s u f f i c i e n t t o r e s t o r e the l o r d o s i s r e f l e x i n o v a r i e c t o m i z e d f e m a l e s , such t r e a t m e n t w i l l markedly f a c i l i t a t e l o r d o s i s b e h a v i o u r i n e s t r o g e n - t r e a t e d o v a r i e c t o m i z e d r a t s . Meyerson (1964a) obser v e d t h a t the i n c i d e n c e of l o r d o s i s b e h a v i o u r was d e c r e a s e d f o l l o w i n g the a d m i n i s t r a t i o n of monoamine o x i d a s e (MAO) i n h i b i t o r s i n female r a t s primed w i t h e s t r o g e n and p r o g e s t e r o n e . The MAO enzymes i n the b r a i n serve t o l i m i t the a c t i v i t y of s e r o t o n i n and o t h e r monoamine n e u r o t r a n s m i t t e r s by a l t e r i n g t h e i r m o l e c u l a r s t r u c t u r e s i n t o i n a c t i v e forms. The i n h i b i t i o n of t h e s e MAO enzymes r e s u l t s i n i n c r e a s e s i n the l e v e l s of a c t i v e n e u r o t r a n s m i t t e r s a v a i l a b l e i n the b r a i n . Meyerson a l s o o b s e r v e d t h a t the c o a d m i n i s t r a t i o n of the m e t a b o l i c p r e c u r s o r t o s e r o t o n i n , 5 - h y d r o x y t r y p t o p h a n , enhanced the l o r d o s i s - i n h i b i t i n g e f f e c t s of MAO i n h i b i t o r s , whereas the c o a d m i n i s t r a t i o n of the p r e c u r s o r s of t h e monoamine t r a n s m i t t e r s dopamine and n o r a d r e n a l i n e were l e s s e f f e c t i v e i n t h i s r e g a r d . In a f o l l o w i n g e x p e r i m e n t , Meyerson (1964b) found t h a t the a d m i n i s t r a t i o n of r e s e r p i n e and t e t r a b e n a z i n e , drugs t h a t reduce l e v e l s of s e r o t o n i n and the o t h e r monoamine n e u r o t r a n s m i t t e r s i n the b r a i n , f a c i l i t a t e d l o r d o s i s b e h a v i o u r i n e s t r o g e n - p r i m e d f e m a l e s . Moreover, i t appeared t h a t these f a c i l i t a t o r y e f f e c t s were a t t e n u a t e d by r e s t o r i n g s e r o t o n e r g i c 3 a c t i v i t y by t r e a t m e n t w i t h 5 - h y d r o x y t r y p t o p h a n . These d a t a l e d Meyerson t o propose a t h e o r y of s e r o t o n e r g i c i n h i b i t i o n of l o r d o s i s b e h a v i o u r . In the y e a r s t h a t f o l l o w e d Meyerson's i n i t i a l s t u d i e s , many ex p e r i m e n t s were performed i n the e f f o r t t o s u b s t a n t i a t e h i s h y p o t h e s i s of s e r o t o n e r g i c i n h i b i t i o n of l o r d o s i s b e h a v i o u r . For the most p a r t , these s t u d i e s c o n s i s t e d of p h a r m a c o l o g i c a l m a n i p u l a t i o n s of s e r o t o n e r g i c a c t i v i t y i n female r a t s primed w i t h v a r i o u s c o m b i n a t i o n s of e s t r o g e n and p r o g e s t e r o n e . Much of the d a t a c o l l e c t e d i n the e v a l u a t i o n of the e f f e c t s of s e r o t o n e r g i c drugs appeared t o s u pport Meyerson's h y p o t h e s i s . For example, a v a r i e t y of r e s e a r c h e r s r e p o r t e d t h a t the a d m i n i s t r a t i o n of the s e r o t o n i n s y n t h e s i s i n h i b i t o r p-c h l o r o p h e n y l a l a n i n e , a t r e a t m e n t t h a t reduces the a v a i l a b i l i t y of s e r o t o n i n , f a c i l i t a t e d l o r d o s i s b e h a v i o u r i n e s t r o g e n - p r i m e d females ( E v e r i t t , Fuxe, H o k f e l t & J o n s s o n , 1975; Meyerson & Lewander, 1966; Zemlan, Ward, Crowley & M a r g u l e s , 1973). A d m i n i s t r a t i o n of s e r o t o n i n a n t a g o n i s t s , drugs t h a t b l o c k the e f f e c t s of s e r o t o n i n , were a l s o r e p o r t e d t o f a c i l i t a t e l o r d o s i s b e h a v i o u r . The s e r o t o n i n a n t a g o n i s t s m e t h y s e r g i d e ( D a v i s & K o h l , 1978; H e n r i k & G e r a l l , 1976; Foremann & Moss, 1978; Franck & Ward, 1981; Zemlan et a l . , 1973), c i n n a n s e r i n (Ward, Crowley, Zemlan & M a r g u l e s , 1975; Zemlan et a l . , 1973), and, i n low d oses, m e t e r g o l i n e (Fuxe, E v e r i t t , A g n a t i , Fredholm & J o n s s o n , 1976) were r e p o r t e d t o produce l o r d o s i s - f a c i l i t a t i n g e f f e c t s . Treatments t h a t i n c r e a s e s e r o t o n e r g i c a c t i v i t y were g e n e r a l l y r e p o r t e d t o i n h i b i t l o r d o s i s b e h a v i o u r . For example, the s e r o t o n i n r e l e a s i n g a g ents f e n f l u r a m i n e ( E v e r i t t et a l . , 1975) 4 and p-chloroamphetamine (Zemlna, Trulson, Howell & Hoebel, 1977) were reported to i n h i b i t lordosis in females primed with estrogen and progesterone. The administration of serotonin agonists, drugs that mimic the effects of serotonin, were also reported to i n h i b i t l o r d o s i s . Moderately high doses of the serotonin agonists LSD (Eliasson, Michanek & Meyerson, 1972; Meyerson, Carrer & Eliasson, 1974; Eliasson & Meyerson, 1976; Sietnieks, 1980), n,n,dimethyltryptamine, 5-methoxydimethyltryptamine, and psylocybin (Eve r i t t and Fuxe, 1977) were reported to produce l o r d o s i s - i n h i b i t i n g e f f e c t s . Although there was a good deal of evidence in the l i t e r a t u r e to support Meyerson's theory of serotonergic i n h i b i t i o n of lordosis, there were also many inconsistencies (Mendelson & Gorzalka, 1985b). In some cases, serotonergic drugs were found to have no eff e c t on lordosis behaviour. For example, some researchers found the serotonin synthesis i n h i b i t o r s a propyldopacetamide (Meyerson & Lewander, 1970) and p-chlorophenylalanine (Ahlenius, Engel, Eriksson, Modigh & Sodersten, 1972; Wilson, Bonney Everard, Parrot & Wise, 1982) to be i n e f f e c t i v e in estrogen-primed females. In several cases, p-chlorophenylalanine was actually found to i n h i b i t lordosis behaviour ( Segal & Whalen, 1970; Gorzalka & Whalen, 1977). Moreover, in at least one study the serotonin re-uptake blockers Org6582, femoxitine and chloimipramine, drugs that would be expected to increase serotonergic a c t i v i t y , were found to f a c i l i t a t e lordosis behaviour (Hamburger-Bar, Rigter & Dekker, 1978) . Because of the inconsistencies in the l i t e r a t u r e , the 5 p r e c i s e n a t u r e of the r o l e p l a y e d by s e r o t o n i n i n the m o d u l a t i o n of l o r d o s i s b e h a v i o u r remained c o n t r o v e r s i a l . In 1985, Mendelson and G o r z a l k a suggested t h a t . t h e a p parent i n c o n s i s t e n c i e s i n the e f f e c t s of s e r o t o n e r g i c drugs on l o r d o s i s b e h a v i o u r might be due t o d i f f e r e n t i a l r o l e s of subtypes of s e r o t o n i n r e c e p t o r s i n the m o d u l a t i o n of female s e x u a l b e h a v i o u r . N e u r o t r a n s m i t t e r s such as s e r o t o n i n a c t as c h e m i c a l messengers i n the b r a i n . They are r e l e a s e d from one neuron onto the s u r f a c e of a second neuron where they produce t h e i r e f f e c t s by a c t i n g a t s p e c i a l s i t e s known as r e c e p t o r s . When the n e u r o t r a n s m i t t e r b i n d s t o i t s r e c e p t o r , i t i s the changes i n the shape and e l e c t r i c a l p r o p e r t i e s of the r e c e p t o r t h a t a c t u a l l y t r a n s l a t e t h e c h e m i c a l message i n t o changes i n n e u r a l a c t i v i t y . Many r e c e p t o r s , f o r example, a re l i n k e d t o s p e c i a l c h a n n e l s i n the n e u r a l membrane. When th e s e r e c e p t o r s a re a c t i v a t e d , t he c h a n n e l s open and a l l o w the passage of c e r t a i n i o n s t h r o u g h the membrane. T h i s movement of charged p a r t i c l e s a l t e r s the e l e c t r i c a l b a l a n c e a l o n g the n e u r a l membrane and, depending on the s p e c i e s of i o n , the p r o b a b i l i t y t h a t the neuron w i l l d i s c h a r g e i s e i t h e r i n c r e a s e d or d e c r e a s e d . In o t h e r c a s e s , r e c e p t o r s may be l i n k e d t o enzyme systems, s o - c a l l e d second messenger systems, i n the n e u r a l membrane. The a c t i v a t i o n of the s e r e c e p t o r s may r e s u l t i n more l o n g - t e r m changes i n the i n t e r n a l c h e m i s t r y of the neuron. I t i s c h a r a c t e r i s t i c of a r e c e p t o r t o d i s p l a y a h i g h degree of s e l e c t i v i t y f o r a s p e c i f i c n e u r o t r a n s m i t t e r . The r e c o g n i t i o n of the shape of the n e u r o t r a n s m i t t e r appears t o p l a y a c r i t i c a l r o l e i n t h i s s e l e c t i v i t y . The p r o c e s s by which a r e c e p t o r 6 recognizes and responds to i t s neurotransmitter has in fact been likened to the mechanism of a lock and key. When a molecule possesses the correct structure, i t can bind, that i s , mold i t s e l f into the contours of the receptor, and produce ac t i v a t i o n . Molecules of improper shape are simply excluded. In a c t u a l i t y the lock and key model i s too simple to re f l e c t the f u l l complexity of the interaction of a receptor and a neurotransmitter. For example, in a simple lock and key model, any molecule of proper shape might be expected to activate the receptor. Some drugs, c a l l e d receptor agonists, do in fact mimic the e f f e c t s of neurotransmitters by binding at pa r t i c u l a r receptors and producing a c t i v a t i o n . However, some drugs c a l l e d receptor antagonists bind to receptors and prevent a c t i v a t i o n . Other drugs c a l l e d p a r t i a l agonists (or, just as co r r e c t l y , p a r t i a l antagonists) bind to receptors and produce only p a r t i a l a c t i v a t i o n . Receptors in the brain are, for the most part, categorized according to their a b i l i t y to recognize s p e c i f i c transmitter molecules. However, using drugs as chemical probes, pharmacologists have found that differences may exist even within a population of receptors that responds to the same neurotransmitter. For example, i t has long been known that within the population of receptors that responds to the neurotransmitter acetylcholine, there is one subpopulation that responds to the drug nicotine, and another subpopulation that responds to the drug muscarine. These n i c o t i n i c and muscarinic receptors are referred to as subtypes of acetylcholine receptors. In the "lock and key" analogy, acetylcholine may be 7 thought of as a "master key". Whereas n i c o t i n e ' u n l o c k s ' one subtype of a c e t y l c h o l i n e r e c e p t o r , and muscarine ' u n l o c k s ' a n o ther subtype of r e c e p t o r , a c e t y l c h o l i n e i t s e l f i s a b l e t o 'unlock' b oth s u b t y p e s . E v i d e n c e d e r i v e d from a v a r i e t y of t e c h n i q u e s has suggested t h a t c e n t r a l s e r o t o n i n r e c e p t o r s do not e x i s t as a s i n g l e homogenous group, but r a t h e r c o n s i s t of s u b t y p e s . A t e c h n i q u e t h a t has been e x t r e m e l y u s e f u l i n i d e n t i f y i n g subtypes of s e r o t o n i n r e c e p t o r s has been i_n v i t r o l i g a n d b i n d i n g a n a l y s i s . The term _in v i t r o r e f e r s t o the f a c t t h a t the a n a l y s i s of b i n d i n g t a k e s p l a c e not i n the b r a i n s of l i v i n g a n i m a l s but i n the " t e s t tube" u s i n g homogenates or s l i c e s of b r a i n t i s s u e removed from a n i m a l s . The term l i g a n d r e f e r s t o any s u b s t a n c e , e i t h e r a drug or a n a t u r a l t r a n s m i t t e r , t h a t b i n d s t o a r e c e p t o r . The b a s i c p r i n c i p l e i n v o l v e d i n i_n v i t r o l i g a n d b i n d i n g a n a l y s i s i s s i m p l y t h a t a drug t h a t b i n d s t o a s p e c i f i c r e c e p t o r w i l l a l s o compete w i t h o t h e r drugs or even the n a t u r a l n e u r o t r a n s m i t t e r i t s e l f f o r b i n d i n g s i t e s on t h a t r e c e p t o r . I f a drug b i n d s r e a d i l y and w i t h a h i g h degree of t e n a c i t y t o a p a r t i c u l a r c l a s s of r e c e p t o r s , t h a t i s , i f i t has a h i g h b i n d i n g a f f i n i t y , then r e l a t i v e l y low c o n c e n t r a t i o n s of the drug w i l l be s u f f i c i e n t t o d i s p l a c e c o m p e t i t o r s from t h e s e r e c e p t o r s . On the o t h e r hand, i f a drug p o s s e s s e s a low b i n d i n g a f f i n i t y , then o n l y v e r y h i g h c o n c e n t r a t i o n s of the drug w i l l a l l o w the drug t o compete e f f e c t i v e l y f o r r e c e p t o r s i t e s . The most o b v i o u s use of t h i s c o m p e t i t i v e b i n d i n g t e c h n i q u e i s t o i d e n t i f y the r e c e p t o r systems w i t h which a drug i n t e r a c t s . For example, i f h i g h c o n c e n t r a t i o n s of a drug f a i l t o d i s p l a c e r a d i o a c t i v e l y l a b e l l e d 8 neurotransmitter from i t s receptor, then the drug may be considered inactive at that receptor. I f , within a reasonable range of concentrations, the drug displaces v i r t u a l l y a l l of the lab e l l e d transmitter from i t s receptor, then a c t i v i t y of the drug at that type of receptor can be strongly suspected. However, i f only a portion of la b e l l e d transmitter i s displaced, and far higher concentrations of the drug must be used to displace the remaining portion, then i t is possible that the drug d i f f e r e n t i a t e s subtypes of receptors for that transmitter. By analysing and comparing the binding c h a r a c t e r i s t i c s of serotonin, and the serotonergic drugs LSD and spiperone, Peroutka and Snyder (1979) were able to demonstrate the existence of two pharmacologically and anatomically d i s t i n c t populations of central serotonin receptors. One population of serotonin receptors displayed high a f f i n i t y binding of la b e l l e d serotonin and was designated as the 5-HT, subtype. (The common abbreviation for serotonin, 5-HT, i s derived from the chemical name of serotonin, 5-hydroxytryptamine.) The second population displayed high a f f i n i t y binding of la b e l l e d spiperone and was designated as the 5-HT2 subtype. LSD was actually found to bind to both receptor subtypes with approximately equal a f f i n i t y . The most recent evaluations of the central serotonin receptor have indicated that the 5-HT, class of receptors i t s e l f consists of subtypes. Two d i s t i n c t subtypes of the 5-HT, receptor have been determined on the basis of high and low a f f i n i t y components in the displacement by spiperone of la b e l l e d serotonin from 5-HT, receptors (Pedigo, Yamamura & Nelson, 1981). These subtypes have been designated as 5-HT,A and 5-HT,B, 9 respectively. Even more recently, the existence of a t h i r d subtype of the 5-HT, receptor has been determined on the basis of a high a f f i n i t y component in the displacement by mesulergine of la b e l l e d serotonin from s i t e s in choroid plexus tissue. The uniqueness of thi s receptor, designated as 5-HT,C, i s suggested by the finding that l a b e l l e d 5-HT is not displaced from these s i t e s by known ligands of either 5-HT,A, 5-HT,B, or 5-HT2 receptors (Pazos, Hoyer & Palacios, 1984). It i s important to note that brain tissue contains a wide variety of proteins with the potential to bind serotonin, and the binding of the transmitter to a part i c u l a r s i t e does not in i t s e l f prove that that s i t e i s a functional serotonin receptor. There i s , however, growing evidence that the subtypes of central serotonergic binding s i t e s as characterized by in v i t r o binding analyses do represent functional serotonin receptors. There i s evidence that 5-HT,A receptors act as somato-dendritic autoreceptors on serotonergic neurons (Sprouse & Aghajanian, 1986), that i s , as receptors on serotonergic c e l l bodies that mediate in h i b i t o r y feedback of serotonergic a c t i v i t y . Post-synaptic 5-HT,A receptors, that i s , 5-HT,A receptors on target neurons, appear to mediate stimulation of adenylate cyclase, a chemical second messenger system (Markstein, Hoyer & Engel, 1986). 5-HT,B receptors appear to act as prejunctional autoreceptors, (Engel, Gothert, Hoyer, Schlicker & Hillenbrand, 1986), that i s , as receptors on the terminals of serotonergic neurons that mediate inhi b i t o r y feedback of serotonergic a c t i v i t y . 5-HT,C receptors have been found to mediate serotonergic stimulation of phosphoinositide hydrolysis, another 10 second messenger mechanism, in the choroid plexus (Sanders-Bush & Conn, 1986). Evidence indicates that 5-HT2 receptors mediate the neural excitatory e f f e c t s of serotonin in brain tissue (Peroutka & Snyder, 1979). F i n a l l y , i t must be mentioned that the discovery of subtypes of central serotonin receptors complements the e a r l i e r characterization of the D and M subtypes of peripheral serotonin receptors (Gaddum & P i c a r e r l l i , 1957). The D receptor i s now thought to be similar i f not i d e n t i c a l to the 5-HT2 receptor (Bradley, Engel, Fenuik, Fozard, Humphrey, Middlemiss, Mylecharane, Richardson & Saxena, 1986). The M receptor appears d i s t i n c t from the 5-HT, and 5-HT2 subtypes, and i t has been suggested that i t be designated as the 5-HT3 receptor. With the discovery of the subtypes of central 5-HT receptors, the p o s s i b i l i t y arose that the d i f f e r e n t subtypes of receptors might mediate d i f f e r e n t effects of serotonin on female sexual behaviour. As was suggested by Mendelson and Gorzalka, much of the inconsistency in the reports concerning the role of serotonin in female of sexual behaviour may have been due to a lack of receptor-subtype s e l e c t i v i t y of - the drugs used to evaluate serotonergic a c t i v i t y . The use of drugs such as the c l a s s i c a l serotonin antagonists or agonists , for example, LSD, which bind in varying degrees to a l l of the 5-HT receptor subtypes, would not have allowed the precise evaluation of the effe c t s that serotonin might have produced in acting upon each receptor subtype alone. The 5-HT2 selective antagonists pirenperone and ketanserin were among the f i r s t of the receptor subtype selective drugs to 11 become a v a i l a b l e . U n l i k e the c l a s s i c a l s e r o t o n i n a n t a g o n i s t s , t h e s e new drugs were found t o be v i r t u a l l y i n a c t i v e a t 5-HT, r e c e p t o r s ( J a n s s e n , 1983). In 1985, Mendelson and G o r z a l k a r e p o r t e d t h a t p i r e n p e r o n e and k e t a n s e r i n i n h i b i t e d l o r d o s i s b e h a v i o u r i n s t e r o i d primed females (Mendelson & G o r z a l k a , 1985b). Moreover, q u i p a z i n e , a s e r o t o n i n a g o n i s t w i t h r e l a t i v e l y h i g h a f f i n i t y f o r 5-HT2 r e c e p t o r s , was found t o a t t e n u a t e the i n h i b i t o r y e f f e c t of p i r e n p e r o n e . These r e s u l t s l e d t o the p r o p o s a l of a d u a l r o l e h y p o t h e s i s of s e r o t o n e r g i c m o d u l a t i o n of female s e x u a l b e h a v i o u r . S p e c i f i c a l l y , i t was proposed t h a t the c l a s s i c a l i n h i b i t o r y e f f e c t s of s e r o t o n i n a r e mediated by 5-HT, r e c e p t o r s , whereas f a c i l i t a t o r y e f f e c t s of s e r o t o n i n a re mediated by 5-HT2 r e c e p t o r s . In the f o l l o w i n g s t u d i e s I w i l l attempt t o c o n f i r m the d u a l r o l e h y p o t h e s i s of Mendelson and G o r z a l k a by p e r f o r m i n g a more e x t e n s i v e e v a l u a t i o n of the e f f e c t s of drugs t h a t a c t a t 5-HT2 r e c e p t o r s . I w i l l a l s o attempt t o e x t e n d the h y p o t h e s i s . In the ex p e r i m e n t s t h a t formed the b a s i s f o r the o r i g i n a l d u a l r o l e h y p o t h e s i s , no attempt was made t o d i s t i n g u i s h between e f f e c t s t h a t might be produced by a c t i v a t i o n of the v a r i o u s subtypes of the 5-HT, r e c e p t o r . I t i s c o n c e i v a b l e t h a t the sub t y p e s of 5-HT, r e c e p t o r s s e r v e d i f f e r e n t i a l r o l e s i n the m o d u l a t i o n of l o r d o s i s b e h a v i o u r . There i s i n a d d i t i o n the p o s s i b i l i t y t h a t 5-HT3 r e c e p t o r s p l a y a r o l e i n the m o d u l a t i o n of l o r d o s i s . A l t h o u g h the 5-HT3 r e c e p t o r has g e n e r a l l y been c h r a a c t e r i z e d as a p e r i p h e r a l r e c e p t o r , r e c e n t e v i d e n c e i n d i c a t e s t h a t t h i s subtype of r e c e p t o r does e x i s t i n b r a i n t i s s u e ( K i l p a t r i c k , Jones and T y e r s , i n p r e s s , c i t e d i n T y e r s , 1988). T h e r e f o r e , i n a d d i t i o n 12 t o e v a l u a t i n g the e f f e c t s of drugs a c t i v e a t 5 - H T 2 r e c e p t o r s , I w i l l a l s o e v a l u a t e the e f f e c t s of drugs t h a t have been dete r m i n e d t o a c t s e l e c t i v e l y a t S - H T ^ A , 5 - H T T B , and 5 - H T 3 r e c e p t o r s . T o g e t h e r , these s t u d i e s w i l l p r o v i d e a more complete u n d e r s t a n d i n g of the r o l e of s e r o t o n i n and the v a r i o u s s e r o t o n i n r e c e p t o r s i n the m o d u l a t i o n of l o r d o s i s b e h a v i o u r i n the female r a t . G e n e r a l Methods Ani m a l s and Sur g e r y Female Sprague-Dawley and, i n some c a s e s , Long-Evans r a t s were bred i n our f a c i l i t i e s from s t o c k o r i g i n a l l y o b t a i n e d from C h a r l e s R i v e r Canada I n c . , M o n t r e a l . At a p p r o x i m a t e l y 70 days of age, t h e s e females were b i l a t e r a l l y o v a r i e c t o m i z e d t h r o u g h lumbar i n c i s i o n s . S u r g e r y was performed w h i l e the a n i m a l s were under e t h e r a n e s t h e s i a . Immediately f o l l o w i n g s u r g e r y , a l l females were housed i n groups of s i x i n s t a n d a r d l a b o r a t o r y w i r e mesh cag e s , i n a room m a i n t a i n e d under a r e v e r s e d 12 hr dark/12 hr l i g h t c y c l e a t 21±1°C . Animals were a l l o w e d f r e e a c c e s s t o food and wa t e r . 1 3 S t e r o i d Treatments In a l l c a s e s , e s t r a d i o l benzoate and p r o g e s t e r o n e ( S t e r a l o i d s ) have been d i s s o l v e d i n warm peanut o i l , and i n j e c t e d s u b c u t a n e o u s l y i n 0.1 ml of t h i s v e h i c l e . C o n t r o l of Drug C a r r y - o v e r E f f e c t s In the f o l l o w i n g s t u d i e s , e f f e c t s of drugs were o f t e n e v a l u a t e d i n a n i m a l s t h a t had had p r i o r drug t r e a t m e n t s . In some cas e s t h i s i n v o l v e d a n i m a l s b e i n g s u b j e c t e d t o a s e r i e s of t r e a t m e n t s w i t h v a r y i n g doses of the same dr u g . In o t h e r c a s e s t h i s i n v o l v e d a n i m a l s b e i n g used i n c o n s e c u t i v e e v a l u a t i o n s of d i f f e r e n t drug t r e a t m e n t s . In s i t u a t i o n s such as t h e s e , some conc e r n must be g i v e n t o the p o s s i b i l i t y t h a t responses t o a dr u g , or even b a s e l i n e b e h a v i o u r were i n f l u e n c e d by p r i o r t r e a t m e n t ( s ) . One way i n which the a d m i n i s t r a t i o n of a drug may a l t e r subsequent e v a l u a t i o n s i s f o r the drug t o remain or accumulate i n t i s s u e s of the e x p e r i m e n t a l a n i m a l s . In r e g a r d t o the p r e s e n t s e r i e s of s t u d i e s , t h e r e a r e a t l e a s t two reasons t o suggest t h a t t h i s was u n l i k e l y . F i r s t , drug t r e a t m e n t s were w e l l spaced i n t i m e , w i t h t r e a t m e n t s , o c c u r r i n g a t no l e s s than weekly i n t e r v a l s . S e c o n d l y , a l l of the drugs a d m i n i s t e r e d i n the s e s t u d i e s a r e r e l a t i v e l y h y d r o p h i l i c , t h a t i s , r e l a t i v e l y s o l u b l e i n w ater. Drugs (and t h e i r m e t a b o l i t e s ) t h a t a r e r e a s o n a b l y s o l u b l e i n water a re g e n e r a l l y e x c r e t e d q u i t e r e a d i l y i n the 14 urine and tend not to accumulate. A second way in which the administration of a drug may a l t e r subsequent drug t r i a l s i s by i n i t i a t i n g a p h y s i o l g i c a l process that continues beyond the time the drug has disappeared from the animal's body. Perhaps most notable in t h i s regard is the p o s s i b i l i t y of a drug producing an up- or down-regulation of receptors. When the receptors of a neurotransmitter system are under- or over-stimulated, the system w i l l sometimes adapt to these conditions by increasing or decreasing the number or s e n s i t i v i t y of the transmitter's receptors. These processes are refered to as up- and down regulation, respectively. Although I cannot with certainty state that up- or down-regulation of receptors did not occur, I do believe i t unlikely to have occurred. Generally, up- and down-regulation of receptors occurs with rather extreme treatment, that i s , with the administration of very large doses or with prolonged chronic administration of moderate doses of drugs. To the best of my knowledge, there is l i t t l e in the l i t e r a t u r e to suggest that at the doses and frequencies at which they were administered, the drugs evaluated in the present series of studies would have produced these ef f ects. A f i n a l mechanism by which i t may have been possible for drug treatments to have altered the effects of subsequent t r i a l s i s by t o x i c i t y . However, to the best of my knowledge, none of the drugs evaluated in the following experiments have been found to be toxic within the dose ranges that were administered. Although there was l i t t l e reason to suspect carry-over effects of drugs, several measures were taken to insure that 15 d a t a would not be unduly e f f e c t e d by p r i o r t r e a t m e n t s . For example, no a n i m a l s were used i n more than t h r e e c o n s e c u t i v e e x p e r i m e n t s . Moreover, b a s e l i n e l e v e l s of a n i m a l s were m o n i t o r e d a t the b e g i n n i n g of each experiment. I f e x p e c t e d b a s e l i n e l e v e l s of b e h a v i o u r were not obs e r v e d , the experiment was a b o r t e d and new a n i m a l s were p r e p a r e d . B e h a v i o u r a l T e s t i n g B e h a v i o u r a l t e s t i n g i n v o l v e d p r e s e n t a t i o n of an e x p e r i m e n t a l female t o a s t u d male r a t i n a c y l i n d r i c a l Pyrex t e s t i n g arena measuring 45 cm i n h e i g h t , and 29 cm i n d i a m e t e r . In some c a s e s , a narrow b i - l e v e l chamber w i t h d i m e n s i o n s of 51 X 60 X 15 cm was employed. T h i s chamber ( f u l l y d e s c r i b e d i n Mendelson & G o r z a l k a , 1987) a l l o w s the e x p e r i m e n t a l female an avenue of escape from the male, and thus a l l o w s the o b s e r v a t i o n of s e x u a l b e h a v i o u r t h a t more c l o s e l y resembles t h a t o b s e r v e d i n the n a t u r a l s t a t e . Stud males were g i v e n b r i e f a c c e s s t o f u l l y r e c e p t i v e females (each g i v e n 10 jug e s t r a d i o l benzoate 48 hr and 500 nq p r o g e s t e r o n e 4 hr b e f o r e p r e s e n t a t i o n ) i m m e d i a t e l y p r i o r t o s e s s i o n s w i t h e x p e r i m e n t a l f e m a l e s . S e s s i o n s were conducted 4-6 hr a f t e r commencement of the dark c y c l e . Each e x p e r i m e n t a l female was p l a c e d w i t h a s i n g l e male u n t i l 10 mounts w i t h p e l v i c t h r u s t i n g had o c c u r r e d . On the r a r e o c c a s i o n t h a t a male would not mount, the female was p l a c e d i n a d i f f e r e n t chamber c o n t a i n i n g a n other male. A female's response t o a mount was c o n s i d e r e d a l o r d o s i s response i f some degree of c o n c a v i t y of the back was o b s e r v e d . L o r d o s i s q u o t i e n t s were c a l c u l a t e d as the 16 p e r c e n t a g e of mounts w i t h p e l v i c t h r u s t i n g r e s u l t i n g i n a l o r d o s i s r e s p onse. EXPERIMENT 1 In a r e c e n t s e r i e s of e x p e r i m e n t s , the s e l e c t i v e 5-HT2 a n t a g o n i s t s p i r e n p e r o n e and k e t a n s e r i n was found t o i n h i b i t l o r d o s i s b e h a v i o u r i n female r a t s primed w i t h e s t r o g e n , or w i t h e s t r o g e n and p r o g e s t e r o n e (Mendelson & G o r z a l k a , 1985b). Q u i p a z i n e , an a g o n i s t w i t h r e l a t i v e l y h i g h a f f i n i t y f o r 5-HT2 r e c e p t o r s (Leysen & T o l l e n a e r e , 1982), was found t o a t t e n u a t e the i n h i b i t o r y e f f e c t s of p i r e n p e r o n e . No attempt was made i n t h i s s tudy t o a t t e n u a t e the l o r d o s i s - i n h i b i t i n g e f f e c t s of k e t a n s e r i n w i t h q u i p a z i n e . S e r o t o n i n has g e n e r a l l y been thought t o s e r v e an i n h i b i t o r y r o l e i n the m o d u l a t i o n of female s e x u a l b e h a v i o u r (Meyerson, 1966); however, the above r e s u l t s l e d us t o h y p o t h e s i z e a d u a l r o l e f o r 5-HT (Mendelson & G o r z a l k a , 1985b). S p e c i f i c a l l y , we proposed t h a t s e x u a l l y f a c i l i t a t o r y e f f e c t s of 5-HT a r e mediated by 5-HT2 r e c e p t o r s , whereas i n h i b i t o r y e f f e c t s of s e r o t o n i n a re mediated by 5-HT, r e c e p t o r a c t i v i t y . A l t h o u g h p i r e n p e r o n e and k e t a n s e r i n have been found t o i n h i b i t l o r d o s i s , these f i n d i n g s do not guarantee t h a t a l l 5-HT2 a n t a g o n i s t s would i n h i b i t t h i s b e h a v i o u r . Indeed, p i r e n p i r o n e and k e t a n s e r i n r e p r e s e n t a new c l a s s of s e r o t n i n a n t a g o n i s t s w i t h unique m o l e c u l a r s t r u c t u r e s and, perhaps, unique p h a r m a c o l o g i c a l p r o f i l e s . I t i s p o s s i b l e t h a t the l o r d o s i s -i n h i b i t i n g e f f e c t s of these drugs a r e unique and are not t y p i c a l 1 7 of 5-HT2 a n t a g o n i s t s . In o r d e r t o s t r e n g t h e n the c o n c l u s i o n t h a t b l o c k a d e of a c t i v i t y a t 5-HT2 r e c e p t o r s produces i n h i b i t i o n of l o r d o s i s , i t was n e c e s s a r y t o e v a l u a t e the e f f e c t s of a wider v a r i e t y of 5-HT2 a n t a g o n i s t s . In the f o l l o w i n g e x p e r i m e n t , I e v a l u a t e d the e f f e c t s upon l o r d o s i s b e h a v i o u r of k e t a n s e r i n and the 5-HT a n t a g o n i s t s pipamperone, m e t i t e p i n e , p i z o t e f i n , and c y p r o h e p t a d i n e . I t was hoped t h a t the e v a l u a t i o n of thes e drugs would p r o v i d e e v i d e n c e as t o whether the i n h i b i t i o n of l o r d o s i s i s an e f f e c t t y p i c a l of 5-HT2 a n t a g o n i s t s . To t e s t f o r 5-HT2 s p e c i f i c i t y of thes e e f f e c t s , the e f f e c t s of t h e s e drugs were a l s o e v a l u a t e d a f t e r c o a d m i n i s t r a t i o n w i t h g u i p a z i n e . Methods Drugs Pipamperone and k e t a n s e r i n t a r t r a t e ( k e t a n s e r i n ) were o b t a i n e d as g i f t s from Janssen P h a r m a c e u t i c a , as was p i z o t e f i n from Sandoz, c y p r o h e p t a d i n e from Mercke, Sharp & Dohme, m e t i t e p i n e from Hoffmann-La Roche, and g u i p a z i n e maleate ( g u i p a z i n e ) from M i l e s L a b o r a t o r i e s . A l l drugs were a d m i n i s t e r e d i n t r a p e r i t o n e a l l y i n a p p r o x i m a t e l y 0.1 ml of s a l i n e v e h i c l e , r e g a r d l e s s of dose. Drugs were a d m i n i s t e r e d b l i n d . P r o c e d u r e s In Experiment 1A, 5 groups of 12 females were used t o det e r m i n e the dose response t o each of the 5-HT2 a n t a g o n i s t s 18 pipamperone, p i z o t e f i n , c y p r o h e p t a d i n e , m e t i t e p i n e , and k e t a n s e r i n . W i t h i n each group, a n i m a l s were a d m i n i s t e r e d 10 Mg EB 48 h r , 500 P 4 h r , and e i t h e r 0, 0.1, 0.3, 1, or 3 mg/kg of the r e s p e c t i v e 5-HT a n t a g o n i s t 1 hr p r i o r t o b e h a v i o u r a l t e s t i n g . The i n t e r v a l between s u c c e s s i v e t e s t s was 1 week, w i t h the experiment b e i n g c o n d u c t e d over a 5 week p e r i o d . The o r d e r s of treatment f o r a n i m a l s w i t h i n each group were a r r a n g e d i n a si m p l e L a t i n square d e s i g n . In Experiment 1B, the e f f e c t s of those 5-HT2 a n t a g o n i s t s found t o a l t e r l o r d o s i s b e h a v i o u r were e v a l u a t e d i n a n i m a l s c o -a d m i n i s t e r e d the 5-HT2 a g o n i s t q u i p a z i n e . Groups of 12 new females each were used, and w i t h i n each group a n i m a l s r e c e i v e d 10 Mg EB 48 h r , 500 Mg P 4 h r , and e i t h e r s a l i n e , the mi n i m a l e f f e c t i v e dose of the r e s p e c t i v e 5-HT2 antagonist', 3 mg/kg q u i p a z i n e , or the 5-HT2 a n t a g o n i s t p l u s q u i p a z i n e 1 hr p r i o r t o b e h a v i o u r a l t e s t i n g . The i n t e r v a l between s u c c e s s i v e t e s t s was 1 week, and t r e a t m e n t s were c o u n t e r b a l a n c e d a c r o s s the f o u r weeks of t e s t i n g . R e s u l t s The r e s u l t s of Experiment 1a a r e d i s p l a y e d i n F i g . 1a i n the form of dose-response c u r v e s . An a n a l y s i s of v a r i a n c e (ANOVA) was used t o e v a l u a t e the e f f e c t s of dose, d r u g , and or d e r of t r e a t m e n t . The a n a l y s i s c o n f i r m e d a g e n e r a l i n h i b i t o r y e f f e c t of i n c r e a s e d dosage of the 5-HT2 a n t a g o n i s t s , F (4,100)=35.94, 2 < « 0 0 0 1 ' Moreover, the ANOVA i n d i c a t e d s i g n i f i c a n t d i f f e r e n c e s i n e f f e c t i v e n e s s among the dr u g s , 19 F i g . 1a Mean l o r d o s i s q u o t i e n t s ± S.E.M. of f i v e groups of females primed w i t h 10 nq e s t r a d i o l benzoate and 500 nq p r o g e s t e r o n e , f o l l o w i n g the a d m i n i s t r a t i o n of v a r y i n g doses of a 5-HT2 a n t a g o n i s t 1 hr p r i o r t o b e h a v i o u r a l t e s t i n g . For each group, LORDOSIS QUOTIENT % M yi v i o o ui a in o I i I 1 I 21 F(4,25)=6.18, • 0 0 2 • T n e Newman-Keuls method of m u l t i p l e comparison r e v e a l e d t h a t m e t i t e p i n e was s i g n i f i c a n t l y more e f f e c t i v e than e i t h e r pipamperone (2<.05), or p i z o t e f i n (p_<.05). A s i g n i f i c a n t i n t e r a c t i o n between dose and drug was a l s o r e v e a l e d , F (1 6 ,1 00) =4. 42 , p_<'0001« This a l l o w e d the e f f e c t s of s p e c i f i c doses of each drug t o be compared by use of the Newman-K e u l s method. I n h i b i t i o n of l o r d o s i s was demonstrated i n those a n i m a l s r e c e i v i n g k e t a n s e r i n , p i z o t e f i n , c y p r o h e p t a d i n e , and m e t i t e p i n e , w i t h the m i n i m a l e f f e c t i v e dose b e i n g 1 mg/kg f o r each drug (g<.05). In the case of m e t i t e p i n e , l o r d o s i s b e h a v i o u r a f t e r 3 mg/kg was s i g n i f i c a n t l y lower than a f t e r 1 mg/kg of the drug (p_<.05). Moreover, 3 mg/kg m e t i t e p i n e was s i g n i f i c a n t l y more e f f e c t i v e than 3 mg/kg of any of the f o u r o t h e r drugs (2<.05). Whereas 1 mg/kg p i z o t e f i n s i g n i f i c a n t l y i n h i b i t e d l o r d o s i s b e h a v i o u r , 3 mg/kg of the drug was i n e f f e c t i v e . No s i g n i f i c a n t i n h i b i t i o n of l o r d o s i s was o b s e r v e d i n those a n i m a l s t h a t r e c e i v e d pipamperone. F i n a l l y , the a n a l y s i s of v a r i a n c e r e v e a l e d t h a t t h e r e were no s i g n i f i c a n t o r d e r e f f e c t s , t h a t i s , a n i m a l s developed n e i t h e r t o l e r a n c e nor s e n s i t i v i t y t o the d r u g s . The r e s u l t s of Experiment 1b, which a r e d i s p l a y e d i n F i g . 1b, remained c o n s i s t e n t w i t h t h o s e of the f i r s t e x p e r i m e n t , a l t h o u g h the e f f e c t s were more pronounced. Because pipamperone was i n e f f e c t i v e i n the f i r s t e x p e r i m e n t , i t was not e v a l u a t e d i n the second e x p e r i m e n t . A s e p a r a t e ANOVA was used t o e v a l u a t e the e f f e c t s of each 5-HT2 a n t a g o n i s t i n c o m b i n a t i o n w i t h q u i p a z i n e . In t h e s e a n a l y s e s , the i n h i b i t o r y e f f e c t s of t h e s e drugs were 22 F i g . 1b Mean l o r d o s i s q u o t i e n t s of f o u r groups of females primed w i t h 10 Mg e s t r a d i o l benzoate and 500 Mg p r o g e s t e r o n e , f o l l o w i n g the a d m i n i s t r a t i o n of 1 mg/kg of a 5-HT2 a n t a g o n i s t , 3 mg/kg q u i p a z i n e , a 5-HT2 a n t a g o n i s t p l u s q u i p a z i n e , or the s a l i n e v e h i c l e 1 hr p r i o r t o b e h a v i o u r a l t e s t i n g . The 5-HT2 a n t a g o n i s t s i n c l u d e d k e t a n s e r i n (KETA), p i z o t e f i n (PIZO), c y p r o h e p t a d i n e (CYPRO), and m e t i t e p i n e (METI). For each group, n=12. 24 a g a i n c o n f i r m e d , w i t h s i g n i f i c a n t main e f f e c t s b e i n g demonstrated f o r p i z o t e f i n , F ( 1 ,1 1 ) =49.75 ,p_<. 0001 ; c y p r o h e p t a d i n e , F(1 , 1 1 ) = 51 . 06 , p_<.000l; m e t i t e p i n e , F(1,11)=43.84,p<.0001; and k e t a n s e r i n , F (1 ,1 1 )=43.17,p<.0001 . The Newman-Keuls method was s u b s e q u e n t l y used t o e v a l u a t e the i n t e r a c t i v e e f f e c t s of each drug w i t h q u i p a z i n e . A l t h o u g h q u i p a z i n e a l o n e d i d not a f f e c t l o r d o s i s b e h a v i o u r i n any of the f o u r drug groups, i t s i g n i f i c a n t l y b l o c k e d the i n h i b i t o r y e f f e c t s of p i z o t e f i n (p_<.05), c y p r o h e p t a d i n e (p_<.05), and k e t a n s e r i n (p_<.05). Q u i p a z i n e d i d not a t t e n u a t e the i n h i b i t o r y e f f e c t of m e t i t e p i n e . P i s c u s s i o n In Experiment 1, m e t i t e p i n e and, t o a l e s s e r degree, p i z o t e f i n , c y p r o h e p t a d i n e , and k e t a n s e r i n were found t o i n h i b i t l o r d o s i s b e h a v i o u r i n female r a t s primed w i t h e s t r o g e n and p r o g e s t e r o n e . Pipamperone a l s o appeared t o i n h i b i t l o r d o s i s , however the e f f e c t of the drug was not s i g n i f i c a n t w i t h i n the range of doses e v a l u a t e d . One e x p l a n a t i o n f o r the apparent d i f f e r e n c e s i n potency i n the p r e s e n t group of 5-HT2 a n t a g o n i s t s may be d i f f e r e n c e s i n the b i o a v a i l a b i l i t y of the s e d r u g s . For example, i n an _in v i t r o p r e p a r a t i o n , pipamperone and c y p r o h e p t a d i n e were found t o be e q u a l l y e f f e c t i v e i n d i s p l a c i n g 3 H - s p i p e r o n e from c o r t i c a l 5-HT2 r e c e p t o r s (Leysen, 1981). However, when a d m i n i s t e r e d i n t r a p e r i t o n e a l l y t o l i v e r a t s , 1.5 jumol/kg of pipamperone was needed t o b l o c k 50% of the b i n d i n g of 3 H - s p i p e r o n e t o c o r t i c a l 5-HT2 r e c e p t o r s , whereas o n l y 0.06 25 Mmol/kg of c y p r o h e p t a d i n e was r e q u i r e d (Ortman, B i s c h o f f , Radeke, Buech & D e l i n i s t u l a , 1982). The p r e s e n t 5-HT2 a n t a g o n i s t s a l s o d i f f e r i n t h e i r a f f i n i t y f o r 5-HT, r e c e p t o r s , however i t i s u n l i k e l y t h a t t h i s c o n t r i b u t e d t o the apparent d i f f e r e n c e s i n potency. For example, c y p r o h e p t a d i n e has a s i g n i f i c a n t degree of 5-HT, a c t i v i t y (Leysen & T o l l e n a e r e , 1982) and k e t a n s e r i n i s v i r t u a l l y i n a c t i v e a t 5-HT, r e c e p t o r s (Leysen & T o l l e n a e r e , 1982); however, th e s e drugs were e q u a l l y e f f e c t i v e i n i n h i b i t i n g l o r d o s i s b e h a v i o u r . The s u g g e s t i o n t h a t a c t i v i t y a t 5-HT, r e c e p t o r s was not a s i g n i f i c a n t f a c t o r i n d e t e r m i n i n g the e f f e c t s of the p r e s e n t group of a n t a g o n i s t s i s c o n s i s t e n t w i t h the e a r l i e r r e p o r t t h a t the l o r d o s i s response i s b l o c k e d by the a d m i n i s t r a t i o n of the 5-HT2 a n t a g o n i s t p i r e n p e r o n e (Mendelson & G o r z a l k a , 1985b). L i k e k e t a n s e r i n , p i r e n p e r o n e i s i n a c t i v e a t 5-HT, r e c e p t o r s (Leysen & T o l l e n a e r e , 1982). A l t h o u g h c y p r o h e p t a d i n e , m e t i t e p i n e , and k e t a n s e r i n i n h i b i t e d l o r d o s i s a t the 1 mg/kg and 3 mg/kg dose, p i z o t e f i n i n h i b i t e d l o r d o s i s a t o n l y the 1 mg/kg dose. I t was i n e f f e c t i v e a t the h i g h e r dose. T h i s dose-dependent e f f e c t of p i z o t e f i n may r e f l e c t the r e p o r t e d p a r t i a l a g o n i s t a c t i v i t y of the drug ( C o l p a e r t & J a n s s e n , 1983). Thus i t may be t h a t a t the h i g h e r dose, the 5-HT a g o n i s t component of p i z o t e f i n r e s t o r e d 5-HT2 a c t i v i t y t o a l e v e l t h a t was s u f f i c i e n t f o r l o r d o s i s b e h a v i o u r . However, t h i s s p e c u l a t i v e argument i s c o u n t e r e d by e v i d e n c e t h a t c y p r o h e p t a d i n e and m e t i t e p i n e may a l s o have p a r t i a l a g o n i s t a c t i v i t y ( C o l p a e r t & J a n s s e n , 1983). In the p r e s e n t s t u d y , q u i p a z i n e was found t o r e v e r s e the i n h i b i t o r y e f f e c t s of p i z o t e f i n , c y p r o h e p t a d i n e , and k e t a n s e r i n . 26 These f i n d i n g s a re c o n s i s t e n t w i t h the p r e v i o u s f i n d i n g of the a t t e n u a t i o n of the i n h i b i t o r y e f f e c t of p i r e n p e r o n e by q u i p a z i n e (Mendelson & G o r z a l k a , 1985b), as w e l l as w i t h a r e c e n t r e p o r t of f a c i l i t a t o r y e f f e c t s of the drug (Hunter, Hole & W i l s o n , 1985). I suggest t h a t i n the p r e s e n t study q u i p a z i n e r e v e r s e d the i n h i b i t o r y e f f e c t s of p i z o t e f i n , c y p r o h e p t a d i n e and k e t a n s e r i n upon l o r d o s i s by a c t i n g as a 5-HT2 a g o n i s t . T h i s c o n c l u s i o n i s c o n s i s t e n t w i t h _in v i t r o b i n d i n g d a t a (Leysen & T o l l e n a e r e , 1982), as w e l l as da t a from b e h a v i o u r a l s t u d i e s . For example, q u i p a z i n e has been r e p o r t e d t o g e n e r a l i z e as a s t i m u l u s t o the 5-HT2 a g o n i s t DOM (Glennon, Young & Rosen c r a n s , 1983) and t o produce the h e a d - t w i t c h response (Green, 0'Shaughnessy, Hammond, S c h a c h t e r & Grahame-Smith, 1983), a b e h a v i o u r b e l i e v e d t o be mediated by 5-HT2 r e c e p t o r a c t i v i t y ( P e r o u t k a , L e b o v i t z & Snyder, 1981). Q u i p a z i n e d i d not r e v e r s e the i n h i b i t o r y e f f e c t of m e t i t e p i n e . A l t h o u g h in v i t r o b i n d i n g d a t a suggest t h a t p i z o t e f i n , c y p r o h e p t a d i n e , k e t a n s e r i n , and m e t i t e p i n e have s i m i l a r a f f i n i t i e s f o r 5-HT2 r e c e p t o r s (Leysen & T o l l e n a e r e , 1982) , i t i s p o s s i b l e t h a t m e t i t e p i n e may be more p o t e n t i n  v i v o . Indeed, i n the absence of q u i p a z i n e , m e t i t e p i n e was found t o i n h i b i t l o r d o s i s more e f f e c t i v e l y than the o t h e r a n t a g o n i s t s ( F i g . 1 ). Thus a l a r g e r dose of q u i p a z i n e may have been r e q u i r e d t o a t t e n u a t e the e f f e c t of m e t i t e p i n e . However, the p o s s i b i l i t y remains t h a t the i n h i b i t o r y e f f e c t of m e t i t e p i n e was a t l e a s t p a r t i a l l y mediated by a n o n s e r o t o n e r g i c mechanism. The p r e s e n t r e s u l t s suggest t h a t the obser v e d i n h i b i t i o n of l o r d o s i s was due t o the b l o c k a d e of 5-HT2 r e c e p t o r s . However, i_n v i t r o b i n d i n g 27 s t u d i e s have demonstrated t h a t the 5-HT2 a n t a g o n i s t s e v a l u a t e d i n the p r e s e n t study a r e a l s o a c t i v e a t a , - a d r e n e r g i c r e c e p t o r s (Leysen, Awouters, K e n n i s , Laudron, Vandenberk & J a n s s e n , 1981). The r o l e of a - a d r e n e r g i c a c t i v i t y i n female s e x u a l b e h a v i o u r remains c o n t r o v e r s i a l , and thus i t i s p o s s i b l e t h a t the bl o c k a d e of a , - a d r e n e r g i c r e c e p t o r s was r e s p o n s i b l e f o r the i n h i b i t i o n of l o r d o s i s . However, i n view of the r e v e r s a l of the i n h i b i t o r y e f f e c t s of p i z o t e f i n , c y p r o h e p t a d i n e , and k e t a n s e r i n by q u i p a z i n e , i t appears u n l i k e l y t h a t the i n h i b i t o r y e f f e c t s of these drugs c o u l d have been mediated e n t i r e l y by an a d r e n e r g i c mechanism. Indeed, e v i d e n c e s u g g e s t s t h a t q u i p a z i n e i s i n a c t i v e a t a d r e n e r g i c r e c e p t o r s ( R o d r i g u e z & Pardo, 1971; W i n t e r , 1979). The p r e s e n t d a t a s t r o n g l y suggest t h a t 5-HT2 a n t a g o n i s t s i n h i b i t l o r d o s i s b e h a v i o u r . N o n e t h e l e s s , i t may be t h a t the bl o c k a d e of 5-HT2 r e c e p t o r a c t i v i t y has a d e b i l i t a t i n g e f f e c t upon b e h a v i o u r i n g e n e r a l , but not a s p e c i f i c i n h i b i t o r y e f f e c t upon l o r d o s i s b e h a v i o u r . However, t h i s appears u n l i k e l y , as the 5-HT2 a n t a g o n i s t p i r e n p e r o n e has been r e p o r t e d not t o a f f e c t e i t h e r open f i e l d b e h a v i o u r i n male r a t s (Mendelson & G o r z a l k a , 1985a) or wheel r u n n i n g a c t i v i t y i n s t e r o i d - p r i m e d female r a t s (Mendelson & G o r z a l k a , 1985b), a l t h o u g h the drug was a d m i n i s t e r e d t o those a n i m a l s i n doses t h a t have been found t o p r o f o u n d l y i n h i b i t the l o r d o s i s response (Mendelson & G o r z a l k a , 1985b). S e r o t o n e r g i c a c t i v i t y has g e n e r a l l y been c o n s i d e r e d t o i n h i b i t l o r d o s i s b e h a v i o u r i n the female r a t (Meyerson, 1966). However a v a r i e t y of 5-HT2 a n t a g o n i s t s have now been r e p o r t e d t o i n h i b i t l o r d o s i s b e h a v i o u r under some c o n d i t i o n s . These drugs 28 i n c l u d e p i z o t e f i n , c y p r o h e p t a d i n e , m e t i t e p i n e , and k e t a n s e r i n , as w e l l as c h l o r p r o m a z i n e (Meyerson, 1966), m e t e r g o l i n e (Fuxe, E v e r i t t , A g n a t i , Fredholm & J o n s s o n , 1976), m e t h y s e r g i d e (Clemens, 1978; Meyerson & E l i a s s o n , 1972), c i n a n s e r i n , m i a n s e r i n (Hunter, Hole & W i l s o n , 1985), p i r e n p e r o n e , and s p i p e r o n e (Mendelson & G o r z a l k a , 1985b). These d a t a a re c o n s i s t e n t w i t h our h y p o t h e s i s of a f a c i l i t a t o r y r o l e f o r 5-HT i n female s e x u a l b e h a v i o u r . Moreover, these f i n d i n g s i n d i c a t e t h a t the f a c i l i t a t o r y r o l e of 5-HT i s mediated by 5-HT2 r e c e p t o r s . EXPERIMENT 2 The 5-HT2 r e c e p t o r s e l e c t i v e a n t a g o n i s t s p i r e n p e r o n e and k e t a n s e r i n (Mendelson & G o r z a l k a , 1985b) and a v a r i e t y of the p o t e n t , though l e s s s e l e c t i v e c l a s s i c a l 5-HT a n t a g o n i s t s (Experiment 1) have been found t o i n h i b i t l o r d o s i s b e h a v i o u r i n the female r a t . These r e s u l t s a r e c o n s i s t e n t w i t h the h y p o t h e s i s t h a t a c t i v i t y at 5-HT2 r e c e p t o r s f a c i l i t a t e s l o r d o s i s b e h a v i o u r . However, whereas a l l these drugs b i n d w i t h h i g h a f f i n i t y t o 5-HT 2 r e c e p t o r s , they a l s o b i n d , i n v a r y i n g d e g r e e s , t o a, a d r e n e r g i c s i t e s ( J a n s s e n , 1983). T h e r e f o r e , the p o s s i b i l i t y remains t h a t the i n h i b i t i o n of l o r d o s i s t h a t has been observed f o l l o w i n g the a d m i n i s t r a t i o n of 5-HT2 a n t a g o n i s t s , has a t l e a s t p a r t i a l l y been due t o the bl o c k a d e of a, a d r e n e r g i c r e c e p t o r s . The e r g o l i n e d e r i v a t i v e LY53857 has r e c e n t l y been r e p o r t e d t o be a h i g h l y s e l e c t i v e a n t a g o n i s t of a c t i v i t y a t 5-HT2 29 r e c e p t o r s (Cohen, F u l l e r & K u r z , 1983). However, u n l i k e the m a j o r i t y of 5-HT2 a n t a g o n i s t s , LY53857 appears t o be r e l a t i v e l y i n a c t i v e a t a, a d r e n e r g i c s i t e s . I f LY53857 i s found t o i n h i b i t the l o r d o s i s r e sponse, then i t c o u l d be more c o n f i d e n t l y c o n c l u d e d t h a t the blo c k a d e of a c t i v i t y a t 5-HT2 r e c e p t o r s i s s u f f i c i e n t t o i n h i b i t l o r d o s i s b e h a v i o u r . In t he f o l l o w i n g study the e f f e c t s of v a r y i n g doses of LY53857 on l o r d o s i s b e h a v i o u r were e v a l u a t e d . Moreover, to s t r e n g t h e n the p o s s i b i l i t y t h a t e f f e c t s of LY53857 are due t o i t s a c t i o n as a s e l e c t i v e 5-HT2 a n t a g o n i s t , e f f e c t i v e doses of LY53857 w i l l c o a d m i n i s t e r e d w i t h a s u i t a b l e dose of the 5-HT2 a g o n i s t q u i p a z i n e . I f the e f f e c t s of LY53857 have ind e e d been mediated by 5-HT2 r e c e p t o r s , then the e f f e c t s of the drug s h o u l d be a t l e a s t p a r t i a l l y r e v e r s e d by q u i p a z i n e . F i n a l l y , i n s e v e r a l s t u d i e s i t has been found t h a t the e f f e c t s of s e r o t o n e r g i c drugs may d i f f e r somewhat i n the presence or absence of p r o g e s t e r o n e In o r d e r t o determine whether the e f f e c t s of a 5-HT2 a n t a g o n i s t might be a l t e r e d by p r o g e s t e r o n e , the e f f e c t s of LY53857 were e v a l u a t e d i n females primed w i t h e s t r o g e n and w i t h e s t r o g e n and p r o g e s t e r o n e . Methods Drugs LY 53857 and q u i p a z i n e maleate ( q u i p a z i n e ) were o b t a i n e d as g i f t s from L i l l y P h a r m a c e u t i c a l s and from M i l e s L a b o r a t o r i e s , r e s p e c t i v e l y . A l l drugs were a d m i n i s t e r e d i n t r a p e r i t o n e a l l y i n 30 a p p r o x i m a t e l y 0.3 ml of s a l i n e v e h i c l e , r e g a r d l e s s of dose. Drugs were a d m i n i s t e r e d b l i n d . P r o c e d u r e s In Experiment 2a, the dose response t o LY53857 was de t e r m i n e d i n e s t r o g e n - p r i m e d , o v a r i e c t o m i z e d f e m a l e s . Females were p l a c e d randomly i n t o 5 groups of 11 a n i m a l s . A l l females r e c e i v e d 10 jug EB 48 h r , and each group r e c e i v e d e i t h e r 0, 0.1, 0.3, 1, or 3 mg/kg of LY35758 1 hr p r i o r t o b e h a v i o u r a l t e s t i n g . In Experiment 2b, t h i s p r o c e d u r e was r e p e a t e d ; however, the experiment was performed w i t h new a n i m a l s t h a t r e c e i v e d 10 Mg EB 48 hr and 500 Mg p r o g e s t e r o n e 4 t o 6 hr p r i o r t o t e s t i n g . In Experiment 2c, l o r d o s i s b e h a v i o u r was e v a l u a t e d i n a n i m a l s t h a t r e c e i v e d LY53857 c o n c u r r e n t l y w i t h q u i p a z i n e . Females were d i v i d e d randomly i n t o 4 groups of 16 a n i m a l s . W i t h i n each group, a n i m a l s r e c e i v e d 10 Mg EB 48 h r , 500 Mg P 4 t o 6 h r , and e i t h e r s a l i n e , 1 mg/kg LY53857, 3 mg/kg q u i p a z i n e , or LY53857 p l u s q u i p a z i n e 1 hr p r i o r t o b e h a v i o u r a l t e s t i n g . R e s u l t s In F i g . 2a i t can be seen t h a t LY53857 produced a dose-dependent i n h i b i t i o n of l o r d o s i s b e h a v i o u r i n females primed w i t h e s t r o g e n . An a n a l y s i s of v a r i a n c e c o n f i r m e d a s i g n i f i c a n t i n h i b i t o r y e f f e c t of LY53857 i n e s t r o g e n - p r i m e d f e m a l e s , F ( 4 , 50) = 1 0.11 , p_<.000l. By use of the Newman-Keuls method, i t was d e t e r m i n e d t h a t the 0.1 mg/kg dose of LY53857 was 31 F i g . 2a. Mean l o r d o s i s q u o t i e n t s ± S.E.M. of females primed w i t h 10 jug e s t r a d i o l benzoate f o l l o w i n g the a d m i n i s t r a t i o n of v a r y i n g doses of LY 53857 1 hr p r i o r t o b e h a v i o u r a l t e s t i n g . 32 % 1N3I10H0 SISOQeJOl NV3H 33 F i g . 2b. Mean l o r d o s i s q u o t i e n t s ± S.E.M. of females primed w i t h 10 uq e s t r a d i o l benzoate and 500 jug p r o g e s t e r o n e f o l l o w i n g the a d m i n i s t r a t i o n of v a r y i n g doses of LY 53857 1 hr p r i o r t o b e h a v i o u r a l t e s t i n g . 34 % INGIlOnO SISOQclOl 35 F i g . 2c. Mean l o r d o s i s q u o t i e n t s ± S.E.M. of females primed w i t h 10 vq e s t r a d i o l benzoate f o l l o w i n g the a d m i n i s t r a t i o n of e i t h e r 1 mg/kg LY 53857, 3 mg/kg q u i p a z i n e , LY 53857 and q u i p a z i n e , or the s a l i n e v e h i c l e 1 hr p r i o r t o b e h a v i o u r a l t e s t i n g . LORDOSIS QUOTIENT % o o o o o o o o o _ l I I I I I I I I ID '•< cn c CD £ z 13 co m o ^4 37 i n e f f e c t i v e , whereas the 0.3, 1, and 3 mg/kg doses of LY53857 s i g n i f i c a n t l y i n h i b i t e d l o r d o s i s b e h a v i o u r (p<.05). In F i g . 2b, i t can be seen t h a t LY53857 produced a s i m i l a r i n h i b i t i o n of l o r d o s i s i n females primed w i t h both e s t r o g e n and p r o g e s t e r o n e . The s i g n i f i c a n t i n h i b i t o r y e f f e c t of LY53857 was c o n f i r m e d by a n a l y s i s of v a r i a n c e , F(4,50)=5.32, 2<.0013. By use of the Newman-Keuls method i t was de t e r m i n e d t h a t the 0.1 mg/kg dose of LY53857 was i n e f f e c t i v e . However, the 0.3, 1, and 3 mg/kg doses of the drug produced s i g n i f i c a n t i n h i b i t i o n of l o r d o s i s b e h a v i o u r . The d a t a d i s p l a y e d i n F i g . 2c a g a i n show an i n h i b i t o r y e f f e c t of a 1 mg/kg dose of LY53857 i n females primed w i t h e s t r o g e n and p r o g e s t e r o n e . However, i t i s apparent t h a t the i n h i b i t o r y e f f e c t of LY53857 was r e v e r s e d by c o a d m i n i s t r a t i o n of the 5-HT2 a g o n i s t q u i p a z i n e . A 2 X 2 a n a l y s i s of v a r i a n c e c o n f i r m e d a s i g n i f i c a n t i n h i b i t o r y e f f e c t of LY53857, F(1,60)=10.126, 2<.0024. A l t h o u g h t h e r e was no s i g n i f i c a n t main e f f e c t of q u i p a z i n e , a s i g n i f i c a n t i n t e r a c t i o n between LY53857 and q u i p a z i n e was r e v e a l e d , F(1 , 60) = 25. 3 ,p_<. 0001 . By use of the Newman-Keuls method i t was de t e r m i n e d t h a t the i n h i b i t o r y e f f e c t of LY53857 was s i g n i f i c a n t l y a t t e n u a t e d by q u i p a z i n e (p_<.05). D i s c u s s i o n In Experiment 1, a v a r i e t y of 5-HT2 a n t a g o n i s t s were found t o i n h i b i t l o r d o s i s b e h a v i o u r . However, because a l l of these drugs b i n d w i t h r e l a t i v e l y h i g h a f f i n i t y t o a - a d r e n e r g i c r e c e p t o r s , t h e r e was some doubt as t o what r o l e the b l o c k a d e of 38 a - a d r e n e r g i c r e c e p t o r s might have p l a y e d i n p r o d u c i n g t h e s e e f f e c t s . In the p r e s e n t e x p e r i m e n t , the s e l e c t i v e 5-HT2 a n t a g o n i s t LY53857 was a l s o found t o i n h i b i t l o r d o s i s . Moreover, as was observ e d w i t h p i z o t e f i n , k e t a n s e r i n and c y p r o h e p t a d i n e i n Experiment 1, the l o r d o s i s - i n h i b i t i n g e f f e c t of LY53857 was r e v e r s e d by c o a d m i n i s t r a t i o n of the 5-HT2 a g o n i s t q u i p a z i n e . Because LY53857 has a v e r y h i g h a f f i n i t y f o r 5-HT2 r e c e p t o r s , but a v e r y low a f f i n i t y f o r a - a d r e n e r g i c r e c e p t o r s , these d a t a suggest t h a t the bl o c k a d e of a c t i v i t y a t 5-HT2 r e c e p t o r s i s s u f f i c i e n t t o i n h i b i t l o r d o s i s . EXPERIMENT 3 I n t r o d u c t i o n In E x p e r i m e n t s 1 and 2, the 5-HT2 a n t a g o n i s t s p i z o t e f i n , c y p r o h e p t a d i n e , m e t i t e p i n e , k e t a n s e r i n and LY 53857 were found t o i n h i b i t l o r d o s i s b e h a v i o u r . Moreover, w i t h the e x c e p t i o n of m e t i t e p i n e , the e f f e c t s of thes e drugs were r e v e r s e d by c o a d m i n i s t r a t i o n of the n o n - s e l e c t i v e 5-HT2 a g o n i s t q u i p a z i n e . These e f f e c t s a r e s i m i l a r t o those o b s e r v e d by Mendelson and G o r z a l k a i n 1985 and a r e c o n s i s t e n t w i t h the h y p o t h e s i s t h a t a c t i v i t y a t 5-HT2 r e c e p t o r s f a c i l i t a t e s the e x p r e s s i o n of l o r d o s i s b e h a v i o u r . However, the r e s u l t s of t h e s e e x p e r i m e n t s appear somewhat i n c o n s i s t e n t w i t h a number of r e p o r t s on the e f f e c t s of the n o n - s e l e c t i v e 5-HT a n t a g o n i s t m e t h y s e r g i d e on l o r d o s i s . A l t h o u g h t h e r e have been a t l e a s t t h r e e r e p o r t s of i n h i b i t i o n of l o r d o s i s b e h a v i o u r f o l l o w i n g the a d m i n i s t r a t i o n of meth y s e r g i d e (Meyerson and E l i a s s o n , 1977; Clemens, 1978; 39 S i e t n i e k s , 1985), i n most c a s e s the drug has been found t o f a c i l i t a t e t h i s b e h a v i o u r . M e t h y s e r g i d e has been r e p o r t e d t o f a c i l i t a t e l o r d o s i s i n both o v a r i e c t o m i z e d (Ward, Crowley, Zemlan and M a r g u l e s , 1975; H e n r i k and G e r a l l , 1976; D a v i s and K o h l , 1978; Foreman and Moss, 1978; R o d r i g u e z - S i e r r a and D a v i s , 1979; Franck and Ward, 1981; Hunter, Hole and W i l s o n , 1985) and o v a r i e c t o m i z e d - a d r e n a l e c t o m i z e d females (Zemlan, Ward, Crowley and M a r g u l e s , 1973) , and a f t e r e i t h e r c e n t r a l (Zemlan et a l . 1973; Ward e t a l . 1975; Foreman and Moss, 1978; Franck and Ward, 1981) or p e r i p h e r a l a d m i n i s t r a t i o n ( Zemlan e t a l . 1973; H e n r i k and G e r a l l , 1976; D a v i s and K o h l , 1978; R o d r i g u e z - S i e r r a and D a v i s , 1979; Hunter e t a l . , 1985). Because m e t h y s e r g i d e b i n d s a t the 5-HT, r e c e p t o r ( P e r o u t k a , L e b o v i t z and Snyder, 1981), the l o r d o s i s - f a c i l i t a t i n g e f f e c t of met h y s e r g i d e c o u l d be due t o the bl o c k a d e of c e r t a i n 5-HT, r e c e p t o r s . Indeed, such a mechanism would be c o n s i s t e n t w i t h the d u a l r o l e h y p o t h e s i s of Mendelson and G o r z a l k a . However, m e t h y s e r g i d e i s known t o be a v e r y p o t e n t a n t a g o n i s t a t 5-HT2 r e c e p t o r s ( J a n s s e n , 1983). I n view of the e v i d e n c e t h a t b l o c k a d e of s e r o t o n e r g i c a c t i v i t y a t 5-HT2 r e c e p t o r s i n h i b i t s t he e x p r e s s i o n of l o r d o s i s b e h a v i o u r , r e p o r t s of l o r d o s i s -f a c i l i t a t i n g e f f e c t s of me t h y s e r g i d e a r e s u r p r i s i n g . In o r d e r t o r e s o l v e t h i s apparent i n c o n s i s t e n c y , i t was n e c e s s a r y t o deter m i n e the c o n d i t i o n s under which the i n h i b i t o r y and f a c i l i t a t o r y e f f e c t s of me t h y s e r g i d e o c c u r . I n h i b i t o r y e f f e c t s of me t h y s e r g i d e have been o b s e r v e d o n l y i n females t h a t had been t r e a t e d w i t h both e s t r o g e n and p r o g e s t e r o n e . Thus i t seemed p o s s i b l e t h a t the i n h i b i t o r y e f f e c t 40 of m e t h y s e r g i d e i s e n t i r e l y p r o g e s t e r o n e - d e p e n d e n t . However, an o t h e r p o s s i b i l i t y was t h a t the l e n g t h of time between the a d m i n i s t r a t i o n of the drug and the commencement of b e h a v i o u r a l t e s t i n g i s the c r i t i c a l f a c t o r i n d e t e r m i n i n g the e f f e c t of me t h y s e r g i d e on l o r d o s i s b e h a v i o u r . I n t e r e s t i n g l y , i t has been r e p o r t e d t h a t the maximal f a c i l i t a t o r y e f f e c t of p e r i p h e r a l l y a d m i n i s t e r e d methysergide o c c u r s 2 t o 6 hr a f t e r a d m i n i s t r a t i o n (Zemlan e t a l . 1973; D a v i s and K o h l , 1978). However, t h e r e i s e v i d e n c e t h a t i n the r a t , m e t h y s e r g i d e i s a c t i v e as a c e n t r a l s e r o t o n i n a n t a g o n i s t as r a p i d l y as 20 t o 30 min a f t e r i n t r a p e r i t o n e a l a d m i n i s t r a t i o n (Browne and Ho, 1975; N o r m a n s e l l and Panksepp, 1985). I f the f a c i l i t a t o r y e f f e c t of m e t h y s e r g i d e i s s i m p l y due t o a r e d u c t i o n of s e r o t o n e r g i c a c t i v i t y , then some degree of f a c i l i t a t i o n s h o u l d be e x p e c t e d w i t h i n 1 hr a f t e r the a d m i n i s t r a t i o n of m e t h y s e r g i d e . A l t h o u g h t h e r e have been f o u r r e p o r t s p u b l i s h e d on the e f f e c t s of m e t h y s e r g i d e 1 hr a f t e r p e r i p h e r a l a d m i n i s t r a t i o n , r e s u l t s have not been c o n s i s t e n t w i t h a s i m p l e f a c i l i t a t o r y e f f e c t of the dr u g . In two c a s e s an i n h i b i t i o n of l o r d o s i s was o b s e r v e d 1 hr a f t e r t h e a d m i n i s t r a t i o n of me t h y s e r g i d e ( S i e t n i e k s , 1985; Meyerson and E l i a s s o n , 1977); i n a t h i r d c a s e , m e t h y s e r g i d e was i n e f f e c t i v e a t 1 hr (Mendelson and G o r z a l k a , 1985b); whereas i n the f o u r t h i n s t a n c e , the e f f e c t s of m e t h y s e r g i d e a t 1 hr were e q u i v o c a l (Hunter e t a l . , 1 9 8 5 ) . In the l a t t e r e x p e r i m e n t , a modest f a c i l i t a t o r y e f f e c t of m e t h y s e r g i d e was obser v e d i n females e x h i b i t i n g low l e v e l s of r e c e p t i v i t y ; however l o r d o s i s a c t i v i t y was reduced i n females d i s p l a y i n g h i g h l e v e l s of r e c e p t i v i t y , though t h i s r e d u c t i o n d i d not re a c h s t a t i s t i c a l s i g n i f i c a n c e . 41 The r e s u l t s of s t u d i e s where the e f f e c t s of me t h y s e r g i d e have been observed 1 hr a f t e r p e r i p h e r a l a d m i n i s t r a t i o n suggest the p o s s i b i l i t y of a b i p h a s i c e f f e c t of the dr u g . I t may be t h a t p e r i p h e r a l l y a d m i n i s t e r e d m e t h y s e r g i d e i n i t i a l l y i n h i b i t s the l o r d o s i s r e f l e x , and t h a t t h i s i n h i b i t i o n may be f o l l o w e d w i t h i n s e v e r a l hours by a f a c i l i t a t i o n . In the c u r r e n t s e r i e s of e x p e r i m e n t s , I e v a l u a t e d the p o s s i b i l i t y of a time-dependent i n h i b i t o r y e f f e c t of me t h y s e r g i d e by o b s e r v i n g l o r d o s i s b e h a v i o u r a t vari.ous times a f t e r the a d m i n i s t r a t i o n of the dr u g . Moreover, t o t e s t f o r the p o s s i b i l i t y t h a t the i n h i b i t o r y e f f e c t s of me t h y s e r g i d e a re p r o g e s t e r o n e dependent, the drug was a d m i n i s t e r e d t o e s t r o g e n -primed females both i n t h e presence and absence of p r o g e s t e r o n e . Methods Drugs M e t h y s e r g i d e b i m a l e a t e (methysergide) was d i s s o l v e d i n warm s a l i n e and a d m i n i s t e r e d i n t r a p e r i t o n e a l l y a t a dose of 7 mg/kg i n a p p r o x i m a t e l y 0.3 ml of the v e h i c l e . M e t h y s e r g i d e was a d m i n i s t e r e d b l i n d . P r o c e d u r e s In Experiment 3a, the e f f e c t s of m e t h y s e r g i d e were e v a l u a t e d i n females primed w i t h w i t h both e s t r a d i o l (EB) and p r o g e s t e r o n e ( P ) . In t h i s e x p e r i m e n t , 10 nq EB was a d m i n i s t e r e d 42 48 h r , and 150 Mg P 3.5 hr p r i o r t o t e s t i n g . In our e x p e r i e n c e t h i s s t e r o i d regimen i n d u c e s m o d e r a t e l y h i g h l e v e l s of l o r d o s i s b e h a v i o u r , g e n e r a l l y a l l o w i n g the e v a l u a t i o n of e i t h e r i n h i b i t o r y or f a c i l i t a t o r y e f f e c t s of drug t r e a t m e n t s . The a n i m a l s were d i v i d e d i n t o two groups and t e s t e d f o r l o r d o s i s b e h a v i o u r . W i t h i n 10 min of the i n i t i a l t e s t , one group r e c e i v e d m e t h y s e r g i d e and the o t h e r group r e c e i v e d the s a l i n e v e h i c l e . B e h a v i o u r a l t e s t i n g was then r e p e a t e d a t 30 and 200 min. The second experiment d i f f e r e d from the f i r s t o n l y i n r e g a r d s t o s t e r o i d t r e a t m e n t . In Experiment 3b, females r e c e i v e d 10 Mg EB 96,72,48, and 24 hr p r i o r t o b e h a v i o u r a l t e s t i n g . T h i s hormone regimen was chosen because i t produced, i n the absence of p r o g e s t e r o n e , l o r d o s i s q u o t i e n t s s i m i l a r t o those produced by t r e a t m e n t w i t h EB and P i n the f i r s t e x p e r i m e n t . I f the r e s u l t s o b t a i n e d were s i m i l a r t o those of the f i r s t e x p e r i m e n t , one c o u l d c o n c l u d e t h a t the e f f e c t s of m e t h y s e r g i d e o b s e r v e d i n the f i r s t two e x p e r i m e n t s were not p r o g e s t e r o n e dependent. In the f i r s t two e x p e r i m e n t s a f a c i l i t a t i o n of l o r d o s i s was not o b s e r v e d a f t e r the a d m i n i s t r a t i o n of m e t h y s e r g i d e , r e s u l t s c o n t r a r y t o much of the r e l e v a n t l i t e r a t u r e . However, i n t h e s e e x p e r i m e n t s the f a c i l i t a t o r y e f f e c t of m e t h y s e r g i d e may have been masked by the m o d e r a t e l y h i g h l e v e l s of l o r d o s i s b e h a v i o u r t h a t were observed i n c o n t r o l a n i m a l s . I t was p o s s i b l e t h a t f a c i l i t a t o r y e f f e c t s of m e t h y s e r g i d e might have been o b s e r v e d had lower doses of EB been employed. Experiments 3c and 3d were s i m i l a r t o the f i r s t two e x p e r i m e n t s . However, i n Experiment 3c a n i m a l s r e c e i v e d 5 Mg EB and 150 Mg P 3.5 hr p r i o r t o l o r d o s i s t e s t i n g , and i n Experiment 3d a n i m a l s r e c e i v e d 5 Mg EB 96,72,48, 43 and 24 hr p r i o r t o t e s t i n g . A l t h o u g h f a c i l i t a t i o n was not o b s e r v e d i n the f i r s t two e x p e r i m e n t s , i n b o t h c a s e s l o r d o s i s q u o t i e n t s were r i s i n g i n d r u g - t r e a t e d a n i m a l s a t 200 min, and i t i s p o s s i b l e t h a t f a c i l i t a t i o n might have been observed had b e h a v i o u r a l t e s t i n g been c o n t i n u e d beyond 200 min. T h e r e f o r e , whereas i n the f i r s t two e x p e r i m e n t s b e h a v i o u r a l t e s t i n g was r e p e a t e d 30 and 200 min a f t e r drug t r e a t m e n t , i n E x p e r i m e n t s 3c and 3d t e s t i n g was r e p e a t e d 30, 200, and 300 min a f t e r t r e a t m e n t . In Experiment 3e, females r e c e i v e d a s i n g l e dose of 2 nq EB 48 hr p r i o r t o b e h a v i o u r a l t e s t i n g , as t h i s dose of e s t r o g e n was e x p e c t e d t o produce o n l y a m i n i m a l l e v e l of l o r d o s i s b e h a v i o u r i n c o n t r o l a n i m a l s . As i n the f i r s t f o u r e x p e r i m e n t s , a n i m a l s were t e s t e d f o r l o r d o s i s b e h a v i o u r , and w i t h i n 10 min of the i n i t i a l t e s t , one group r e c e i v e d m e t h y s e r g i d e and the o t h e r group r e c e i v e d the s a l i n e v e h i c l e . As i n E x p e r i m e n t s 3c and 3d, b e h a v i o u r a l t e s t i n g was r e p e a t e d 30, 200, and 300 min a f t e r t h e s e t r e a t m e n t s . In E x p e r i m e n t s 3a through 3e, m e t h y s e r g i d e and s a l i n e were a d m i n i s t e r e d b l i n d . R e s u l t s : Experiment 3a L o r d o s i s b e h a v i o u r and the t i m e - r e s p o n s e t o m e t h y s e r g i d e i n females a c u t e l y a d m i n i s t e r e d 10 txq EB and 150 uq P. I t i s apparent i n F i g . 3a t h a t m e t h y s e r g i d e i n h i b i t e d l o r d o s i s b e h a v i o u r 30 min a f t e r a d m i n i s t r a t i o n ; however, t h i s 44 F i g . 3a. L o r d o s i s q u o t i e n t s 10 minutes p r i o r t o , and 30 and 200 minutes a f t e r t r e a t m e n t w i t h m e t h y s e r g i d e or the s a l i n e v e h i c l e i n ovar i e c t o m i z e d r a t s a d m i n i s t e r e d 10 jug e s t r a d i o l benzoate and 150 Mg p r o g e s t e r o n e . For each group, n=l2. 100 o SALINE 0 J - 5 0 0 5 0 100 150 MINUTES AFTER TREATMENT 2 0 0 2 5 0 46 i n h i b i t o r y e f f e c t was no l o n g e r p r e s e n t a t 200 min. Indeed, a s l i g h t i n c r e a s e of l o r d o s i s b e h a v i o u r o c c u r r e d i n d r u g - t r e a t e d a n i m a l s a t 200 min. An a n a l y s i s of v a r i a n c e i n d i c a t e d a s i g n i f i c a n t e f f e c t of the time of t e s t i n g , i . e . , the l e n g t h of the p o s t - m e t h y s e r g i d e i n t e r v a l , F(2,44)=6.62, p_< .003, and a s i g n i f i c a n t i n t e r a c t i o n between m e t h y s e r g i d e and the time of t e s t i n g , F(2,44) = 4.97, p_< .011. There was no main e f f e c t of m e t h y s e r g i d e . The Newman-Keuls method of m u l t i p l e comparisons r e v e a l e d t h a t the l o r d o s i s q u o t i e n t s of a n i m a l s t r e a t e d w i t h m e t h y s e r g i d e were s i g n i f i c a n t l y lower a t 30 min than those of the same a n i m a l s when t e s t e d p r i o r t o treatment (p_<.05), and when t e s t e d 200 min a f t e r t r e a t m e n t w i t h the drug (p_<.05). However, a t no time d i d the mean l o r d o s i s q u o t i e n t s of drug t r e a t e d a n i m a l s d i f f e r from those of c o n t r o l a n i m a l s . R e s u l t s : Experiment 3b L o r d o s i s b e h a v i o u r and the t i m e - r e s p o n s e t o m e t h y s e r g i d e i n females c h r o n i c a l l y a d m i n i s t e r e d 10 jug EB. An e x a m i n a t i o n of F i g . 3 b s u g g e s t s t h a t m e t h y s e r g i d e i n h i b i t e d l o r d o s i s 30 min, but not 200 min a f t e r a d m i n i s t r a t i o n . .At 200 min, the l o r d o s i s q u o t i e n t s of both groups appear t o have i n c r e a s e d above those o b s e r v e d i n the i n i t i a l t e s t s . An a n a l y s i s of v a r i a n c e r e v e a l e d a s i g n i f i c a n t e f f e c t of the time of t e s t i n g , F (2,44) = 1 2.34 ,p_<. 0001 , as w e l l as a s i g n i f i c a n t i n t e r a c t i o n between m e t h y s e r g i d e and the time of t e s t i n g , 47 F i g . 3b. L o r d o s i s q u o t i e n t s 10 minutes p r i o r t o , and 30 and 200 minutes a f t e r t r e a tment w i t h m e t h y s e r g i d e or the s a l i n e v e h i c l e i n o v a r i e c t o m i z e d r a t s c h r o n i c a l l y a d m i n i s t e r e d 10 uq e s t r a d i o l b e n z o a t e . For each group, n=12. Ld O ZD O CO CO o on O 100 5 0 -2 5 -0 J -50 o SALINE ® METHYSERGIDE 0 50 100 150 MINUTES AFTER TREATMENT 200 250 oo 49 F(2,44) = 12.52,p_<.000l . There was no main e f f e c t of m e t h y s e r g i d e . Use of the Newman-Keuls method c o n f i r m e d the i n h i b i t o r y e f f e c t of m e t h y s e r g i d e a t 30 min, as the l o r d o s i s q u o t i e n t s of d r u g -t r e a t e d a n i m a l s were lower, than t h o s e of c o n t r o l a n i m a l s a t 30 min (p_<.05), and lower than those of both groups p r i o r t o t r e a t m e n t (p_<.05). The l o r d o s i s q u o t i e n t s of b o t h groups a t 200 min were s i g n i f i c a n t l y h i g h e r than those of the c o n t r o l group p r i o r t o t r e a t m e n t (g<.05), however they d i d not d i f f e r from those of the e x p e r i m e n t a l group p r i o r t o t r e a t m e n t . R e s u l t s : Experiment 3c L o r d o s i s b e h a v i o u r and the t i m e - r e s p o n s e t o m e t h y s e r g i d e i n females a c u t e l y a d m i n i s t e r e d 5 nq EB and 150 jug P. An e x a m i n a t i o n of F i g . 3c suggests t h a t m e t h y s e r g i d e i n h i b i t e d l o r d o s i s b e h a v i o u r 30 min a f t e r a d m i n i s t r a t i o n . In c o n t r a s t t o the d r u g - t r e a t e d a n i m a l s , the l o r d o s i s q u o t i e n t s of c o n t r o l a n i m a l s i n c r e a s e d a t 30 min. At 200 min, i n h i b i t o r y e f f e c t s of m e t h y s e r g i d e were no l o n g e r p r e s e n t , r a t h e r a s l i g h t i n c r e a s e i n r e c e p t i v i t y was apparent i n d r u g - t r e a t e d a n i m a l s a t t h i s t i m e . At 300 min the l o r d o s i s q u o t i e n t s of a n i m a l s t r e a t e d w i t h m e t h y s e r g i d e and those of c o n t r o l a n i m a l s were v i r t u a l l y i d e n t i c a l . An a n a l y s i s of v a r i a n c e i n d i c a t e d a s i g n i f i c a n t e f f e c t of the time of t e s t i n g , F (2, 54) =2 . 95 ,p_<. 04 , and a s i g n i f i c a n t i n t e r a c t i o n between m e t h y s e r g i d e and the time of t e s t i n g , F(2,54)=4.40,p<.008. However, t h e r e was no main e f f e c t 50 F i g . 3C. L o r d o s i s q u o t i e n t s 10 minutes p r i o r t o , and 30, 200, and 300 minutes a f t e r t r e a t m e n t w i t h m e t h y s e r g i d e or the s a l i n e v e h i c l e i n o v a r i e c t o m i z e d r a t s a d m i n i s t e r e d 5 Mg e s t r a d i o l benzoate and 150 Mg p r o g e s t e r o n e . For each group, n=l0. 51 % INBIlOnO SISOQdOl 52 of m e t h y s e r g i d e . The Newman-Keuls method r e v e a l e d t h a t a t 30 min the l o r d o s i s q u o t i e n t s of a n i m a l s a d m i n i s t e r e d m e t h y s e r g i d e were s i g n i f i c a n t l y lower than those of c o n t r o l a n i m a l s a t t h a t time (p_<.05). The l o r d o s i s q u o t i e n t s of d r u g - t r e a t e d a n i m a l s were s i g n i f i c a n t l y h i g h e r a t 200 min than those of the same a n i m a l s at 30 min (p_<.05); however, a t 200 and 300 min the l o r d o s i s q u o t i e n t s of d r u g - t r e a t e d a n i m a l s d i d not d i f f e r from those of c o n t r o l a n i m a l s . R e s u l t s ; Experiment 3d L o r d o s i s b e h a v i o u r and the t i m e - r e s p o n s e t o m e t h y s e r g i d e i n females c h r o n i c a l l y a d m i n i s t e r e d 5 nq EB. An e x a m i n a t i o n of F i g . 3d s u g g e s t s t h a t the i n h i b i t o r y e f f e c t of m e t h y s e r g i d e o b s e r v e d i n females a d m i n i s t e r e d both EB and P was a l s o p r e s e n t i n females a d m i n i s t e r e d e s t r o g e n a l o n e . As i n Experiment 3a, an i n h i b i t i o n of l o r d o s i s b e h a v i o u r was apparent i n drug t r e a t e d a n i m a l s a t 30 min, whereas a s l i g h t i n c r e a s e i n l o r d o s i s b e h a v i o u r was o b s e r v e d i n c o n t r o l a n i m a l s a t t h i s t i m e . At 200 min the l o r d o s i s q u o t i e n t s of d r u g - t r e a t e d a n i m a l s were h i g h e r than those of c o n t r o l a n i m a l s ; however, a t 300 min the two groups d i d not appear t o d i f f e r . An a n a l y s i s of v a r i a n c e i n d i c a t e d a s i g n i f i c a n t e f f e c t of the time of t e s t i n g , F (2,54) = 3 .07 ,p_<. 035, and a s i g n i f i c a n t i n t e r a c t i o n between m e t h y s e r g i d e and the time of t e s t i n g , F (2 , 54) = 5. 077 ,p_<. 0037 . A g a i n , t h e r e was no main e f f e c t of m e t h y s e r g i d e . The Newman-Keuls method c o n f i r m e d the i n h i b i t o r y e f f e c t of m e t h y s e r g i d e a t 30 min, as the l o r d o s i s q u o t i e n t s of 53 F i g . 3d. L o r d o s i s q u o t i e n t s 10 minutes p r i o r t o , and 30, 200, and 300 minutes a f t e r t r e a t m e n t w i t h m e t h y s e r g i d e or the s a l i n e v e h i c l e i n o v a r i e c t o m i z e d r a t s c h r o n i c a l l y a d m i n i s t e r e d 5 ug e s t r a d i o l b e nzoate. For each group, n=l0. 100 o SALINE - 5 0 0 5 0 100 150 2 0 0 2 5 0 3 0 0 3 5 0 MINUTES AFTER TREATMENT 55 a n i m a l s r e c e i v i n g m e t h y s e r g i d e were s i g n i f i c a n t l y lower than those of c o n t r o l a n i m a l s a t 30 min (p<„05). At 200 min the l o r d o s i s q u o t i e n t s of d r u g - t r e a t e d a n i m a l s were s i g n i f i c a n t l y h i g h e r than those of the same a n i m a l s a t 30 min (p_<.05); however, a t 200 and 300 min the l o r d o s i s q u o t i e n t s of d r u g -t r e a t e d a n i m a l s d i d not d i f f e r from t h o s e of c o n t r o l a n i m a l s . R e s u l t s ; Experiment 3e L o r d o s i s b e h a v i o u r and the t i m e - r e s p o n s e t o m e t h y s e r g i d e i n females a c u t e l y a d m i n i s t e r e d 2 jug EB. I t can be seen i n F i g . 3e t h a t m e t h y s e r g i d e d i d not i n h i b i t l o r d o s i s b e h a v i o u r i n females primed w i t h a s i n g l e low dose of EB. Indeed, i n c o n t r a s t w i t h E x p e r i m e n t s 1-4, a s l i g h t i n c r e a s e i n r e c e p t i v i t y i s apparent a t 30 min. A more d r a m a t i c f a c i l i t a t i o n of l o r d o s i s b e h a v i o u r i s apparent a t 200 and 300 min. A subsequent a n a l y s i s of v a r i a n c e r e v e a l e d s i g n i f i c a n t e f f e c t s of both m e t h y s e r g i d e , F(1,30)=4.41,p<.042, and the time of t e s t i n g , F(3,90)=7.15,p<.0003. The a n a l y s i s a l s o i n d i c a t e d a s i g n i f i c a n t i n t e r a c t i o n between meth y s e r g i d e and the time of t e s t i n g , F(3,90)=3 . 21 , £<.021. Subsequent use of the Newman-K e u l s method f a i l e d t o r e v e a l a s i g n i f i c a n t d i f f e r e n c e i n l o r d o s i s b e h a v i o u r between d r u g - t r e a t e d and c o n t r o l a n i m a l s a t 30 min. However, at 200 min the l o r d o s i s q u o t i e n t s of a n i m a l s t r e a t e d w i t h m e t h y s e r g i d e were s i g n i f i c a n t l y h i g h e r than t h o s e of c o n t r o l a n i m a l s (p_<.05). A s i g n i f i c a n t f a c i l i t a t i o n of l o r d o s i s a t 300 min was a l s o c o n f i r m e d (p_<.05). 56 F i g . 3e. L o r d o s i s q u o t i e n t s 10 minutes p r i o r t o , and 30, 200, and 300 minutes a f t e r t r e a t m e n t w i t h m e t h y s e r g i d e or the s a l i n e v e h i c l e i n o v a r i e c t o m i z e d r a t s a c u t e l y a d m i n i s t e r e d 2 nq e s t r a d i o l benzoate. For each group, n=16. 100 n o SALINE MINUTES AFTER TREATMENT 58 D i s c u s s i o n The s e r o t o n i n a n t a g o n i s t m e t h y s e r g i d e has g e n e r a l l y been r e p o r t e d t o f a c i l i t a t e l o r d o s i s b e h a v i o u r i n the female r a t . There have, however, been s e v e r a l r e p o r t s of i n h i b i t i o n f o l l o w i n g the a d m i n i s t r a t i o n of the d r u g . In the p r e s e n t s e r i e s of e x p e r i m e n t s , m e t h y s e r g i d e was found t o a c t i n a t i m e -dependent manner t o produce both i n h i b i t o r y and f a c i l i t a t o r y e f f e c t s on l o r d o s i s b e h a v i o u r . In E x p e r i m e n t s 3a and 3b, i n h i b i t i o n of l o r d o s i s was observed 30, but not 200 min a f t e r the p e r i p h e r a l a d m i n i s t r a t i o n of m e t h y s e r g i d e . In E x p e r i m e n t s 3c and 3d, i n h i b i t i o n was a l s o o b s e r v e d 30 , but not 200 or 300 min a f t e r t r e a t m e n t . In Experiment 3e, f a c i l i t a t i o n was o b s e r v e d 200 and 300 min a f t e r the a d m i n i s t r a t i o n of m e t h y s e r g i d e ; however, the drug was i n e f f e c t i v e 30 min a f t e r t r e a t m e n t . I t i s p o s s i b l e t h a t the f a i l u r e of m e t h y s e r g i d e t o f a c i l i t a t e l o r d o s i s a t 200 or 300 min i n the f i r s t f o u r e x p e r i m e n t s was m e r e l y a c e i l i n g problem. That i s , m o d e r a t e l y h i g h l e v e l s of r e c e p t i v i t y o bserved i n the c o n t r o l groups may have masked any f a c i l i t a t o r y e f f e c t s of m e t h y s e r g i d e . N o n e t h e l e s s , i t i s c l e a r t h a t the i n h i b i t i o n of l o r d o s i s o b s e r v e d a t 30 min i n the f i r s t f o u r e x p e r i m e n t s was not s i m p l y a f u n c t i o n of the b a s e l i n e l e v e l of r e c e p t i v i t y . No i n h i b i t i o n was o b s e r v e d a t 200 or 300 min, a l t h o u g h i n e v e r y case b a s e l i n e l e v e l s of l o r d o s i s b e h a v i o u r were s i m i l a r t o those a t 30 min. The p r e s e n t f i n d i n g of a s e x u a l l y i n h i b i t o r y e f f e c t of m e t h y s e r g i d e i s c o n s i s t e n t w i t h a t l e a s t t h r e e r e p o r t s of i n h i b i t i o n f o l l o w i n g the a d m i n i s t r a t i o n of t h i s d rug. In one 59 c a s e , i n h i b i t i o n was observed as e a r l y as 30 min f o l l o w i n g the a d m i n i s t r a t i o n of m e t h y s e r g i d e d i r e c t l y i n t o the p r e o p t i c a r e a of the hypothalamus (Clemens, 1978). In the two a d d i t i o n a l c a s e s , i n h i b i t i o n was o b s e r v e d 1 hr a f t e r the p e r i p h e r a l a d m i n i s t r a t i o n of methysergide,(Meyerson and E l i a s s o n , 1977; S e i t n e i k s , 1985). C o i n c i d e n t a l l y , i n the t h r e e l a t t e r s t u d i e s , a n i m a l s were p r e - t r e a t e d w i t h both e s t r o g e n and p r o g e s t e r o n e , whereas i n the m a j o r i t y of s t u d i e s , they were a d m i n i s t e r e d o n l y e s t r o g e n . On the b a s i s of the p u b l i s h e d d a t a one might c o n c l u d e t h a t m e t h y s e r g i d e i s i n h i b i t o r y i n the presence of p r o g e s t e r o n e , and f a c i l i t a t o r y i n i t ' s absence. However, the p r e s e n t d a t a p r o v i d e no s u p p o r t f o r t h i s c o n c l u s i o n . The i n h i b i t i o n o b s e r v e d 30 minutes f o l l o w i n g m e t h y s e r g i d e a d m i n i s t r a t i o n was a t l e a s t as g r e a t i n the absence ( F i g s . 3b and 3d), as i n the p r e s e n c e of p r o g e s t e r o n e ( F i g s . 3a and 3 c ) . The p e r i p h e r a l a d m i n i s t r a t i o n of m e t h y s e r g i d e has g e n e r a l l y been r e p o r t e d t o f a c i l i t a t e l o r d o s i s b e h a v i o u r , w i t h the maximal e f f e c t of the drug o c c u r r i n g 2 t o 6 hr a f t e r a d m i n i s t r a t i o n (Zemlan et a l . , 1973; D a v i s and K o h l , 1978). However, i n view of p h a r m a c o k i n e t i c data on m e t h y s e r g i d e , l a t e n c i e s of t h i s magnitude a r e unexpected. The uptake and d i s t r i b u t i o n of m e t h y s e r g i d e f o l l o w i n g p e r i p h e r a l a d m i n i s t r a t i o n of the drug s u g g e s t s t h a t r a p i d p h a r m a c o l o g i c a l e f f e c t s a r e l i k e l y (Doepfner, 1962; M e i r and S c h r e i e r , 1976). Indeed , the maximal c o n c e n t r a t i o n of m e t h y s e r g i d e i n the b r a i n and o t h e r t i s s u e s i n the r a t has been r e p o r t e d t o o c c u r 10 t o 15 min a f t e r i n t r a v e n o u s a d m i n i s t r a t i o n (Doepfner, 1962). When a d m i n i s t e r e d i n t r a p e r i t o n e a l l y , the maximal e f f e c t of m e t h y s e r g i d e on whole 60 b r a i n s e r o t o n i n l e v e l s was r e p o r t e d t o occur as e a r l y as 30 min a f t e r t r e a t m e n t ( S o f i a and V a s s a r , 1975). A v a r i e t y of b e h a v i o u r a l s t u d i e s has c o n f i r m e d t h a t m e t h y s e r g i d e i s a r e l a t i v e l y f a s t - a c t i n g d rug. When a d m i n i s t e r e d i n t r a p e r i t o n e a l l y , m e t h y s e r g i d e has been e f f e c t i v e c e n t r a l l y as e a r l y as 20 t o 30 min a f t e r a d m i n i s t r a t i o n (Browne and Ho, 1975; No r m a n s e l l and Panksepp, 1985). These d a t a l e a d me t o c o n c l u d e t h a t the i n h i b i t i o n of l o r d o s i s o b s e r v e d i n the p r e s e n t study 30 min a f t e r the a d m i n i s t r a t i o n of m e t h y s e r g i d e was due t o the d i r e c t a c t i o n of the drug on c e n t r a l 5-HT r e c e p t o r s . Moreover, i n view of r e c e n t e v i d e n c e t h a t 5-HT2 a n t a g o n i s t s i n h i b i t l o r d o s i s b e h a v i o u r (Mendelson and G o r z a l k a , 1985b), I suggest t h a t the i n h i b i t o r y e f f e c t of me t h y s e r g i d e was due s p e c i f i c a l l y t o t he bl o c k a d e of 5-HT2 r e c e p t o r s . A l t h o u g h the maximal f a c i l i t a t o r y e f f e c t of p e r i p h e r a l l y a d m i n i s t e r e d m e t h y s e r g i d e has been r e p o r t e d t o oc c u r from 2 t o 6 hr a f t e r t r e a t m e n t (Zemlan et a l . , 1973; D a v i s and K o h l , 1978), a t l e a s t one r e p o r t on the t i m e - r e s p o n s e t o met h y s e r g i d e i n d i c a t e s t h a t the e f f e c t i v e n e s s of the drug as a 5-HT a n t a g o n i s t d i m i n i s h e s r a p i d l y d u r i n g t h i s p e r i o d of time ( B e r e t t a , F e r r i n i and G l a s s e r , 1965). S i m i l a r l y , t he e f f e c t of me t h y s e r g i d e on b r a i n s e r o t o n i n l e v e l s has been r e p o r t e d t o d e c l i n e w i t h i n 1 hr of a d m i n i s t r a t i o n ( S o f i a and V a s s a r , 1975), and d a t a on the h a l f - l i f e of me t h y s e r g i d e suggest t h a t a t tim e s when me t h y s e r g i d e has been r e p o r t e d t o f a c i l i t a t e l o r d o s i s b e h a v i o u r , t i s s u e l e v e l s of the drug a r e s u b s t a n t i a l l y reduced ( M e i r and S c h r e i e r , 1976). I t may be t h a t the f a c i l i t a t o r y e f f e c t of me t h y s e r g i d e o f t e n r e p o r t e d i n the l i t e r a t u r e , and 61 o b s e r v e d i n the p r e s e n t study 200 and 300 min a f t e r a d m i n i s t r a t i o n , i s due t o the e f f e c t of a m e t a b o l i t e of m e t h y s e r g i d e . A l t e r n a t i v e l y , the f a c i l i t a t o r y e f f e c t of me t h y s e r g i d e upon l o r d o s i s 2 t o 6 hr a f t e r a d m i n s t r a t i o n may be due t o an enhancement of 5-HT2 a c t i v i t y by low, r e s i d u a l l e v e l s of the drug . I t has been r e p o r t e d t h a t low, but not h i g h c o n c e n t r a t i o n s of m e t h y s e r g i d e enhance the e x c i t a t o r y e f f e c t of m e s c a l i n e on s p o n t a n e o u s l y a c t i v e , neurons of the somatosensory c o r t e x (Bevan, Bradshaw and S z a b a d i , 1974). M e s c a l i n e , a 5-HT a g o n i s t , b i n d s s e l e c t i v e l y t o 5-HT2 r e c e p t o r s , and produces the h e a d - t w i t c h r e s p o n s e , a be h a v i o u r b e l i e v e d t o be mediated by 5-HT2 r e c e p t o r a c t i v i t y (Leysen and T o l l e n a e r e , 1982 ). The enhancement of a c t i v i t y a t 5-HT2 r e c e p t o r s by low l e v e l s of me t h y s e r g i d e might a l s o e x p l a i n the marked f a c i l i t a t i o n of l o r d o s i s t h a t has been ob s e r v e d i n e s t r o g e n - p r i m e d females 1 hr a f t e r the c o a d m i n i s t r a t i o n of met h y s e r g i d e (3 mg/kg) and the 5-HT2 a g o n i s t q u i p a z i n e (Mendelson and G o r z a l k a , 1985b). A l t h o u g h the p r e s e n t r e s u l t s a r e c o n s i s t e n t w i t h the h y p o t h e s i s t h a t m e t h y s e r g i d e i n h i b i t s l o r d o s i s by the bl o c k a d e of 5-HT2 r e c e p t o r s , the p o s s i b i l i t y remains t h a t o t h e r n e u r o t r a n s m i t t e r systems might mediate t h i s e f f e c t . M e t h y s e r g i d e has been r e p o r t e d t o have a low, but s i g n i f i c a n t a f f i n i t y f o r dopamine r e c e p t o r s ( J a n s s e n , 1983). A l t h o u g h t h e r e i s e v i d e n c e t o suggest t h a t b l o c k a d e of dopamine a c t i v i t y f a c i l i t a t e s l o r d o s i s b e h a v i o u r ( E v e r i t t e t a l . 1974), c o n t r a r y e v i d e n c e a l s o e x i s t s (Foreman and Moss, 1979). N o t w i t h s t a n d i n g the c o n t r o v e r s i a l r o l e of dopamine i n female s e x u a l b e h a v i o u r , 62 dopaminergic m e d i a t i o n of the i n h i b i t o r y e f f e c t of me t h y s e r g i d e can not be c o m p l e t e l y r u l e d out. However, i t i s u n l i k e l y t h a t a d r e n e r g i c r e c e p t o r s mediate the i n h i b i t o r y e f f e c t of m e t h y s e r g i d e . In c o n t r a s t t o many o t h e r 5-HT2 a n t a g o n i s t s , m e t h y s e r g i d e has r e l a t i v e l y l i t t l e a d r e n e r g i c a c t i v i t y ( J a n s s e n , 1983). F i n a l l y , I note t h a t m e t h y s e r g i d e has been r e p o r t e d t o have p a r t i a l a g o n i s t a c t i v i t y a t 5-HT r e c e p t o r s ( C o l p a e r t and J a n s s e n , 1983). Thus the i n h i b i t o r y e f f e c t of methy s e r g i d e may r e f l e c t a t r a n s i t o r y i n c r e a s e i n s e r o t o n e r g i c a c t i v i t y . I suggest t h a t t h i s e x p l a n a t i o n i s u n l i k e l y . Research i n our l a b o r a t o r y i n d i c a t e s t h a t o t h e r 5-HT a n t a g o n i s t s w i t h p a r t i a l a g o n i s t a c t i v i t y , i n c l u d i n g p i z o t e f i n and c y p r o h e p t a d i n e ( C o l p a e r t and J a n s s e n , 1983), i n h i b i t l o r d o s i s , and t h e s e i n h i b i t o r y e f f e c t s a r e r e v e r s e d by the c o a d m i n i s t r a t i o n of q u i p a z i n e (Mendelson and G o r z a l k a , 1985b). EXPERIMENT 4 In Experiment 3, I observed what appeared t o be t i m e -dependent e f f e c t s of me t h y s e r g i d e on l o r d o s i s b e h a v i o u r . When t e s t i n g o c c u r r e d 30 min a f t e r t r e a t m e n t , 7 mg/kg of met h y s e r g i d e produced i n h i b i t i o n of l o r d o s i s . However, when t e s t i n g o c c u r r e d 200 min a f t e r t r e a t m e n t , the same dose of me t h y s e r g i d e produced f a c i l i t a t i o n of t h i s b e h a v i o u r . I suggested t h a t the i n h i b i t o r y e f f e c t of me t h y s e r g i d e was due t o i t s a c t i o n as a 5-HT2 a n t a g o n i s t , whereas the f a c i l i t a t o r y e f f e c t of me t h y s e r g i d e may have been due t o the a c t i o n of a m e t a b o l i t e of m e t h y s e r g i d e . The above e x p l a n a t i o n of the time response t o met h y s e r g i d e i s c o n s i s t e n t w i t h the h y p o t h e s i z e d f a c i l i t a t o r y r o l e of 5-HT2 63 r e c e p t o r s i n the m o d u l a t i o n of l o r d o s i s b e h a v i o u r . There i s , however, a n o t h e r e q u a l l y p l a u s i b l e e x p l a n a t i o n . I t may be noted t h a t 30 min a f t e r t r e a t m e n t , the l e v e l s of m e t h y s e r g i d e i n b r a i n t i s s u e would be c o n s i d e r a b l y h i g h e r than those t h a t would be found 200 min a f t e r t r e a t m e n t . T h i s f a c t s u g g ests the p o s s i b i l i t y t h a t the apparent time-dependent i n h i b i t o r y and f a c i l i t a t o r y e f f e c t s of m e t h y s e r g i d e may a c t u a l l y be c o n c e n t r a t i o n - d e p e n d e n t e f f e c t s of m e t h y s e r g i d e . I f t h i s were the c a s e , then f o l l o w i n g the p e r i p h e r a l a d m i n i s t r a t i o n of a s u i t a b l y s m a l l dose of m e t h y s e r g i d e , f a c i l i t a t i o n r a t h e r than i n h i b i t i o n of l o r d o s i s might be o b s e r v e d 30 min a f t e r t r e a t m e n t . Such a r e s u l t s might be used t o argue a g a i n s t the h y p o t h e s i s t h a t the antagonism of a c t i v i t y a t 5-HT2 r e c e p t o r s i n h i b i t s l o r d o s i s b e h a v i o u r . In o r d e r t o r u l e out t h a t p o s s i b i l i t y , I examined the e f f e c t s of a v a r i e t y of doses of m e t h y s e r g i d e on l o r d o s i s b e h a v i o u r both a t 30 min and a t 200 min a f t e r t r e a t m e n t . Method Drugs M e t h y s e r g i d e b i m a l e a t e (methysergide) was d i s s o l v e d i n warm s a l i n e and a d m i n i s t e r e d i n t r a p e r i t o n e a l l y i n a p p r o x i m a t e l y 0.3 ml of the v e h i c l e . M e t h y s e r g i d e was a d m i n i s t e r e d b l i n d . P r o c e d u r e s In Experiment 4a, 80 ovar i e c t o m i z e d r a t s r e c e i v e d lOjug EB 48 hr p r i o r t o t e s t i n g . These females were d i v i d e d i n t o 5 groups 64 each of which r e c e i v e d p e r i p h e r a l a d m i n i s t r a t i o n of e i t h e r 7, 1, 0.15, or 0.02 mg/kg m e t h y s e r g i d e or the s a l i n e v e h i c l e 30 min p r i o r t o t e s t i n g . The p r o c e d u r e s f o l l o w e d i n Experiment 4b were i d e n t i c a l t o those of Experiment 4a, except t h a t 35 o v a r i e c t o m i z e d a n i m a l s were used, and doses of me t h y s e r g i d e were a d m i n i s t e r e d 200 min p r i o r t o b e h a v i o u r a l t e s t i n g . R e s u l t s In examining F i g . 4a, i t i s apparent t h a t n e i t h e r low nor h i g h doses of me t h y s e r g i d e produced f a c i l i t a t i o n of l o r d o s i s 30 min a f t e r a d m i n i s t r a t i o n t o e s t r o g e n - p r i m e d f e m a l e s . Indeed, l e v e l s of l o r d o s i s a c t i v i t y appear t o d e c l i n e w i t h i n c r e a s i n g doses of m e t h y s e r g i d e . A l t h o u g h t h i s d e c l i n e i n l o r d o s i s b e h a v i o u r f o l l o w i n g t r e a t m e n t w i t h m e t h y s e r g i d e appears c o n s i s t e n t w i t h the r e s u l t s of Experiment 3, i n the p r e s e n t experiment no s i g n i f i c a n t l o r d o s i s i n h i b i t i n g e f f e c t s of me t h y s e r g i d e were found. Because s e v e r a l females t r e a t e d w i t h the h i g h e s t dose of m e t h y s e r g i d e were found t o be c o m p l e t e l y n o n - r e c e p t i v e , t h a t i s , had l o r d o s i s q u o t i e n t s of 0%, t h i s f a i l u r e t o observe a s i g n i f i c a n t i n h i b i t o r y e f f e c t of me t h y s e r g i d e may have been due a t l e a s t p a r t i a l l y t o a f l o o r e f f e c t . In F i g 4b i t can be seen t h a t the 1 mg/kg dose of me t h y s e r g i d e produced a marked i n c r e a s e i n l o r d o s i s b e h a v i o u r 200 min a f t e r a d m i n i s t r a t i o n t o females t r e a t e d w i t h e s t r o g e n a l o n e . The o t h e r doses of m e t h y s e r g i d e appear t o have been i n e f f e c t i v e . An a n a l y s i s of v a r i a n c e c o n f i r m e d t h a t m e t h y s e r g i d e 65 F i g . 4a. Mean l o r d o s i s q u o t i e n t s ± S.E.M. of females primed w i t h 10 Mg e s t r a d i o l benzoate f o l l o w i n g the i n t r a p e r i t o n e a l a d m i n i s t r a t i o n of v a r y i n g doses of m e t h y s e r g i d e 30 min p r i o r t o b e h a v i o u r a l t e s t i n g . METHYSERGIDE: DOSE RESPONSE 30 MINUTES/ ESTROGEN ALONE 100^ 9 0 -8 0 -f— LxJ 7 0 -r — O LxJ 2 0 -1 0 -i : 1 1 1 1 1 1 1 0 1 2 3 4 5 6 7 METHYSERGIDE mg/kg 67 F i g . 4b. Mean l o r d o s i s q u o t i e n t s ± S.E.M. of females primed w i t h 10 Mg e s t r a d i o l benzoate f o l l o w i n g the i n t r a p e r i t o n e a l a d m i n i s t r a t i o n of v a r y i n g doses of m e t h y s e r g i d e 200 min p r i o r t o b e h a v i o u r a l t e s t i n g . 68 % lN3llOflO SlSOdcJOl NV3kN 69 produced a s i g n i f i c a n t e f f e c t upon l o r d o s i s b e h a v i o u r 200 min a f t e r a d m i n i s t r a t i o n F (4, 30) =6.554 ,p_<. 0007. By subsequent use of the Newman-Keuls method i t was found t h a t a s i g n i f i c a n t f a c i l i t a t i o n of l o r d o s i s was produced by the 1 mg/kg dose, (p_<.05). Other doses of m e t h y s e r g i d e were i n e f f e c t i v e . D i s c u s s i o n In E x p e r i m e n t s 3 and 4 i t was d e t e r m i n e d t h a t the i n h i b i t o r y e f f e c t s of p e r i p h e r a l l y a d m i n i s t e r e d m e t h y s e r g i d e occur i n a " t i m e - r a t h e r than a dose dependent manner. I n h i b i t i o n , or a t l e a s t r e d u c t i o n i n l e v e l s of l o r d o s i s b e h a v i o u r o c c u r s a t 30 min, whereas f a c i l i t a t i o n of l o r d o s i s o c c u r s a t 200 min a f t e r t r e a t m e n t . Because p e r i p h e r a l l y a d m i n i s t e r e d m e t h y s e r g i d e has been r e p o r t e d t o be most a c t i v e i n the b r a i n as a 5-HT a n t a g o n i s t w i t h i n an hour a f t e r a d m i n i s t r a t i o n ( S o f i a and V a s s a r , 1 9 7 5 ) , i t was suggested t h a t the e f f e c t of m e t h y s e r g i d e a c t i n g as a 5-HT a n t a g o n i s t was t o i n h i b i t l o r d o s i s b e h a v i o u r . I t must be n o t e d , however, t h a t i n some cases where m e t h y s e r g i d e has been a d m i n i s t e r e d d i r e c t l y i n t o b r a i n t i s s u e , f a c i l i t a t i o n of l o r d o s i s has been obse r v e d as e a r l y as 30 min a f t e r t r e a t m e n t . Areas of the b r a i n i n which the a d m i n i s t r a t i o n of m e t h y s e r g i d e has been found t o produce a l o r d o s i s -f a c i l i t a t i n g e f f e c t w i t h i n 30 min are the p r e o p t i c and h y p o t h a l a m i c a r e a s (Zemlan e t a l . , 1973; Ward e t a l . , 1975), and the hippocampus and amygdala (Franck and Ward, 1981). I n t e r e s t i n g l y , these a r e a s of the b r a i n a r e a l l found i n the 70 f o r e b r a i n . When a d m i n i s t e r e d p e r i p h e r a l l y , m e t h y s e r g i d e would have reached a r e a s i n both the f o r e b r a i n and the h i n d b r a i n . The apparent i n c o n s i s t e n c y i n the time c o u r s e of the e f f e c t s of met h y s e r g i d e a d m i n i s t e r e d p e r i p h e r a l l y as opposed t o d i r e c t l y i n t o the b r a i n may s i m p l y r e f l e c t r e g i o n a l d i f f e r e n c e s i n the e f f e c t s of m e t h y s e r g i d e . A l t h o u g h the b l o c k a d e of c e r t a i n 5-HT r e c e p t o r s i n the f o r e b r a i n may f a c i l i t a t e l o r d o s i s , t he bl o c k a d e of 5-HT2 r e c e p t o r s i n the h i n d b r a i n may i n h i b i t the l o r d o s i s r e s p onse. EXPERIMENT 5 In E x p e r i m e n t s 1 thr o u g h 4, I p r o v i d e d e v i d e n c e of a f a c i l i t a t o r y r o l e f o r 5-HT2 r e c e p t o r s i n the m o d u l a t i o n of l o r d o s i s b e h a v i o u r . These d a t a t e n d t o c o n f i r m the d u a l r o l e h y p o t h e s i s of Mendelson and G o r z a l k a . The 5-HT a g o n i s t 8-h y d r o x y - 2 - ( d i - n - p r o p y l a m i n o ) t e t r a l i n (8-OH DPAT) appears t o b i n d s e l e c t i v e l y and w i t h h i g h a f f i n i t y t o the 5-HT,A r e c e p t o r ( M i d d l e m i s s & F o z a r d , 1983). I t may be t h a t 5-HT,A and 5-HT,B r e c e p t o r subtypes s e r v e d i s t i n c t b e h a v i o u r a l f u n c t i o n s , as has been proposed f o r 5-HT, and 5-HT2 r e c e p t o r s . T h e r e f o r e , the e f f e c t s of 8-OH DPAT on l o r d o s i s i n the female r a t were e v a l u a t e d i n the p r e s e n t s t u d y . A l t h o u g h i n c r e a s e s i n s e r o t o n e r g i c a c t i v i t y have g e n e r a l l y been thought t o i n h i b i t male s e x u a l b e h a v i o u r (see Mendelson & G o r z a l k a , 1985a f o r r e v i e w ) , t h e a d m i n i s t r a t i o n of 8-OH DPAT has been r e p o r t e d t o produce d r a m a t i c f a c i l i t a t i o n of homotypic 71 s e x u a l b e h a v i o u r i n the male r a t ( A h l e n i u s , L a r s s o n , Svensson, H j o r t h , C a r l s s o n , L i n d b e r g , Wikstrom, Sanchez, A r v i d s s o n , H a c k s e l l & N i l s s o n , 1981; A h l e n i u s & L a r s s o n , 1984a; A h l e n i u s & L a r s s o n , 1984b). I n t e r e s t i n g l y , male s e x u a l b e h a v i o u r can be o b s e r v e d i n female r a t s , e s p e c i a l l y those t h a t have been t r e a t e d w i t h t e s t o s t e r o n e ( S o d e r s t e n , 1972). By c o n t r a s t i n g the e f f e c t s of 8-OH DPAT upon the e x p r e s s i o n of male and female s e x u a l b e h a v i o u r i n the female i t seemed p o s s i b l e t o c o n t r o l f o r non-s p e c i f i c e f f e c t s of the d r u g . That i s , i f 8-OH DPAT i n h i b i t e d the e x p r e s s i o n of l o r d o s i s b e h a v i o u r , but f a c i l i t a t e d the e x p r e s s i o n of male s e x u a l b e h a v i o u r i n female r a t s , then i t would i t seem u n l i k e l y t h a t the i n h i b i t i o n of l o r d o s i s would have be due t o s e d a t i o n , motor impairment, or some o t h e r non-s p e c i f i c mechanism. T h e r e f o r e , i n Experiment 5 the e f f e c t s of 8-OH DPAT on the e x p r e s s i o n of male s e x u a l b e h a v i o u r i n females were a l s o examined. METHODS Drugs T e s t o s t e r o n e ( S t e r a l o i d s ) , was d i s s o l v e d i n warm peanut o i l and a d m i n i s t e r e d s u b c u t a n e o u s l y i n 0.05 ml of the v e h i c l e . The 8 - h y d r o x y - 2 - ( d i - n - p r o p y l a m i n o ) t e t r a l i n HBr (8-OH DPAT, Res e a r c h B i o c h e m i c a l s Inc.) was d i s s o l v e d i n warm s a l i n e and c o n c e n t r a t i o n s were a d j u s t e d such t h a t a l l doses of the drug were d e l i v e r e d i n t r a p e r i t o n e a l l y i n a p p r o x i m a t e l y 0.3 ml of the s o l v e n t . Because bromide s a l t s have l o n g been known t o d e p r e s s 72 c e n t r a l nervous system a c t i v i t y (Harvey, 1975), a d e s i g n was employed t h a t c o n t r o l l e d f o r any p o t e n t i a l e f f e c t s of bromide i o n s upon s e x u a l b e h a v i o u r . NaBr was added p r o p o r t i o n a t e l y t o each drug and c o n t r o l s o l u t i o n such t h a t e v e r y a n i m a l r e c e i v e d a dose of 0.7 mg /kg Br" w i t h each t r e a t m e n t , r e g a r d l e s s of the dose of 8-OH DPAT r e c e i v e d . T h i s amount of bromide i o n approxi m a t e d the amount d e l i v e r e d w i t h the h i g h e s t dose of 8-OH DPAT. Experiment 5a I t has been h y p o t h e s i z e d t h a t the 5-HT, r e c e p t o r mediates an i n h i b i t o r y e f f e c t of s e r o t o n i n on l o r d o s i s b e h a v i o u r , whereas the 5-HT2 r e c e p t o r mediates a f a c i l i t a t o r y e f f e c t (Mendelson & G o r z a l k a , 1985b). However, the e x i s t e n c e of 5-HT,A and 5-HT,B r e c e p t o r subtypes may n e c e s s i t a t e r e v i s i o n of the h y p o t h e s i s . To examine t h i s p o s s i b i l i t y , the e f f e c t on l o r d o s i s of 8-OH DPAT, a 5-HT,A a g o n i s t , was a s s e s s e d i n e s t r o g e n - p r i m e d , o v a r i e c t o m i z e d r a t s . Method Females were d i v i d e d i n t o 7 groups of 10 a n i m a l s , and 48 hr p r i o r t o t e s t i n g each a n i m a l r e c e i v e d 10 Mg of e s t r a d i o l benzoate (EB ) . In our l a b o r a t o r y , t h i s EB dose has been shown t o produce m o d e r a t e l y low l e v e l s of l o r d o s i s i n c o n t r o l a n i m a l s , which would a l l o w the e v a l u a t i o n of any p o t e n t i a l f a c i l i t a t o r y or i n h i b i t o r y e f f e c t s of 8-OH DPAT. T h i r t y minutes b e f o r e t e s t i n g , each group of a n i m a l s r e c e i v e d i n t r a p e r i t o n e a l 73 a d m i n i s t r a t i o n of e i t h e r 0.01, 0.03, 0.1, 0.3, 1, or 3 mg/kg 8-OH DPAT, or the N a B r - s a l i n e v e h i c l e . 8-OH DPAT was a d m i n i s t e r e d b l i n d . R e s u l t s At the 0.01 mg /kg dose, 8-OH DPAT appeared t o produce a s l i g h t f a c i l i t a t i o n of l o r d o s i s b e h a v i o u r ( F i g . 5 a ) . However, a t h i g h e r doses, 8-OH DPATappeared t o produce a s t r o n g l o r d o s i s -i n h i b i t o r y e f f e c t . An a n a l y s i s of v a r i a n c e c o n f i r m e d a s i g n i f i c a n t e f f e c t of 8-OH DPAT , F (6, 63) = 1 9.31 , 2<-00°1« B v subsequent use of the Newman-Keuls method of m u l t i p l e c o m p a r i s o n s , i t was de t e r m i n e d t h a t the 0.01 mg/kg dose of 8-OH DPAT was i n e f f e c t i v e . However, each dose g r e a t e r than 0.01 mg/kg produced a s i g n i f i c a n t i n h i b i t i o n of l o r d o s i s b e h a v i o u r (2<«05). Experiment 5b In Experiment 5a, 8-OH DPAT was found t o i n h i b i t l o r d o s i s b e h a v i o u r i n the female r a t , r e s u l t s c o n s i s t e n t w i t h the d u a l r o l e h y p o t h e s i s of Mendelson and G o r z a l k a . I n t e r e s t i n g l y , t h i s f i n d i n g i s i n marked c o n t r a s t w i t h the d r a m a t i c f a c i l i t a t i o n of s e x u a l b e h a v i o u r t h a t has been r e p o r t e d t o oc c u r i n the male r a t f o l l o w i n g t r e a t m e n t w i t h 8-OH DPAT ( A h l e n i u s e t a l . , 1981; A h l e n i u s & L a r s s o n , 1984a; A h l e n i u s & L a r s s o n , I984ba). In view of t h e s e d i f f e r e n c e s , i t may be u s e f u l t o determine what e f f e c t s 74 F i g . 5. Mean l o r d o s i s q u o t i e n t s ±S.E.M. of o v a r i e c t o m i z e d r a t s primed w i t h 10 jug e s t r a d i o l b enzoate, f o l l o w i n g the a d m i n i s t r a t i o n of v a r y i n g doses of 8 - h y d r o x y - 2 - ( d i - n -p r o p y l a m i n o ) t e t r a l i n (8-OH DPAT) 30 min p r i o r t o b e h a v i o u r a l t e s t i n g . MEAN LORDOSIS QUOTIENT % 76 8-OH DPAT would have upon the e x p r e s s i o n of male s e x u a l b e h a v i o u r i n females. Mounting w i t h p e l v i c t h r u s t i n g i s a s t e r e o t y p i c a l l y male s e x u a l b e h a v i o u r . However, female r a t s t h a t have r e c e i v e d c h r o n i c t r e a t m e n t w i t h e s t r o g e n or t e s t o s t e r o n e w i l l o c c a s i o n a l l y attempt t o mount a s e x u a l l y r e c e p t i v e female ( S o d e r s t e n , 1972). Indeed, i n some ca s e s b e h a v i o u r s c l o s e l y r e s e m b l i n g those d i s p l a y e d by male r a t s d u r i n g p e n i l e i n t r o m i s s i o n and e j a c u l a t i o n can be obser v e d i n s t e r o i d - p r i m e d females t h a t have been p l a c e d w i t h r e c e p t i v e s t i m u l u s f e m a l e s . I f 8-OH DPAT were found t o i n h i b i t male s e x u a l b e h a v i o u r i n fe m a l e s , as i t had been found t o i n h i b i t l o r d o s i s i n females i n Experiment 5a, then i t c o u l d be c o n c l u d e d t h a t the drug has a gender-dependent and p o s s i b l y n o n - s p e c i f i c i n h i b i t o r y e f f e c t on s e x u a l b e h a v i o u r i n f e m a l e s . However, i f 8-OH DPAT were found t o f a c i l i t a t e male s e x u a l b e h a v i o u r i n f e m a l e s , as i t has been found t o do i n males ( A h l e n i u s e t a l . , 1981), then i t might be c o n c l u d e d t h a t the drug a c t s i n a b e h a v i o u r - r a t h e r than a gender- dependent manner. Such a r e s u l t would make i t seem u n l i k e l y t h a t the i n h i b i t i o n of l o r d o s i s by 8-OH DPAT i s due t o t o x i c i t y , motor impairment, or some o t h e r n o n - s p e c i f i c e f f e c t . T h e r e f o r e , i n Experiment 5b I e v a l u a t e d the e f f e c t of 8-OH DPAT upon the d i s p l a y of male s e x u a l b e h a v i o u r i n females t h a t had been c h r o n i c a l l y t r e a t e d w i t h t e s t o s t e r o n e . Method Females were d i v i d e d i n t o 3 groups of 9 a n i m a l s , and a l l a n i m a l s r e c e i v e d d a i l y i n j e c t i o n s of 100 Mg t e s t o s t e r o n e 77 p r o p i o n a t e ( T P ) . On day 21 of TP t r e a t m e n t , the f i r s t group r e c e i v e d 1 mg/kg of 8-OH DPAT, the second group r e c e i v e d 0.1 mg/kg 8-OH DPAT, and the t h i r d group r e c e i v e d the s a l i n e - N a B r v e h i c l e 30 min p r i o r t o b e h a v i o u r a l t e s t i n g . B e h a v i o u r a l T e s t i n g B e h a v i o u r a l t e s t i n g i n v o l v e d p r e s e n t a t i o n of a s t i m u l u s female t o an e x p e r i m e n t a l female i n a Pyrex t e s t i n g a r e n a . S e x u a l r e c e p t i v i t y was induced i n s t i m u l u s female r a t s by the a d m i n i s t r a t i o n of 10 /jg EB 48 hr and 500 uq p r o g e s t e r o n e 4 hr p r i o r t o t e s t i n g . The T P - t r e a t e d females were p l a c e d i n t e s t i n g a r e nas and a l l o w e d 10 min t o h a b i t u a t e t o t h e arena b e f o r e p r e s e n t a t i o n of r e c e p t i v e s t i m u l u s f e m a l e s . The b e h a v i o u r a l parameters a n a l y z e d were the number of a n i m a l s mounting, the number of a n i m a l s d i s p l a y i n g i n t r o m i s s i o n - l i k e b e h a v i o u r , mount l a t e n c y , i . e . , time from p r e s e n t a t i o n of the s t i m u l u s female t o the f i r s t mount w i t h p e l v i c t h r u s t i n g ; i n t r o m i s s i o n l a t e n c y , i . e . , time from p r e s e n t a t i o n t o the f i r s t d i s p l a y of i n t r o m i s s i o n - l i k e b e h a v i o u r ; , mount f r e q u e n c y , i n t r o m i s s i o n f r e q u e n c y , and c o p u l a t o r y e f f i c i e n c y . The d i s p l a y of male s e x u a l b e h a v i o u r by each female was ob s e r v e d f o r 30 min and s t i m u l u s females were s h i f t e d a t 10 min i n t e r v a l s . R e s u l t s and D i s c u s s i o n The d a t a d i s p l a y e d i n Table 1 show t h a t the a d m i n i s t r a t i o n of 8-OH DPAT enhanced the e x p r e s s i o n of male s e x u a l b e h a v i o u r i n females t r e a t e d w i t h t e s t o s t e r o n e . T h i s f a c i l i t a t i o n was most apparent i n the i n c r e a s e d mount f r e q u e n c y , and i n the number of 78 TABLE 1. The e f f e c t s of 8 - h y d r o x y - 2 - ( d i - n - p r o p y l a m i n o ) t e t r a l i n (8-OH DPAT) on the e x p r e s s i o n of male s e x u a l b e h a v i o u r by ovar i e c t o m i z e d females c h r o n i c a l l y a d m i n i s t e r e d 100 jug t e s t o s t e r o n e p r o p i o n a t e . T H E E F F E C T S OF 8-OH DPAT ON T H E EXPRESSION OF M A L E S E X U A L BEHAVIOR BY OVARIECTOMIZED F E M A L E S C H R O N I C A L L Y ADMINISTERED TESTOSTERONE PROPIONATE 0.1 mg/kg 1.0 mg/kg Behavioral Parameter Control 8-OH DPAT 8-OH DPAT Number of animals 3 5 8 mounting Number of animals 0 2 3 intromitting Mount 1312.89 ± 206.0 978.44 ± 285.6 579.11 ± 236 latency Intromission 1800.00 ± 0.00 1575.33 ± 1.91 1287.22 ± 256 latency Mount 0.08 ± 0.04 0.53 ± 0.2 0.56 ± 0.15 frequency Intromission 0.00 ± 0.00 0.01 ± 0.01 0.03 ± 0.02 frequency Copulatory 0.00 ± 0.00 0.01 ± 0.01 0.04 ± 0.02 efficiency Values are means ± S.F..M. All latencies are in seconds; frequency scores are per minute; and copulatory efficiency scores are calculated from the formula 1/1 +M, where I = number of intromissions and M = number of mounts in 30 min. 80 a n i m a l s showing mounting b e h a v i o u r . Treatment w i t h 8-OH DPAT a l s o produced a s m a l l , but n o t a b l e i n c r e a s e i n the number of a n i m a l s showing i n t r o m i s s i o n b e h a v i o u r , and t h i s was r e f l e c t e d t o a s m a l l degree i n the i n t r o m i s s i o n l a t e n c y and c o p u l a t o r y e f f i c i e n c y s c o r e s . The s i g n i f i c a n c e of the e f f e c t s of 8-OH DPAT on the number of a n i m a l s d i s p l a y i n g mounting and i n t r o m i t t i n g b e h a v i o u r was e v a l u a t e d by a Chi square t e s t . The d i f f e r e n c e s i n the number of mounting a n i m a l s approached s i g n i f i c a n c e , x 2 ( 2 ) = 5 . 8 3 , p<.0542.The o t h e r parameters were e v a l u a t e d i n s e p a r a t e a n a l y s e s of v a r i a n c e f o r independent groups. 8-OH DPAT was found t o s i g n i f i c a n t l y i n c r e a s e the mount f r e q u e n c y , F (2, 24) =3.39, p_<.05. However, subsequent use of the Newman-Keuls method d i d not r e v e a l a dose dependent e f f e c t of 8-OH DPAT. G e n e r a l D i s c u s s i o n In Experiment 5a, the h i g h l y s e l e c t i v e 5-HT,A a g o n i s t 8-OH DPAT was found t o su p p r e s s l o r d o s i s b e h a v i o u r i n e s t r o g e n - p r i m e d f e m a l e s . However, the drug was found t o s l i g h t l y f a c i l i t a t e the e x p r e s s i o n of male s e x u a l b e h a v i o u r i n females a t doses even h i g h e r than those s u f f i c i e n t t o e l i m i n a t e l o r d o s i s . The l a t t e r d a t a would i n d i c a t e t h a t the e f f e c t of 8-OH DPAT was not due s i m p l y t o t o x i c i t y or motor impairment. Together, t h e s e r e s u l t s suggest t h a t the c l a s s i c a l l o r d o s i s - i n h i b i t i n g e f f e c t s of s e r o t o n i n a r e mediated a t l e a s t p a r t i a l l y by a c t i v i t y a t 5-HT,A r e c e p t o r s . A v a r i e t y of 5-HT a g o n i s t s , i n c l u d i n g LSD ( E v e r i t t et a l . , 1975), N , N - d i m e t h y l t r y p t a m i n e , and 5-methoxy-N,N-81 d i m e t h y l t r y p t a m i n e (Fuxe e t a l . , 1976), have been r e p o r t e d t o i n h i b i t l o r d o s i s b e h a v i o u r . A r e c e n t r e p o r t i n d i c a t e s t h a t LSD b i n d s t o bo t h 5-HT,A and 5-HT,B r e c e p t o r s ( S i l l s , Wolfe & F r a z e r , 1984). The a g o n i s t s 5-methoxy-N,N-dimethyltryptamine and N , N - d i m e t h y l t r y p t a m i n e a l s o b i n d t o both 5-HT, r e c e p t o r s u b t y p e s ; a l t h o u g h , w i t h some s e l e c t i v i t y f o r the 5-HT,A subtype ( S i l l s et a l , 1984). These d a t a a r e c o n s i s t e n t w i t h the p o s s i b i l i t y of an i n h i b i t o r y e f f e c t of a c t i v i t y a t 5~HT,A r e c e p t o r s on l o r d o s i s b e h a v i o u r . I t i s of i n t e r e s t t o note t h a t a number of the 5-HT, a g o n i s t s t h a t have been r e p o r t e d t o i n h i b i t l o r d o s i s , i n c l u d i n g LSD ( E v e r i t t e t a l , 1975), N , N - d i m e t h y l t r y p t a m i n e , 5-methoxy-N , N - d i m e t h y l t r y p t a m i n e , and p s i l o c y b i n (Fuxe e t a l , 1976) have a l s o been r e p o r t e d t o f a c i l i t a t e l o r d o s i s i n e s t r o g e n - p r i m e d r a t s when a d m i n i s t e r e d i n v e r y low doses. These f a c i l i t a t o r y e f f e c t s of the 5-HT a g o n i s t s have been c o n s i d e r e d t o be the r e s u l t of p r e s y n a p t i c i n h i b i t i o n of s e r o t o n e r g i c a c t i v i t y ( E v e r i t t e t a l , 1975; Fuxe et a l , 1976). The synapse i s the p o i n t of c o n t a c t where a neuron r e l e a s e s i t s n e u r o t r a n s m i t t e r onto the t a r g e t neruon. A l t h o u g h most s e r o t o n i n r e c e p t o r s a r e l o c a t e d on the t a r g e t neuron ( p o s t s y n a p t i c ) , some s e r o t o n i n r e c e p t o r s a r e l o c a t e d on the s e r o t o n e r g i c neuron i t s e l f ( p r e s y n a p t i c ) . When the s e r o t o n e r g i c neuron f i r e s and r e l e a s e s i t s s e r o t o n i n , most of t h a t s e r o t o n i n reaches the t a r g e t neuron and a c t i v a t e s the p o s t s y n a p t i c s e r o t o n i n r e c e p t o r s . However, some of t h i s s e r o t o n i n may d i f f u s e back toward the s e r o t o n e r g i c neruon and b i n d t o p r e s y n a p t i c r e c e p t o r s . When p r e s y n a p t i c s e r o t o n i n r e c e p t o r s ( a u t o r e c e p t o r s ) a r e a c t i v a t e d , the r e s u l t i s 82 a d e c r e a s e i n the f i r i n g r a t e of the s e r o t o n e r g i c neuron and a de c r e a s e i n the amount of s e r o t o n i n r e l e a s e d a t the synapse. T h i s p r o c e s s , known as p r e s y n a p t i c i n h i b i t i o n , i s b e l i e v e d t o be one means by which s e r o t o n e r g i c neurons can r e g u l a t e t h e i r f i r i n g r a t e s . The p o s s i b i l i t y t h a t 8-OH DPAT p r e s y n a p t i c a l l y i n h i b i t s s e r o t o n e r g i c a c t i v i t y remains c o n t r o v e r s i a l . One group of a u t h o r s has r e p o r t e d t h a t 8-OH DPAT i n h i b i t s the d e p o l a r i z a t i o n - i n d u c e d r e l e a s e of [ 3H]5-HT from c o r t i c a l t i s s u e ( G o z l a n , Mestikawy, Bougoin, H a l l , P i c h a t , G l o w i n s k i & Hamon, 1983); however, another group has found the drug t o be i n a c t i v e a t a u t o r e c e p t o r s ( M i d d l e m i s s , 1984). In the p r e s e n t e x p e r i m e n t , the o n l y e f f e c t s of 8-OH DPAT upon l o r d o s i s b e h a v i o u r were i n h i b i t o r y . I f p r e s y n a p t i c i n h i b i t i o n of s e r o t o n e r g i c a c t i v i t y per se f a c i l i t a t e s l o r d o s i s b e h a v i o u r , then the p r e s e n t d a t a a r e c o n s i s t e n t w i t h the c o n c l u s i o n t h a t 8-OH DPAT i s i n a c t i v e a t a u t o r e c e p t o r s . However, l i s u r i d e , a n o t h e r h i g h l y s e l e c t i v e 5-HT,A a g o n i s t ( S.J. P e r o u t k a , p e r s o n a l c o m m u n i c a t i o n ) , has been r e p o r t e d t o p r e s y n a p t i c a l l y i n h i b i t s e r o t o n e r g i c a c t i v i t y (Rogawski & A g h a j a n i a n , 1979). As w i t h 8-OH DPAT, the o n l y r e p o r t e d e f f e c t s of l i s u r i d e upon l o r d o s i s b e h a v i o u r have been i n h i b i t o r y ( S i e t n i e k s , 1985). I t may be t h a t the p o s t s y n a p t i c l o r d o s i s - i n h i b i t i n g e f f e c t s of thes e drugs a re s i m p l y dominant over any p r e s y n a p t i c e f f e c t s . I have suggested t h a t 8-OH DPAT i n h i b i t s l o r d o s i s b e h a v i o u r by a c t i n g a t 5-HT,A r e c e p t o r s . However, i t has been r e p o r t e d t h a t some e f f e c t s of 8-OH DPAT are a t t e n u a t e d by the dopamine a n t a g o n i s t h a l o p e r i d o l and the a, a d r e n o c e p t o r a n t a g o n i s t p r a z o s i n ( T r i c k l e b a n k , F o r l e r & F o z a r d , 1985). Thus, i t c o u l d be 83 t h a t the i n h i b i t o r y e f f e c t s of 8-OH DPAT on l o r d o s i s b e h a v i o u r a r e mediated by dopaminergic or a, a d r e n e r g i c mechanisms. The r o l e of dopamine i n the m o d u l a t i o n of female s e x u a l b e h a v i o u r remains c o n t r o v e r s i a l . For example, t h e r e a r e r e p o r t s of l o r d o s i s f a c i l i t a t i o n f o l l o w i n g t r e atment w i t h e i t h e r the dopamine a n t a g o n i s t p i m o z i d e ( E v e r i t t e t a l . , 1975) or the dopamine a g o n i s t apomorphine (Foreman & Moss, 1979). In view of t h i s c o n t r o v e r s y , the p o s s i b i l i t y of dopaminergic m e d i a t i o n of the i n h i b i t o r y e f f e c t s of 8-OH DPAT on l o r d o s i s b e h a v i o u r cannot be r u l e d o u t . S i m i l a r l y , the r o l e of a c t i v i t y a t a - a d r e n e r g i c r e c e p t o r s i n female s e x u a l b e h a v i o u r remains i l l - d e f i n e d . In one case the c e n t r a l a d m i n i s t r a t i o n of the a - a d r e n e r g i c b l o c k e r s p h entolamine or phenoxybenzamine was r e p o r t e d t o f a c i l i t a t e l o r d o s i s i n e s t r o g e n - p r i m e d females (Foreman & Moss, 1978b). However, i n another case the p e r i p h e r a l a d m i n i s t r a t i o n of phenoxybenzamine or p r a z o s i n was r e p o r t e d t o be i n e f f e c t i v e i n e s t r o g e n - p r i m e d f e m a l e s , and i n h i b i t o r y i n females t r e a t e d w i t h b oth e s t r o g e n and p r o g e s t e r o n e ( F e r n a n d e z - G u a s t i , L a r s s o n & Beyer, 1985). N o t w i t h s t a n d i n g the c o n t r a d i c t i o n s w i t h i n the l i t e r a t u r e , the p o s s i b i l i t y remains t h a t the e f f e c t s of 8-OH DPAT on l o r d o s i s were mediated by an a d r e n e r g i c system. EXPERIMENT 6 In Experiment 5, the s e l e c t i v e 5-HT,A a g o n i s t 8-OH DPAT was found t o i n h i b i t l o r d o s i s b e h a v i o u r . I t was h y p o t h e s i z e d t h a t the l o r d o s i s - i n h i b i t i n g e f f e c t s of s e r o t o n i n a r e mediated a t l e a s t p a r t i a l l y by a c t i v i t y a t 5-HT,A r e c e p t o r s . The p u t a t i v e 84 a n x i o l y t i c drugs b u s p i r o n e , TVX Q 7821 ( i p s a p i r o n e ) ( P e r o u t k a , 1985) and g e p i r o n e ( p e r s o n a l communication, Dr. S.J. P e r o u t k a ) have a l s o been found t o b i n d s e l e c t i v e l y and w i t h h i g h a f f i n i t y t o 5-HT,A r e c e p t o r s i t e s . These drugs may a c t as a g o n i s t s or p a r t i a l a g o n i s t s a t 5-HT,A r e c e p t o r s (Smith and P e r o u t k a , 1986; E i s o n et a l . , 1986). In view of the r e s u l t s of Experiment 5, i t was of i n t e r e s t t o determine what e f f e c t the a d m i n i s t r a t i o n of these 5 - H T 1 A - s e l e c t i v e drugs would have on l o r d o s i s b e h a v i o u r . In Experiment 5, the e f f e c t s of 8-OH DPAT were e v a l u a t e d o n l y i n females t h a t had r e c e i v e d e s t r o g e n a l o n e . I n t e r e s t i n g l y , t h e r e i s e v i d e n c e i n the l i t e r a t u r e t h a t the e f f e c t s of some s e r o t o n e r g i c drugs on l o r d o s i s may be a l t e r e d by t r e a t m e n t w i t h p r o g e s t e r o n e . For example, p r o g e s t e r o n e has been r e p o r t e d t o enhance b o t h the f a c i l i t a t o r y and the i n h i b i t o r y e f f e c t s of LSD on l o r d o s i s b e h a v i o u r ( S i e t n i e k s and Meyerson, 1980, 1983). T h e r e f o r e , i n Experiment 6 the e f f e c t s of b u s p i r o n e , i p s a p i r o n e , and g e p i r o n e upon l o r d o s i s b e h a v i o u r were e v a l u a t e d . Because of p o s s i b l e i n t e r a c t i o n s between th e s e s e r o t o n e r g i c a g o n i s t s and p r o g e s t e r o n e , the e f f e c t s of t h e s e drugs were e v a l u a t e d i n a n i m a l s t h a t had been a d m i n i s t e r e d e i t h e r e s t r o g e n , or e s t r o g e n and p r o g e s t e r o n e . Methods Drugs B u s p i r o n e HC1 ( b u s p i r o n e ) and g e p i r o n e HCl ( g e p i r o n e ) were o b t a i n e d as g i f t s from the B r i s t o l - M e y e r s Company, as was i p s a p i r o n e from M i l e s L a b o r a t o r i e s . A l l drugs were a d m i n i s t e r e d 85 i n t r a p e r i t o n e a l l y i n a p p r o x i m a t e l y 0.3 ml of s a l i n e v e h i c l e . Drugs were a d m i n i s t e r e d b l i n d . P r o c e d u r e s In Experiment 6a, the dose responses t o b u s p i r o n e , g e p i r o n e , and i p s a p i r o n e were det e r m i n e d i n e s t r o g e n - t r e a t e d f e m a l e s . A l l females r e c e i v e d 10 uq EB 48 h, and each of 5 groups r e c e i v e d e i t h e r 0, 0.1, 0.3, 1, or 3 mg/kg of the e x p e r i m e n t a l drug 45 min p r i o r t o b e h a v i o u r a l t e s t i n g . In Experiment 6b, i d e n t i c a l p r o c e d u r e s were f o l l o w e d except t h a t a n i m a l s a l s o r e c e i v e d 500 jug p r o g e s t e r o n e 4-6 h p r i o r t o b e h a v i o u r a l t e s t i n g . R e s u l t s In Experiment 6a, i n which females r e c e i v e d EB a l o n e , lower doses of b u s p i r o n e , i p s a p i r o n e , and g e p i r o n e produced i n c r e a s e s i n l o r d o t i c a c t i v i t y . At the h i g h e s t dose of each drug ( F i g . 6 ) , l o r d o s i s b e h a v i o u r was v i r t u a l l y e l i m i n a t e d . A n a l y s e s of v a r i a n c e c o n f i r m e d s i g n i f i c a n t e f f e c t s of b u s p i r o n e , F(4,70) = 6.06,2<.0003; i p s a p i r o n e , F(4,70)=9.53,p_<.000l ; and gepirone,F(4,55)=5.76,p<.0007. By the Newman-Keuls method i t was de t e r m i n e d t h a t 0.1 mg/kg i p s a p i r o n e (p_<.05) and 0.3 mg/kg g e p i r o n e (p_<.05) f a c i l i t a t e d l o r d o s i s b e h a v i o u r . L o r d o s i s was i n h i b i t e d by 3 mg/kg of e i t h e r b u s p i r o n e (p_<.05) or i p s a p i r o n e (p_<.05). However, the apparent f a c i l i t a t o r y e f f e c t of b u s p i r o n e and i n h i b i t o r y e f f e c t of g e p i r o n e were not s t a t i s t i c a l l y s i g n i f i c a n t . In females t r e a t e d w i t h EB and p r o g e s t e r o n e , i n c r e a s i n g 86 F i g . 6. Mean l o r d o s i s q u o t i e n t s ± S.E.M. of female r a t s primed w i t h 10 uq e s t r a d i o l benzoate ( E B ) , or w i t h 10 uq e s t r a d i o l benzoate and 500 uq p r o g e s t e r o n e (EB+P), f o l l o w i n g the a d m i n i s t r a t i o n of v a r y i n g doses of b u s p i r o n e , i p s a p i r o n e , or g e p i r o n e . MEAN LORDOSIS QUOTIENT % MEAN LORDOSIS QUOTCNT % MEAN LORDOSIS QUOTIENT % o « 8 8 S S 8 3 S 8 § O S 8 8 S 8 8 3 8 8 8 o 6 8 8 £ 8 8 3 8 8 § 1 1 1 1 1 1 ' 1 1 1 1 I 1 -1——1 I I U t I I I I I I i ' o 8 8 8 S 8 8 3 § 8 § o S 8 8 S 8 8 3 8 8 S o s 8 8 S 8 8 3 8 8 § I 1 1 1 1 1 1 1 1 1 ! ' 1 1 1 1 1 I I I I I I I I f 88 a n i m a l s showing mounting b e h a v i o u r , doses of b u s p i r o n e , g e p i r o n e , and i p s a p i r o n e r e s u l t e d i n p r o g r e s s i v e l y reduced d i s p l a y of l o r d o s i s b e h a v i o u r ( F i g . 6 ) . A n a l y s e s of v a r i a n c e c o n f i r m e d the i n h i b i t o r y e f f e c t s of b u s p i r o n e ,F(4 ,55) = 19.86, P<.0001; i p s a p i r o n e F ( 4 , 50) =20 . 62 , p_<.000l; and g e p i r o n e , F(4,50)=22.55, £<.0001. By the Newman-Keuls method i t was de t e r m i n e d t h a t 0.3 mg/kg b u s p i r o n e s i g n i f i c a n t l y i n h i b i t e d l o r d o s i s b e h a v i o u r (p_<.05), and t h a t 1.0 and 3.0 mg/kg b u s p i r o n e were s t i l l more e f f e c t i v e (p<.05). I t was a l s o d e t e r m i n e d t h a t 1.0 mg/kg i p s a p i r o n e i n h i b i t e d l o r d o s i s b e h a v i o u r (p_<.05), and s t i l l f u r t h e r i n h i b i t i o n was produced by 3.0 mg/kg i p s a p i r o n e (p_<.05). The 0.3 and 1.0 mg/kg doses of g e p i r o n e a l s o i n h i b i t e d l o r d o s i s b e h a v i o u r (p_<.05), and f u r t h e r i n h i b i t i o n was produced by the 3.0 mg/kg dose (p_<.05). D i s c u s s i o n In Experiment 6, the h i g h e s t doses of b u s p i r o n e , i p s a p i r o n e , and g e p i r o n e v i r t u a l l y e l i m i n a t e d the d i s p l a y of l o r d o s i s b e h a v i o u r i n females t r e a t e d w i t h e s t r o g e n . These r e s u l t s a r e c o n s i s t e n t w i t h the p o s s i b i l i t y t h a t a c t i v i t y a t 5-HT,A r e c e p t o r s i n h i b i t s l o r d o s i s . However, lower doses of i p s a p i r o n e and g e p i r o n e were found t o f a c i l i t a t e l o r d o s i s i n th e s e a n i m a l s . F a c i l i t a t o r y e f f e c t s of some 5-HT a g o n i s t s have been a t t r i b u t e d t o a r e d u c t i o n i n s e r o t o n e r g i c a c t i v i t y t h r ough p r e s y n a p t i c i n h i b i t i o n ( S i e t n i e k s and Meyerson, 1983). The p r e s e n t r e s u l t s a r e c o n s i s t e n t w i t h t h i s e x p l a n a t i o n , as i p s a p i r o n e ( D o u r i s h e t a l . , 1986) and g e p i r o n e ( E i s o n et a l . , 1986) have both been found t o reduce a c t i v i t y i n the d o r s a l 89 raphe. A l t h o u g h b u s p i r o n e reduces s e r o t o n e r g i c a c t i v i t y ( D o u r i s h et a l . , 1986), the drug d i d not f a c i l i t a t e l o r d o s i s . I t i s p o s s i b l e t h a t some component p e c u l i a r t o the p h a r m a c o g i c a l p r o f i l e of b u s p i r o n e masked the appearance of f a c i l i t a t i o n . For example, u n l i k e i p s a p i r o n e and g e p i r o n e , b u s p i r o n e p o s s e s s e s a h i g h a f f i n i t y f o r dopamine r e c e p t o r s ( P e r o u t k a , 1986; E i s o n et a l . , 1986). 8-OH DPAT a l s o i n h i b i t e d , but d i d not f a c i l i t a t e l o r d o s i s i n e s t r o g e n - t r e a t e d females (see Experiment 5) As w i t h b u s p i r o n e i n the p r e s e n t s t u d y , a s m a l l i n c r e a s e i n l o r d o t i c a c t i v i t y was observed a t the l o w e s t dose of 8-OH DPAT, however t h i s i n c r e a s e was not s i g n i f i c a n t . Of p a r t i c u l a r i n t e r e s t i n the p r e s e n t s t u d y a r e the d i f f e r e n c e s i n the e f f e c t s of b u s p i r o n e , i p s a p i r o n e and g e p i r o n e when a d m i n i s t e r e d t o females t r e a t e d w i t h e s t r o g e n and p r o g e s t e r o n e as opposed t o those t r e a t e d w i t h e s t r o g e n a l o n e . Doses of t h e s e drugs t h a t had e i t h e r f a c i l i t a t e d l o r d o s i s or been i n e f f e c t i v e i n a n i m a l s t r e a t e d w i t h e s t r o g e n a l o n e were found t o i n h i b i t l o r d o s i s b e h a v i o u r i n a n i m a l s t r e a t e d w i t h both s t e r o i d s . I t has been h y p o t h e s i z e d t h a t p r o g e s t e r o n e enhances l o r d o s i s b e h a v i o u r i n e s t r o g e n - p r i m e d females by r e d u c i n g s e r o t o n e r g i c a c t i v i t y (Kow, M a l s b u r y & P f a f f , 1974). Thus, the a d m i n i s t r a t i o n of the 5-HT,A a g o n i s t may have r e s t o r e d s e r o t o n e r g i c a c t i v i t y and s i m p l y reduced l e v e l s of l o r d o s i s b e h a v i o u r t o those o b s e r v e d i n females w i t h e s t r o g e n a l o n e . In a n i m a l s primed w i t h e s t r o g e n a l o n e , s m a l l i n c r e a s e s i n s e r o t o n e r g i c a c t i v i t y may be of l i t t l e consequence. On the o t h e r hand, t h e s e data suggest t h a t p r o g e s t e r o n e may enhance the 90 e f f e c t s of a c t i v i t y a t 5-HT,A r e c e p t o r s . T h i s p o s s i b i l i t y i s c o n s i s t e n t w i t h the r e p o r t t h a t b o t h the l o r d o s i s - i n h i b i t i n g e f f e c t s of l a r g e doses and the l o r d o s i s - f a c i i i t a t i n g e f f e c t s of s m a l l doses LSD a r e enhanced by tre a t m e n t w i t h p r o g e s t e r o n e ( S i e t n i e k s and Meyerson, 1980, 1983). A l t h o u g h n o n - s e l e c t i v e i n i t s b i n d i n g , LSD i s known t o b i n d w i t h v e r y h i g h a f f i n i t y t o 5-HT!A r e c e p t o r s ( E n g e l e t a l . , 1986). E v i d e n c e of the a b i l i t y of p r o g e s t e r o n e t o enhance the l o r d o s i s - f a c i l i t a t i n g e f f e c t s of 5-HT,A a g o n i s t s was not apparent i n the p r e s e n t s t u d y , a l t h o u g h i t i s p o s s i b l e t h a t i t may have been o b s e r v e d had s m a l l e r doses of p r o g e s t e r o n e or the 5-HT,A a g o n i s t s been a d m i n i s t e r e d . The e f f e c t i v e n e s s of b u s p i r o n e , i p s a p i r o n e , and g e p i r o n e 45 min a f t e r a d m i n i s t r a t i o n i n the p r e s e n t study appears t o c o n t r a s t w i t h the r e p o r t t h a t b u s p i r o n e and i p s a p i r o n e f a i l t o induce symptoms of s e r o t o n i n syndrome a t t h i s time (Smith and P e r o u t k a , 1986). I t s h o u l d be n o t e d , however, t h a t 8-OH DPAT a l s o e f f e c t s l o r d o s i s b e h a v i o u r a t tim e s and doses a t which i t does not induce symptoms of s e r o t o n i n syndrome (Experiment 5; Smith and P e r o u t k a , 1986). These d a t a suggest t h a t the n e u r a l s u b s t r a t e of l o r d o s i s b e h a v i o u r may be more s e n s i t i v e t o s e r o t o n e r g i c s t i m u l a t i o n than the s u b s t r a t e ( s ) of s e r o t o n i n syndrome. EXPERIMENT 7 The s e l e c t i v e 5-HT,A a g o n i s t s i p s a p i r o n e and g e p i r o n e have been b e h a v i o u r i n females primed e i t h e r 8-OH DPAT, b u s p i r o n e , found t o i n h i b i t l o r d o s i s w i t h e s t r o g e n , or w i t h 91 e s t r o g e n and p r o g e s t e r o n e . These d a t a suggest t h a t p o s t s y n a p t i c 5 - H T T A r e c e p t o r s mediate i n h i b i t o r y e f f e c t s of s e r o t o n i n on l o r d o s i s b e h a v i o u r . At lower doses, i p s a p i r o n e and g e p i r o n e were found t o f a c i l i t a t e l o r d o s i s i n e s t r o g e n primed f e m a l e s . These d a t a suggest t h a t s o m a t o - d e n d r i t i c 5-HT,A a u t o r e c e p t o r s may mediate l o r d o s i s - f a c i l i t a t i n g e f f e c t s of s e r o t o n i n . O s t e n s i b l y , t h i s would be due t o r e d u c t i o n s i n the a c t i v i t y of c e r t a i n l o r d o s i s - i n h i b i t i n g s e r o t o n e r g i c pathways. I f a c t i v i t y a t p o s t s y n a p t i c 5-HT,A r e c e p t o r s i n h i b i t s l o r d o s i s b e h a v i o u r , then drugs t h a t b l o c k the e f f e c t s of s e r o t o n i n a t S-H^A r e c e p t o r s would be e x p e c t e d t o f a c i l i t a t e l o r d o s i s . U n t i l v e r y r e c e n t l y , t h e r e have been no drugs a v a i l a b l e t h a t a c t s e l e c t i v e l y as 5-H^A r e c e p t o r a n t a g o n i s t s . Recent e v i d e n c e i n d i c a t e s t h a t the new drug BMY 7378 a c t s as a s e l e c t i v e 5-HT,A a n t a g o n i s t (Yocca, H y s l o p , Smith & Maayani,1987). In the f o l l o w i n g e x p e r i m e n t s I w i l l e v a l u a t e the e f f e c t s of BMY 7378 on l o r d o s i s b e h a v i o u r i n females primed w i t h e s t r o g e n , or w i t h e s t r o g e n and p r o g e s t e r o n e . Methods Drugs BMY 7378 was o b t a i n e d as a g i f t from the B r i s t o l - M e y e r s Company. The drug was d i s s o l v e d i n warm s a l i n e and a d m i n i s t e r e d i n t r a p e r i t o n e a l l y i n a p p r o x i m a t e l y 0.3 ml of the v e h i c l e . The drug was a d m i n i s t e r e d b l i n d . 92 P r o c e d u r e s In Experiment 7, 10 females r e c e i v e d 10 uq EB 48 h and, over a p e r i o d of f i v e weekly t e s t s , e i t h e r 0, 0.04, 0.2, 1, or 5 mg/kg of the e x p e r i m e n t a l drug 30 min p r i o r t o b e h a v i o u r a l t e s t i n g i n a r e p e a t e d measures d e s i g n . For a second group of 10 f e m a l e s , i d e n t i c a l p r o c e d u r e s were f o l l o w e d e x c e p t t h a t a n i m a l s a l s o r e c e i v e d 500 uq p r o g e s t e r o n e 4-6 h p r i o r t o b e h a v i o u r a l t e s t i n g . R e s u l t s and D i s c u s s i o n Females a d m i n i s t e r e d e s t r o g e n and p r o g e s t e r o n e appeared somewhat more r e s p o n s i v e than females t h a t r e c e i v e d e s t r o g e n a l o n e . However, the d a t a d i s p l a y e d i n F i g . 7 show t h a t the dose response t o BMY 7378 was s i m i l a r i n each group. Low doses of BMY 7378 appeared t o produce s l i g h t i n c r e a s e s i n l o r d o s i s b e h a v i o u r , whereas the h i g h e s t dose of BMY 7378 appeared t o i n h i b i t l o r d o s i s b e h a v i o u r . An a n a l y s i s of v a r i a n c e c o n f i r m e d t h a t a n i m a l s t r e a t e d w i t h e s t r o g e n and p r o g e s t e r o n e were more r e s p o n s i v e than t h o s e t h a t r e c e i v e d e s t r o g e n a l o n e , F(1 , 18)=4.76,p_<.04. The a n a l y s i s a l s o c o n f i r m e d a s i g n i f i c a n t e f f e c t of i n c r e a s i n g doses of BMY 7378, F (4 , 72) = 4. 57 ,p_ <.003. Having found s i g n i f i c a n t e f f e c t s of both s t e r o i d t r e a t m e n t and dose of BMY 7378, d a t a were p a r t i t i o n e d t o examine the s i m p l e e f f e c t s of dose w i t h i n each s t e r o i d t r e a t m e n t group. The e f f e c t s of BMY 7378 were found not t o be s i g n i f i c a n t i n females t r e a t e d w i t h e s t r o g e n and p r o g e s t e r o n e . However, s i g n i f i c a n t dose e f f e c t s were found i n females t r e a t e d w i t h e s t r o g e n a l o n e 93 F i g . 7. Mean l o r d o s i s q u o t i e n t s ± S.E.M. of females primed w i t h 10 jug e s t r a d i o l benzoate or 10 Mg e s t r a d i o l benzoate and 500 Mg p r o g e s t e r o n e f o l l o w i n g the a d m i n i s t r a t i o n of v a r y i n g doses of BMY 7378 30 min p r i o r t o b e h a v i o u r a l t e s t i n g . % JLNBIiOnt) SISOQcJOl NV3h 95 F(4,36)=5.11 ,2<.002. B Y t n e Newman-Keuls method i t was de t e r m i n e d t h a t the 0.2 mg/kg dose of BMY 7378 produced l e v e l s of l o r d o s i s b e h a v i o u r s i g n i f i c a n t l y h i g h e r than t h o s e observed a f t e r t r e a t m e n t w i t h s a l i n e , (p_<.05). However, l o r d o s i s q u o t i e n t s were s i g n i f i c a n t l y lower a f t e r t r e a t m e n t w i t h 5 mg/kg of BMY 7378 than a f t e r t r e a t m e n t w i t h 0.2 mg/kg (p_<.05). In Experiment 7, the dose-response t o BMY 7378 appeared b i p h a s i c . Under both s t e r o i d t r e a t m e n t s , l o r d o s i s b e h a v i o u r was i n c r e a s e d a t the lower doses and d e c r e a s e d at the h i g h e r doses of the dr u g . I f BMY 7378 a c t s as 5-HT,A r e c e p t o r a n t a g o n i s t , then the apparent weak f a c i l i t a t o r y e f f e c t of the drug c o u l d be due t o b l o c k a d e of l o r d o s i s - i n h i b i t i n g a c t i v i t y a t p o s t - s y n a p t i c 5-HT,A r e c e p t o r s . However, i n view of the h y p o t h e s i s t h a t a c t i v i t y a t 5-HT,A r e c e p t o r s r e s u l t s i n i n h i b i t i o n of l o r d o s i s , i t seems u n l i k e l y t h a t a drug t h a t b l o c k s a c t i v i t y a t 5-HT,A r e c e p t o r s would produce l o r d o s i s - i n h i b i t i n g e f f e c t s . Of c o u r s e , one cannot r u l e out the p o s s i b i l i t y t h a t a c t i v i t y a t c e r t a i n 5-HT,A r e c e p t o r s i s n e c e s s a r y f o r the e x p r e s s i o n of l o r d o s i s b e h a v i o u r . However, i t would seem more l i k e l y t h a t BMY 7378 does not a c t as a pure a n t a g o n i s t , but r a t h e r a c t s as a weak, p a r t i a l a g o n i s t ( p a r t i a l a n t a g o n i s t ) . Indeed, i n the i n i t i a l r e p o r t on the e f f e c t s of BMY 7378 on s e r o t o n i n - s e n s i t i v e a d e n y l a t e c y c l a s e i n t he r a t hippocampus i t was r e p o r t e d t h a t BMY 7378 does, t o a v e r y s m a l l degree, mimic t h e e f f e c t s of s e r o t o n i n (Yocca e t a l . , 1987). I f BMY 7378 a c t s as a weak p a r t i a l a g o n i s t , then a low dose of the drug would tend t o b l o c k the e f f e c t s of s e r o t o n i n w i t h o u t i t s e l f p r o d u c i n g a s t r o n g s t i m u l a t i o n of 5-HT,A r e c e p t o r s . However a t h i g h e r doses, enough 5-HT,A r e c e p t o r s 96 might be a c t i v a t e d t o produce a l o r d o s i s - i n h i b i t i n g e f f e c t . In t h i s r e g a r d i t s h o u l d be noted t h a t v e r y r e c e n t e v i d e n c e i n d i c a t e s t h a t BMY 7378 a l s o produces a b i p h a s i c dose response i n male r a t s (Mendelson and G o r z a l k a , u n p u b l i s h e d d a t a ) . Moreover, as would be e x p e c t e d from a drug a c t i v e a t 5-HT,A r e c e p t o r s , the e f f e c t of the drug upon s e x u a l b e h a v i o u r i n males appears t o be the o p p o s i t e of t h a t observed i n fe m a l e s . In male r a t s , low doses of BMY 7378 i n c r e a s e the number of i n t r o m i s s i o n s p r i o r t o e j a c u l a t i o n , an e f f e c t commonly r e g a r d e d as an i n h i b i t o r y e f f e c t . H i g h doses of BMY 7378 d e c r e a s e the number of i n t r o m i s s i o n s p r i o r t o e j a c u l a t i o n . A de c r e a s e i n the number of i n t r o m i s s i o n s p r i o r t o e j a c u l a t i o n , c o n s i d e r e d a f a c i l i t a t o r y e f f e c t on male s e x u a l b e h a v i o u r , i s a l s o produced by the 5-HT,A a g o n i s t 8-OH DPAT ( A h l e n i u s e t a l . , 1981). These d a t a suggest t h a t BMY 7378 a c t s as p a r t i a l a g o n i s t and t e n d t o c o n f i r m the n o t i o n t h a t 5-HT,A r e c e p t o r s mediate i n h i b i t o r y e f f e c t s of s e r o t o n i n on l o r d o s i s b e h a v i o u r . EXPERIMENT 8 Exper i m e n t s 5, 6 and 7 have p r o v i d e d e v i d e n c e t h a t the l o r d o s i s - i n h i b i t i n g e f f e c t s of s e r o t o n i n a r e a t l e a s t p a r t i a l l y m e d iated by a c t i v i t y a t 5-HT,A r e c e p t o r s . Moreover, because low doses of some 5-HT,A a g o n i s t s f a c i l i t a t e l o r d o s i s i n e s t r o g e n -primed f e m a l e s , I have suggested t h a t a c t i v i t y a t s o m a t o d e n d r i t i c 5-HT,A a u t o r e c e p t o r s f a c i l i t a t e s l o r d o s i s . T h i s f a c i l i t a t i o n would l i k e l y be due t o d e c r e a s e s i n the a c t i v i t i e s 97 of l o r d o s i s - i n h i b i t i n g s e r o t o n e r g i c pathways. A l t h o u g h 5 - H T , A r e c e p t o r s appear t o i n h i b i t l o r d o s i s b e h a v i o u r , the r o l e t h a t might be p l a y e d by S - H T ^ B r e c e p t o r s i n the m o d u l a t i o n of l o r d o s i s remains unknown. R e c e n t l y , drugs have become a v a i l a b l e t h a t b i n d s e l e c t i v e l y t o 5 - H T , B r e c e p t o r s i n r a t b r a i n . 1 - ( 3 - T r i f l u o r o m e t h y l p h e n y l ) p i p e r a z i n e and m-c h l o r o p h e n y l p i p e r a z i n e a r e 5 - H T a g o n i s t s t h a t have r e c e n t l y been found t o b i n d w i t h some s e l e c t i v i t y t o 5 - H T , B r e c e p t o r s (Hamon, C o s s e r y , Spampinato and G o z l a n , 1986). In the f o l l o w i n g experiment I e v a l u a t e d the e f f e c t s of t h e s e 5 - H T T B a g o n i s t s on l o r d o s i s b e h a v i o u r . In o r d e r t o e v a l u a t e the p o s s i b l e i n t e r a c t i o n between 5 - H T , B a g o n i s t s and p r o g e s t e r o n e , such as appeared t o occur between 5 - H T ^ a g o n i s t s and p r o g e s t e r o n e i n Experiment 6; t h e s e drugs were e v a l u a t e d i n a n i m a l s primed e i t h e r w i t h e s t r o g e n or w i t h e s t r o g e n and p r o g e s t e r o n e . Method Drugs 1 - ( 3 - t r i f l u o r o m e t h y l p h e n y l ) p i p e r a z i n e (TFMPP) and m-c h l o r o p h e n y l p i p e r a z i n e (MCPP) were purchased from Research B i o c h e m i c a l s . Both drugs were d i s s o l v e d i n warm s a l i n e and a d m i n i s t e r e d i n t r a p e r i t o n e a l l y i n a p p r o x i m a t e l y 0.3 ml of the v e h i c l e . Drugs were a d m i n i s t e r e d b l i n d . P r o c e d u r e s In Experiment 8, the dose r e s p o n s e s t o TFMPP and MCPP were de t e r m i n e d i n e s t r o g e n - t r e a t e d f e m a l e s . In the t e s t i n g of each d r u g , 40 females r e c e i v e d 10 Mg EB 48 h, and each of 5 groups of 98 8 a n i m a l s r e c e i v e d e i t h e r 0, 0.04, 0.2, 1, or 5 mg/kg of the e x p e r i m e n t a l drug 30 min p r i o r t o b e h a v i o u r a l t e s t i n g . In the second s e r i e s of e x p e r i m e n t s , i d e n t i c a l p r o c e d u r e s were f o l l o w e d except t h a t a n i m a l s a l s o r e c e i v e d 500 jug p r o g e s t e r o n e 4-6 h p r i o r t o b e h a v i o u r a l t e s t i n g . R e s u l t s and D i s c u s s i o n As may be seen i n the t o p p a n e l of F i g . 8a, the lowe s t dose of TFMPP appeared t o be i n e f f e c t i v e , whereas doses from 0.2 t o 5 mg/kg of the drug produced d r a m a t i c i n c r e a s e s i n l o r d o s i s b e h a v i o u r i n e s t r o g e n - p r i m e d f e m a l e s . The l o r d o s i s - f a c i l i t a t i n g e f f e c t of TFMPP was c o n f i r m e d by an a n a l y s i s of v a r i a n c e , F(4,35)=8.53,p_<.000l . By the Newman-Keuls method i t was dete r m i n e d t h a t the 0.04 mg/kg dose of TFMPP was inde e d i n e f f e c t i v e . However, the 0.2, 1, and 5 mg/kg doses of the drug each produced s i g n i f i c a n t i n c r e a s e s i n l o r d o s i s (p_<.05). In the bottom p a n e l of F i g . 8a i t i s e v i d e n t t h a t doses of TFMPP up t o 1 mg/kg were i n e f f e c t i v e i n females primed w i t h e s t r o g e n and p r o g e s t e r o n e . However, the 5 mg/kg dose of the drug appeared t o produce a r e d u c t i o n i n the l e v e l of l o r d o s i s r e s p o n d i n g . By a n a l y s i s of v a r i a n c e i t was c o n f i r m e d t h a t TFMPP d i d indeed produce a s i g n i f i c a n t e f f e c t upon l o r d o s i s b e h a v i o u r i n females primed w i t h e s t r o g e n and p r o g e s t e r o n e , F(4,35)=4.695, p_<.004. By the Newman-Keuls method i t was found t h a t the s i g n i f i c a n t e f f e c t of TFMPP was due s o l e l y t o an i n h i b i t o r y e f f e c t of the 5 mg/kg dose. In the t o p p a n e l of F i g . 8b i t appears t h a t MCPP produced 99 F i g . 8a. Mean l o r d o s i s q u o t i e n t s ± S.E.M. of females primed w i t h 10 jug e s t r a d i o l benzoate (Top p a n e l ) or 10 jug e s t r a d i o l benzoate and 500 Mg p r o g e s t e r o n e (Bottom p a n e l ) f o l l o w i n g the a d m i n i s t r a t i o n of v a r y i n g doses of TFMPP 30 min p r i o r t o b e h a v i o u r a l t e s t i n g . MEAN LORDOSIS QUOTIENT % MEAN LORDOSIS QUOTIENT % M CM * . O O O _ J I L_ O _ L _ O _ l _ o _ L _ 00 <£> o o o o —1 1 I o o-. O I o • I o i _. 00 o TJ "0 m CO + 3 (O 101 F i g . 8b. Mean l o r d o s i s q u o t i e n t s ± S.E.M. of females primed w i t h 10 /ig e s t r a d i o l benzoate (Top p a n e l ) or 10 Mg e s t r a d i o l benzoate and 500 Mg p r o g e s t e r o n e (Bottom p a n e l ) f o l l o w i n g the a d m i n i s t r a t i o n of v a r y i n g doses of MCPP 30 min p r i o r t o b e h a v i o u r a l t e s t i n g . 103 an e f f e c t on l o r d o s i s s i m i l a r t o , though l e s s marked than TFMPP i n f e males primed w i t h e s t r o g e n a l o n e . A s l i g h t i n c r e a s e i n l o r d o s i s b e h a v i o u r can be noted a t the 1 mg/kg dose of the drug. However, an a n a l y s i s of v a r i a n c e i n d i c a t e d t h a t MCPP produced no s i g n i f i c a n t e f f e c t s upon l o r d o s i s i n females primed w i t h e s t r o g e n . MCPP was a l s o i n e f f e c t i v e i n females primed w i t h e s t r o g e n and p r o g e s t e r o n e ( F i g 8b, bottom p a n e l ) . In Experiment 8 the 5 - H T T B a g o n i s t TFMPP was found t o produce a s t r o n g f a c i l i t a t i o n of l o r d o s i s b e h a v i o u r i n females primed w i t h e s t r o g e n a l o n e . These d a t a suggest t h a t s t i m u l a t i o n of S - H T T B r e c e p t o r s f a c i l i t a t e s l o r d o s i s . 5 - H T T B r e c e p t o r s a r e b e l i e v e d t o a c t as p r e j u n c t i o n a l a u t o r e c e p t o r s ( E n g e l e t a l . , 1986). S t i m u l a t i o n of S - H ^ B a u t o r e c e p t o r s would be e x p e c t e d t o produce a de c r e a s e i n the r e l e a s e of s e r o t o n i n from the t e r m i n a l s of s e r o t o n e r g i c neurons. T h e r e f o r e , the l o r d o s i s -f a c i l i t a t i n g e f f e c t of TFMPP c o u l d a c t u a l l y be due t o a net de c r e a s e i n s e r o t o n e r g i c a c t i v i t y . I t s h o u l d be n o t e d , however, t h a t r e c e n t e v i d e n c e s u g g e s t s t h a t 5 - H ^ B r e c e p t o r s may a l s o e x i s t p o s t s y n a p t i c a l l y , t h a t i s , on the s u r f a c e of t a r g e t neurons ( K e n n e t t , D o u r i s h & Curzon, 1987). Indeed, i n the p r e s e n t s t u d y , e s t r o g e n - p r i m e d females r e c e i v i n g the h i g h e s t (5 mg/kg) dose of TFMPP showed s i g n i f i c a n t enhancement of l o r d o s i s b e h a v i o u r w h i l e a t the same time e x h i b i t i n g symptoms of the s e r o t o n i n syndrome, p a r t i c u l a r l y low p o s t u r e and abducted h i n d l i m b s . The d i s p l a y of thes e symptoms i s g e n e r a l l y regarded t o be i n d i c a t i v e of p o s t s y n a p t i c s e r o t o n e r g i c s t i m u l a t i o n . T o g e t h e r , th e s e d a t a open the p o s s i b i l i t y t h a t the l o r d o s i s -f a c i l i t a t i n g e f f e c t of TFMPP i s due t o a mechanism o t h e r than a 1 0 4 net r e d u c t i o n of s e r o t o n e r g i c a c t i v i t y . I n t e r e s t i n g l y , the 5 mg/kg dose of TFMPP produced a s i g n i f i c a n t i n h i b i t i o n of l o r d o s i s i n females primed w i t h e s t r o g e n and p r o g e s t e r o n e . I t c o u l d be t h a t the l o r d o s i s -i n h i b i t i n g e f f e c t of a c t i v i t y a t a c e r t a i n p o p u l a t i o n of 5 - H T , B r e c e p t o r s i s enhanced by exposure t o p r o g e s t e r o n e . However, i t s h o u l d be n o t e d t h a t w h i l e TFMPP b i n d s w i t h h i g h e s t a f f i n i t y t o 5 - H T , B r e c e p t o r s , i t does not b i n d s e l e c t i v e l y t o the s e s i t e s Indeed, whereas the a b i l i t y of TFMPP t o s t i m u l a t e the 5-HT,A r e c e p t o r appears t o be low (Sprouse & A g h a j a n i a n , 1 9 8 7 ) , i t does have a s i g n i f i c a n t l y h i g h a f f i n i t y f o r the s e r e c e p t o r s (Hamon, C o s s e r y , Spampinato & G o z l a n , 1 9 8 6 ) . In view of what appears t o be the a b i l i t y of p r o g e s t e r o n e t o enhance the e f f e c t s of a c t i v a t i o n of 5-HT,A r e c e p t o r s (Experiment 6 ) , i t i s t e m p t i n g t o suggest t h a t the i n h i b i t o r y e f f e c t of the h i g h dose of TFMPP i n females primed w i t h e s t r o g e n and p r o g e s t e r o n e was due t o a c t i v a t i o n of 5-HT,A s i t e s . In Experiment 8 , the 5 - H T T B a g o n i s t MCPP produced a s l i g h t i n c r e a s e i n l o r d o s i s b e h a v i o u r i n females primed w i t h e s t r o g e n ; however, t h i s e f f e c t was not s i g n i f i c a n t . The drug was c o m p l e t e l y i n e f f e c t i v e i n females primed w i t h e s t r o g e n and p r o g e s t e r o n e . The d i f f e r e n c e i n the e f f e c t s of MCPP and TFMPP c o u l d be a t l e a s t p a r t i a l l y due t o d i f f e r e n c e s i n a f f i n i t y f o r the 5-HT , B s i t e . The a f f i n i t y of TFMPP f o r the 5 -H T T B r e c e p t o r appears t o be r o u g h l y 3 t i m e s h i g h e r than t h a t of MCPP (Hamon et a l . , 1 9 8 6 ) . D i f f e r e n c e s i n the responses t o t h e s e drugs c o u l d a l s o p a r t i a l l y be due t o d i f f e r e n c e s i n b i o a v a i l a b i l i t y . I t s h o u l d be not e d , however, t h a t i n e a r l i e r e v a l u a t i o n s of the e f f e c t s of MCPP on l o r d o s i s b e h a v i o u r i n t h i s 105 l a b o r a t o r y , the drug was found t o produce a s l i g h t , but s i g n i f i c a n t f a c i l i t a t i o n of l o r d o s i s (Mendelson & G o r z a l k a , u n p u b l i s h e d d a t a ) . T h e r e f o r e , I suggest t h a t the a c t i v a t i o n of 5-HT,B a g o n i s t s f a c i l i t a t e s l o r d o s i s , and t h a t t h e d i f f e r e n c e s i n the e f f e c t s of TFMPP and MCPP on l o r d o s i s may be q u a n t i t a t i v e r a t h e r than q u a l i t a t i v e . EXPERIMENT 9 The 5 - H T 3 r e c e p t o r has been c h a r a c t e r i z e d as a p e r i p h e r a l 5-HT r e c e p t o r ( B r a d l e y e t a l . , 1986). However, r e c e n t e v i d e n c e i n d i c a t e s the e x i s t e n c e of 5-HT3 b i n d i n g s i t e s i n b r a i n t i s s u e ( K i l p a t r i c k , Jones & T y e r s , i n p r e s s , c i t e d i n T y e r s , 1988). The p o s s i b i l i t y t h a t t h e s e b i n d i n g s i t e s r e p r e s e n t f u n c t i o n a l 5-HT3 r e c e p t o r s i s suggested by the r e c e n t r e p o r t t h a t i n t r a h y p o t h a l a m i c a d m i n i s t r a t i o n of the s e l e c t i v e 5-HT3 a n t a g o n i s t ICS 205-930 f a c i l i t a t e s g a s t r i c emptying i n the g u i n e a - p i g ( C o s t a l l , K e l l y , N a y l o r , Tan & T a t t e r s a l l , 1986). In Experiment 9 I w i l l e v a l u a t e the e f f e c t s of the a d m i n i s t r a t i o n of the s e l e c t i v e 5-HT3 a n t a g o n i s t s ICS 205-930 and MDL 72222 ( F o z a r d , 1984) on l o r d o s i s b e h a v i o u r i n e s t r o g e n - p r i m e d female r a t s . Methods Drugs ICS 205-930 and MDL 72222 were o b t a i n e d as g i f t s from 106 Sandoz and M e r r i l l Dow r e s p e c t i v e l y . Both drugs were d i s s o l v e d i n warm s a l i n e , and a d m i n i s t e r e d i n t r a p e r i t o n e a l l y i n a p p r o x i m a t e l y 0.3 ml of the v e h i c l e . Drugs were a d m i n i s t e r e d b l i n d . P r o c e d u r e In E x p e r i m e n t s 9, the dose responses t o ICS 205-930 and MDL 72222 were de t e r m i n e d i n e s t r o g e n - t r e a t e d f e m a l e s . In the t e s t i n g of each d r u g , 56 females r e c e i v e d 10 uq EB 48 h, and each of 4 groups of 14 a n i m a l s r e c e i v e d e i t h e r 0, 0.05, 0.5, or 5 mg/kg of the e x p e r i m e n t a l drug 1 hr p r i o r t o b e h a v i o u r a l t e s t i n g . R e s u l t s In F i g . 9a i t i s apparent t h a t the a d m i n i s t r a t i o n of ICS 205-930 f a c i l i t a t e s l o r d o s i s b e h a v i o u r . Indeed, l e v e l s of l o r d o s i s b e h a v i o u r appeared t o i n c r e a s e s t e a d i l y w i t h i n c r e a s e s i n dose. The l o r d o s i s - f a c i l i t a t i n g e f f e c t of ICS 205-930 was c o n f i r m e d by a n a l y s i s of v a r i a n c e , F(3,52)=4.254, p_< .009. However, by the Newman-Keuls method i t was d e t e r m i n e d t h a t o n l y t h e 5 mg/kg dose of ICS 205-930 produced a s i g n i f i c a n t f a c i l i t a t i o n of l o r d o s i s (g<.05). U n l i k e ICS 205-930, MDL 72222 was c o m p l e t e l y i n e f f e c t i v e w i t h i n the range of doses e v a l u a t e d ( F i g . 9 b ). D i s c u s s i o n In Experiment 9, ICS 205-930 was found t o f a c i l i t a t e 1 07 F i g . 9a. Mean l o r d o s i s q u o t i e n t s ± S.E.M. of females primed w i t h 10 ixq e s t r a d i o l benzoate f o l l o w i n g the a d m i n i s t r a t i o n of v a r y i n g doses of ICS 205-930 30 min p r i o r t o b e h a v i o u r a l t e s t i n g . 108 % iN3iiono s i s o a y o i Nvaw 109 F i g . 9b. Mean l o r d o s i s q u o t i e n t s ± S.E.M. of females primed w i t h 10 Mg e s t r a d i o l benzoate f o l l o w i n g the a d m i n i s t r a t i o n of v a r y i n g doses of MDL 72222 30 min p r i o r t o b e h a v i o u r a l t e s t i n g . 110 I- tf> D) E CM CM CM CM h C M o o o 00 o CD O O CM ~l o % iN3iiono s i soauo i N V B I A I 111 l o r d o s i s b e h a v i o u r . T h i s f i n d i n g s u g g e s t s t h a t the i n h i b i t o r y e f f e c t s of s e r o t o n i n a re a t l e a s t p a r t i a l l y m e diated by 5-HT3 r e c e p t o r s . I t i s worth n o t i n g t h a t i n an experiment now i n p r o g r e s s , i n t r a h y p o t h a l a m i c a d m i n i s t r a t i o n of the s e l e c t i v e 5-HT 3 a g o n i s t 2 - m e t h y l s e r o t o n i n has been o b s e r v e d t o i n h i b i t l o r d o s i s b e h a v i o u r . T h i s e f f e c t would be c o n s i s t e n t w i t h a l o r d o s i s - i n h i b i t i n g e f f e c t of s t i m u l a t i o n of c e n t r a l 5-HT3 r e c e p t o r s . I n t e r e s t i n g l y , the 5-HT3 a n t a g o n i s t MDL 72222 was found t o be i n e f f e c t i v e i n t h i s e x periment. The d i f f e r e n c e s i n the e f f e c t s of ICS 205-930 and MDL 72222 c o u l d be a t l e a s t p a r t i a l l y due t o d i f f e r e n c e s i n the a f f i n i t i e s of the two drugs f o r 5-HT3 r e c e p t o r s . Indeed, i n some t i s s u e s ICS 205-930 has been found t o be n e a r l y 1000 tim e s more p o t e n t than MDL 72222 i n i t s a b i l i t y t o b l o c k the e f f e c t s of s e r o t o n i n ( R i c h a r d s o n e t a l . , 1985; Round & W a l l i s , 1987). These d i f f e r e n c e s might a l s o r e f l e c t d i f f e r e n t i a l r o l e s of what have been r e c o g n i z e d as subtypes of 5-HT3 r e c e p t o r s ( R i c h a r d s o n et a l . , 1985). On the o t h e r hand, th e s e d i f f e r e n c e s c o u l d s i m p l y r e f l e c t d i f f e r e n c e s i n the a b i l i t i e s of the s e drugs t o pass t h r o u g h the b l o o d b r a i n b a r r i e r i n t o b r a i n t i s s u e , or d i f f e r e n c e s i n t h e i r r e s i s t e n c e t o breakdown by enzymes i n the l i v e r . Of c o u r s e , the p o s s i b i l t y remains t h a t these d i f f e r e n c e s were due t o d i f f e r e n c e s i n non-s e r o t o n e r g i c e f f e c t s of the s e d r u g s . E v a l u a t i o n s of a d d i t i o n a l 5-HT3 a g o n i s t s and a n t a g o n i s t s s h o u l d h e l p . c l a r i f y t h e s e q u e s t i o n s . 1 1 2 GENERAL DISCUSSION In the p r e s e n t s e r i e s of e x p e r i m e n t s , the 5-HT2 a n t a g o n i s t s p i z o t e f i n , c y p r o h e p t a d i n e and m e t i t e p i n e , and the s e l e c t i v e 5-HT 2 a n t a g o n i s t k e t a n s e r i n were found t o i n h i b i t l o r d o s i s b e h a v i o u r i n females primed w i t h e s t r o g e n and p r o g e s t e r o n e . With the e x c e p t i o n of m e t i t e p i n e , the l o r d o s i s - i n h i b i t i n g e f f e c t s of these drugs were r e v e r s e d by c o a d m i n i s t r a t i o n of the 5-HT2 a g o n i s t q u i p a z i n e . The h i g h l y s e l e c t i v e 5-HT2 a n t a g o n i s t LY53857, a drug w i t h o u t s i g n i f i c a n t e f f e c t s on dopaminergic or n o r a d r e n e r g i c systems, was a l s o i n h i b i t e d l o r d o s i s . T h i s e f f e c t was r e v e r s e d w i t h q u i p a z i n e . The n o n - s e l e c t i v e 5-HT a n t a g o n i s t m e t h y s e r g i d e was found t o produce i n h i b i t o r y and f a c i l i t a t i v e e f f e c t s on l o r d o s i s i n a time dependent manner. At 30 min a f t e r t r e a t m e n t , when m e t h y s e r g i d e i s b e l i e v e d t o be most a c t i v e as c e n t r a l , s e r o t o n i n a n t a g o n i s t the drug i n h i b i t e d l o r d o s i s . At 200 min a f t e r t r e a t m e n t , when the s e r o t o n i n - a n t a g o n i z i n g e f f e c t s of the drug have become g r e a t l y d i m i n i s h e d , m e t h y s e r g i d e f a c i l i t a t e d l o r d o s i s . Because the c o n c e n t r a t i o n of me t h y s e r g i d e i n plasma and b r a i n t i s s u e would have d e c l i n e d over 200 min, i t was c o n s i d e r e d t h a t the i n h i b i t o r y and f a c i l i t a t i v e e f f e c t s of me t h y s e r g i d e may have been c o n c e n t r a t i o n - r a t h e r than dose-dependent. However, the e v a l u a t i o n of i n c r e a s i n g l y s m a l l doses of m e t h y s e r g i d e a d m i n i s t e r e d 30 min p r i o r t o b e h a v i o u r a l t e s t i n g f a i l e d t o produce a f a c i l i t a t i o n of l o r d o s i s . Indeed, i n e v a l u a t i n g t h e dose response t o m e t h y s e r g i d e , f a c i l i t a t i v e e f f e c t s of the drug were observed o n l y 200 min a f t e r t r e a t m e n t . I n c r e a s i n g doses of the 5-HT,A a g o n i s t s 8-OH DPAT, 1 13 b u s p i r o n e , i p s a p i r o n e , and g e p i r o n e were found t o i n h i b i t l o r d o s i s i n e s t r o g e n - p r i m e d f e m a l e s . At lower doses, a l l of the 5-HT,A a g o n i s t s produced i n c r e a s e s i n l o r d o s i s b e h a v i o u r i n e s t r o g e n - p r i m e d f e m a l e s . However, o n l y the f a c i l i t a t i o n produced by g e p i r o n e and i p s a p i r o n e was found t o be s i g n i f i c a n t . When a d m i n i s t e r e d t o females primed w i t h e s t r o g e n and p r o g e s t e r e o n e , b u s p i r o n e , i p s a p i r o n e and g e p i r o n e a l l produced s t r o n g i n h i b i t i o n of l o r d o s i s . Indeed, even doses of the drugs t h a t were i n e f f e c t i v e or found t o f a c i l i t a t e l o r d o s i s i n females primed w i t h e s t r o g e n were found t o i n h i b i t l o r d o s i s i n females primed w i t h e s t r o g e n and p r o g e s t e r o n e . The 5-HT,A a n t a g o n i s t BMY 7378 f a c i l i t a t e d l o r d o s i s i n females primed w i t h e s t r o g e n a l o n e . However, t h i s f a c i l i t a t i v e e f f e c t was no l o n g e r observed a t the h i g h e s t dose. BMY 7378 was i n e f f e c t i v e i n females primed w i t h e s t r o g e n and p r o g e s t e r o n e . The 5 - H T T B a g o n i s t TFMPP produced a v e r y s t r o n g f a c i l i t a t i o n of l o r d o s i s b e h a v i o u r i n e s t r o g e n - p r i m e d f e m a l e s . In females primed w i t h e s t r o g e n and p r o g e s t e r o n e o n l y the h i g h e s t dose of TFMPP was e f f e c t i v e . I n t e r e s t i n g l y , the e f f e c t of TFMPP i n females primed w i t h e s t r o g e n and p r o g e s t e r o n e was i n h i b i t i o n of l o r d o s i s . The somewhat weaker 5-H^B a g o n i s t MCPP was i n e f f e c t i v e . F i n a l l y , the 5-HT3 a n t a g o n i s t ICS 205-930 f a c i l i t a t e d l o r d o s i s i n e s t r o g e n - p r i m e d f e m a l e s . However, w i t h i n the l i m i t e d range of doses, the 5-HT3 a n t a g o n i s t MDL 72222 was i n e f f e c t i v e . The r e s u l t s of the s e e v a l u a t i o n s of s e r o t o n i n r e c e p t o r subtype s e l e c t i v e drugs suggest t h a t s e r o t o n i n may produce e i t h e r i n h i b i t i o n or f a c i l i t a t i o n of l o r d o s i s . Whether 114 i n h i b i t i o n or f a c i l i t a t i o n o c c u r s appears t o depend upon which subtype of r e c e p t o r i s a c t i v a t e d . These e x p e r i m e n t s suggest t h a t a c t i v a t i o n of p o s t s y n a p t i c 5-HT,A r e c e p t o r s and, perhaps, 5-HT3 r e c e p t o r s produces i n h i b t i o n of l o r d o s i s . A c t i v a t i o n of 5-HT 2, 5-HT,B and, perhaps, p r e s y n a p t i c 5-HT,A r e c e p t o r s appears t o r e s u l t i n f a c i l i t a t i o n of l o r d o s i s b e h a v i o u r . The r e s u l t s o b t a i n e d i n these e x p e r i m e n t s t e n d both t o c o n f i r m and t o extend the d u a l r o l e h y p o t h e s i s of Mendelson and G o r z a l k a (1985b). I n many c a s e s , the e x p e r i m e n t s performed i n the p r e s e n t s e r i e s r e p r e s e n t the f i r s t e v a l u a t i o n s of the e f f e c t s on l o r d o s i s of drugs t h a t a c t s e l e c t i v e l y a t the subtypes of c e n t r a l s e r o t o n i n r e c e p t o r s . I t must be n o t e d , however, t h a t these e x p e r i m e n t s form o n l y a p o r t i o n of the s t u d i e s t h a t have been performed i n the e f f o r t t o determine the r o l e of s e r o t o n i n i n female s e x u a l b e h a v i o u r . Indeed, f o l l o w i n g the i n i t i a l i n v e s t i g a t i o n s of Meyerson, a wide v a r i e t y of s e r o t o n i n a g o n i s t s and a n t a g o n i s t s have been e v a l u a t e d f o r e f f e c t s on l o r d o s i s . Because many of these e v a l u a t i o n s of s e r o t o n i n a n t a g o n i s t s and a g o n i s t s took p l a c e p r i o r t o the c h a r a c t e r i z a t i o n of the subtypes of c e n t r a l s e r o t o n i n r e c e p t o r s , i t would appear w o r t h w h i l e t o r e - i n t e r p r e t the r e s u l t s of t h e s e e x p e r i m e n t s i n l i g h t of p r e s e n t knowledge. A c c o r d i n g l y , the f o l l o w i n g i s a comprehensive review and r e - e v a l u a t i o n of the e f f e c t s of 5-HT a n t a g o n i s t s and a g o n i s t s on l o r d o s i s b e h a v i o u r i n terms of p r o b a b l e a c t i o n of thes e drugs a t s p e c i f i c s ubtypes of 5-HT r e c e p t o r s . A l t h o u g h none of the drugs d i s c u s s e d b i n d e x c l u s i v e l y t o 5-HT r e c e p t o r s , t h e i r e f f e c t s appear t o be mediated p r i m a r i l y by s e r o t o n e r g i c systems. T h e r e f o r e , I have c o n s i d e r e d these 1 15 drugs o n l y i n r e g a r d t o t h e i r s e r o t o n e r g i c e f f e c t s . In t h i s r e v i e w i t becomes apparent t h a t s e r o t o n i n can produce e i t h e r i n h i b i t o r y or f a c i l i t a t o r y e f f e c t s on l o r d o s i s b e h a v i o u r , as has been s u g g e s t e d i n the r e c e n t d u a l r o l e hypotheses (Mendelson & G o r z a l k a , 1985; W i l s o n & Hunter, 1985). I t i s c o n c l u d e d t h a t i n h i b i t o r y e f f e c t s of s e r o t o n i n a re mediated p r i m a r i l y by p o s t -s y n a p t i c 5-HT,A r e c e p t o r s , whereas f a c i l i t a t o r y e f f e c t s a r e mediated by 5-HT2 r e c e p t o r s . I t i s a l s o c o n c l u d e d t h a t a c t i v i t y a t s o m a t o - d e n d r i t i c 5-HT^ a u t o r e c e p t o r s may f a c i l i t a t e l o r d o s i s . F i n a l l y , on the b a s i s of p r e l i m i n a r y e v i d e n c e , i t i s suggested t h a t 5-HT3 r e c e p t o r s may mediate i n h i b i t o r y , and p r e j u n c t i o n a l 5-HT,B a u t o r e c e p t o r s f a c i l i t a t o r y e f f e c t s of s e r o t o n i n on l o r d o s i s b e h a v i o u r . 5-HT r e c e p t o r a n t a g o n i s t s The c l a s s i c a l 5-HT a n t a g o n i s t s b i n d t o b o t h 5-HT, and 5-HT2 r e c e p t o r s . However, these drugs te n d t o show v a r y i n g degrees of p r e f e r e n c e f o r 5-HT2 r e c e p t o r s ( P e r o u t k a , L e b o v i t z & Snyder, 1981). Recent work i n d i c a t e s t h a t d i f f e r e n c e s may a l s o e x i s t i n the degree t o which a 5-HT a n t a g o n i s t b i n d s t o the v a r i o u s subtypes of the 5-HT, r e c e p t o r . Even drugs c o n s i d e r e d t o be q u i t e s e l e c t i v e 5-HT2 a n t a g o n i s t s tend t o b i n d w i t h h i g h a f f i n i t y t o 5-HT,C r e c e p t o r s . Moreover, i t appears t h a t most 5-HT a n t a g o n i s t s b i n d w i t h a markedly h i g h e r a f f i n i t y t o 5-HT,A than t o 5-HT,B s i t e s . The e f f e c t i v e n e s s of the c l a s s i c a l 5-HT a n t a g o n i s t s a t 5-HT 2 r e c e p t o r s appears w e l l e s t a b l i s h e d . However, w h i l e i t i s 1 16 c l e a r t h a t these drugs b i n d t o the v a r i o u s subtypes of the 5-HT, r e c e p t o r , t h e r e remains some doubt as t o t h e i r e f f e c t i v e n e s s as a n t a g o n i s t s a t the s e s i t e s ( H a i g l e r & A g h a j a n i a n , 1974a). There i s i n f a c t e v i d e n c e t h a t some c l a s s i c a l 5-HT a n t a g o n i s t s may a c t as weak p a r t i a l a g o n i s t s a t 5-HT, r e c e p t o r s ( H a i g l e r & A g h a j a n i a n , 1974a; P e r o u t k a e t a l . , 1981). However, the newer, h i g h l y s e l e c t i v e 5-HT2 a n t a g o n i s t s p o s s e s s l i t t l e , i f any, a g o n i s t a c t i v i t y ( J a n s s e n , 1985). In s t u d i e s i n v e s t i g a t i n g the r o l e of s e r o t o n i n i n l o r d o s i s , m e t h y s e r g i d e has been the most commonly employed r e c e p t o r a n t a g o n i s t . M e t h y s e r g i d e i s one of the l e s s s e l e c t i v e a n t a g o n i s t s , b i n d i n g w i t h h i g h a f f i n i t y t o 5-HT 2, 5-HT,A and 5-HT,C r e c e p t o r s , and w i t h somewhat lower a f f i n i t y t o 5-HT,B s i t e s ( Dr. S.J. P e r o u t k a , p e r s o n a l c o m m u n i c a t i o n ) . The a d m i n i s t r a t i o n of m e t h y s e r g i d e d i r e c t l y i n t o the hypothalamus, hippocampus, or amygdala f a c i l i t a t e s l o r d o s i s i n e s t r o g e n - p r i m e d females (Zemlan, Ward, Crowley and M a r g u l e s , 1973; Ward, Crowley, Zemlan and M a r g u l e s , 1975; Foreman and Moss, 1978; Franck and Ward, 1981). In one i n s t a n c e , i n h i b i t i o n was o b s e r v e d f o l l o w i n g i n j e c t i o n of me t h y s e r g i d e i n t o the p r e o p t i c a r e a (Clemens, 1978). P e r i p h e r a l l y a d m i n i s t e r e d m e t h y s e r g i d e a l s o f a c i l i t a t e s l o r d o s i s i n e s t r o g e n - p r i m e d , o v a r i e c t o m i z e d females (Ward et a l . , 1975; H e n r i k and G e r a l l , 1976; D a v i s and K o h l , 1978; Foreman and Moss, 1978; R o d r i g u e z - S i e r r a and D a v i s , 1979; Franck and Ward, 1981; Hunter e t a l . , 1985; Mendelson & G o r z a l k a , 1986a; U l i b a r r i & Yahr, 1987). However, the maximal f a c i l i t a t o r y e f f e c t s of p e r i p h e r a l l y a d m i n i s t e r e d m e t h y s e r g i d e have been 1 17 r e p o r t e d t o oc c u r 2 t o 6 hr a f t e r t r e a t m e n t (Zemlan e t a l , 1973; D a v i s and K o h l , 1978). P h a r m a c o k i n e t i c d a t a i n d i c a t e t h a t the maximal a n t i s e r o t o n e r g i c e f f e c t s of i n t r a p e r i t o n e a l l y a d m i n i s t e r e d m e t h y s e r g i d e can occur i n 30 min and may d e c l i n e w i t h i n 1 hr ( S o f i a & V a s s a r , 1975). When e v a l u a t e d 30 min t o 1 hr a f t e r i t s p e r i p h e r a l a d m i n i s t r a t i o n , m e t h y s e r g i d e has been found t o be i n e f f e c t i v e i n females primed w i t h a low dose of e s t r o g e n (Mendelson and G o r z a l k a , 1985b), and t o i n h i b i t l o r d o s i s i n females primed w i t h a h i g h dose of e s t r o g e n , or w i t h e s t r o g e n and p r o g e s t e r o n e (Meyerson & E l i a s s o n , 1977; S i e t n i e k s , 1985; Mendelson & G o r z a l k a , 1986a). Together, t h e s e d a t a suggest t h a t a t the times when i t i s most e f f e c t i v e as a 5-HT a n t a g o n i s t , p e r i p h e r a l l y a d m i n i s t e r e d m e t h y s e r g i d e i n h i b i t s l o r d o s i s b e h a v i o u r . I t i s c o n c e i v a b l e t h a t the l o r d o s i s -f a c i l i t a t i n g e f f e c t of m e t h y s e r g i d e a f t e r 2 hr i s due t o the a c t i o n of a m e t a b o l i t e . C i n a n s e r i n i s one of the c l a s s i c a l a n t a g o n i s t s more s e l e c t i v e f o r 5-HT2 r e c e p t o r s (Leysen & T o l l e n a e r e , 1982). When a d m i n i s t e r e d i n t o the m e d i a l p r e o p t i c or p o s t e r i o r a r e a s of the hypothalamus, c i n a n s e r i n f a c i l i t a t e d l o r d o s i s i n e s t r o g e n - p r i m e d females (Zemlan et a l . , 1973; Ward e t a l . , 1975). However, when a d m i n i s t e r e d p e r i p h e r a l l y t o e s t r o g e n - p r i m e d f e m a l e s , 25 mg/kg c i n a n s e r i n d i d not f a c i l i t a t e l o r d o s i s ( E v e r i t t , Fuxe, H o k f e l t , & J o n s s o n , 1975). In females primed w i t h e s t r o g e n and p r o g e s t e r o n e , p e r i p h e r a l a d m i n i s t r a t i o n of 5 mg/kg c i n a n s e r i n appeared i n e f f e c t i v e ( S i e t n i e k s , 1985), whereas 10 mg/kg c i n a n s e r i n s u b s t a n t i a l l y i n h i b i t e d l o r d o s i s (Hunter e t a l . , 1985). Hunter e t a l . , (1985) a l s o r e p o r t e d t h a t 10 mg/kg 1 18 c i n a n s e r i n produced a s l i g h t i n c r e a s e i n l o r d o s i s b e h a v i o u r i n e s t r o g e n - p r i m e d females w i t h v e r y low b a s e l i n e l e v e l s of r e c e p t i v i t y . However, because of the a r b i t r a r y placement of a n i m a l s i n t o " r e c e p t i v e " and " n o n - r e c e p t i v e " groups p r i o r t o s t a t i s t i c a l a n a l y s i s , I s u s p e c t t h a t t h i s apparent f a c i l i t a t i o n i s m e rely an a r t i f a c t of the e x p e r i m e n t a l d e s i g n , t h a t i s , a r e g r e s s i o n toward the mean (see R a i b l e & G o r z a l k a , 1986). N o n e t h e l e s s , these data do i n d i c a t e t h a t w h i l e c i n a n s e r i n may i n h i b i t l o r d o s i s , i t does not e l i m i n a t e t h i s b e h a v i o u r . M e t e r g o l i n e , l i k e m e t h y s e r g i d e , i s somewhat n o n - s e l e c t i v e i n i t s b i n d i n g t o the v a r i o u s 5-HT r e c e p t o r subtypes (Hoyer, E n g e l & Kalkman, 1985). In females t r e a t e d c h r o n i c a l l y w i t h e s t r o g e n , 0.05 mg/kg m e t e r g o l i n e was found t o f a c i l i t a t e and doses over 0.5 mg/kg t o i n h i b i t l o r d o s i s (Fuxe, e t a l . , 1976). In females t r e a t e d e i t h e r w i t h e s t r o g e n (Hunter e t a l . , 1985) , or w i t h e s t r o g e n and p r o g e s t e r o n e (Hunter e t a l . , 1985 ; S i e t n i e k s , 1985), 5 mg/kg m e t e r g o l i n e i n h i b i t e d l o r d o s i s . Other c l a s s i c a l a n t a g o n i s t s t h a t have been e v a l u a t e d f o r t h e i r e f f e c t s upon l o r d o s i s b e h a v i o u r a r e m e t i t e p i n e , m i a n s e r i n , c y p r o h e p t a d i n e , and p i z o t e f i n . M e t i t e p i n e i s somewhat n o n s e l e c t i v e i n i t s s e r o t o n e r g i c b i n d i n g (Hoyer, e t a l . , 1985), whereas m i a n s e r i n , c y p r o h e p t a d i n e and p i z o t e f i n b i n d p r e f e r e n t i a l l y t o 5-HT2 r e c e p t o r s (Leysen & T o l l e n a e r e , 1982). When a d m i n s t e r e d s y s t e m i c a l l y t o females primed w i t h e s t r o g e n and p r o g e s t e r o n e , m e t i t e p i n e (Mendelson and G o r z a l k a , 1986b), and c y p r o h e p t a d i n e (Mendelson & G o r z a l k a , 1986b; S i e t n i e k s , 1985) i n h i b i t e d l o r d o s i s . At a dose lower than our e f f e c t i v e one (Mendelson and G o r z a l k a , 1986b), m e t i t e p i n e d i d not i n h i b i t 119 l o r d o s i s ( F e r n a n d e z - G u a s t i , A h l e n i u s , H j o r t h & L a r s s o n , 1987). The p e r i p h e r a l a d m i n i s t r a t i o n of m i a n s e r i n i n h i b i t e d l o r d o s i s i n females t r e a t e d e i t h e r w i t h e s t r o g e n , or w i t h e s t r o g e n and p r o g e s t e r o n e (Hunter et a l . , 1985; S i e t n i e k s , 1985). P i z o t e f i n a l s o i n h i b i t e d l o r d o s i s i n females primed w i t h e s t r o g e n and p r o g e s t e r o n e (Mendelson and G o r z a l k a , 1986b). R e c e n t l y , h i g h l y s e l e c t i v e 5-HT2 a n t a g o n i s t s have become a v a i l a b l e f o r e v a l u a t i o n . In two s t u d i e s , p e r i p h e r a l a d m i n i s t r a t i o n of the 5 - H T 2 - s e l e c t i v e a n t a g o n i s t p i r e n p e r o n e i n h i b i t e d l o r d o s i s i n s t e r o i d - p r i m e d females (Mendelson and G o r z a l k a , 1985b; S i e t n i e k s , 1985). I n t r a v e n t r i c u l a r a d m i n i s t r a t i o n of p i r e n p e r o n e a l s o i n h i b i t e d l o r d o s i s (Mendelson and G o r z a l k a , u n p u b l i s h e d d a t a ) . In a r e c e n t paper, a s i n g l e dose of p i r e n p e r o n e (0.25 mg/kg) was r e p o r t e d t o be i n e f f e c t i v e i n females primed w i t h e s t r o g e n and p r o g e s t e r o n e (Fernandez-G u a s t i et a l . , 1987). However, w h i l e t h i s dose of p i r e n p e r o n e was h i g h e r than those found e f f e c t i v e i n our own study (Mendelson and G o r z a l k a , 1985), i t was lower than t h a t found m i n i m a l l y e f f e c t i v e by S i e t n i e k s (1985). In a t l e a s t t h r e e s t u d i e s , k e t a n s e r i n ( 1 - 1 0 mg/kg), a 5-HT2 a n t a g o n i s t r e l a t e d i n s t r u c t u r e t o p i r e n p e r o n e , has been found t o i n h i b i t l o r d o s i s b e h a v i o u r (Mendelson & G o r z a l k a , 1985b, 1986b; Hunter et a l . , 1985) However, the 5-HT2 s e l e c t i v e a n t a g o n i s t a l t a n s e r i n d i d not i n h i b i t l o r d o s i s i n s t e r o i d - p r i m e d r a t s a t doses up t o 0.2 mg/kg ( S i e t n i e k s , 1985). The e r g o l i n e d e r i v a t i v e LY53857 has r e c e n t l y been r e p o r t e d t o be a p o t e n t , and h i g h l y s e l e c t i v e 5-HT2 a n t a g o n i s t . U n l i k e most 5-HT2 a n t a g o n i s t s , LY53857 i s r e l a t i v e l y i n a c t i v e a t a. 1 20 a d r e n e r g i c and dopaminergic r e c e p t o r s (Cohen, F u l l e r & K u r z , 1983). I have found t h a t LY53857 i n h i b i t s l o r d o s i s (Experiment 2 ) . R i t a n s e r i n , a n o ther 5-HT2 a n t a g o n i s t w i t h - r e l a t i v e l y l i t t l e a - a d r e n e r g i c a c t i v i t y ( J a n s s e n , 1985), a l s o i n h i b i t s l o r d o s i s ( Mendelson & G o r z a l k a , u n p u b l i s h e d d a t a ) . These d a t a suggest t h a t whether or not 5-HT2 a n t a g o n i s t s a c t a t a, a d r e n e r g i c or dopa m i n e r g i c r e c e p t o r s , the b l o c k a d e of a c t i v i t y a t 5-HT2 r e c e p t o r s i s s u f f i c i e n t t o i n h i b i t l o r d o s i s b e h a v i o u r . U n t i l v e r y r e c e n t l y , t h e r e have been no drugs a c t i n g as s e l e c t i v e a n t a g o n i s t s of a c t i v i t y a t 5-HT1 r e c e p t o r s . The newly d e v e l o p e d drug BMY 7378 has been found t o b i n d s e l e c t i v e l y and w i t h h i g h a f f i n i t y t o 5-HT,A r e c e p t o r s (Yocca e t a l . , 1987). Moreover, the drug has been found t o r e v e r s e the e f f e c t s of the 5-HT,A a g o n i s t 5-carboxamidotryptamine on a d e n y l a t e c y c l a s e i n hippocampal t i s s u e . When a d m i n i s t e r e d t o e s t r o g e n - p r i m e d f e m a l e s , low doses of BMY 7378 were found t o f a c i l i t a t e l o r d o s i s b e h a v i o u r . However, a t h i g h e r doses the l o r d o s i s - f a c i l i t a t i n g e f f e c t s of the drug were s i g n i f i c a n t l y reduced. Because BMY 7378 appears t o be a v e r y weak p a r t i a l a g o n i s t , the i n h i b i t o r y e f f e c t s of the drug a t h i g h doses may have been due t o s t i m u l a t i o n r a t h e r than b l o c k a d e of 5-HT,A r e c e p t o r s . I n t e r e s t i n g l y , a t doses from 0.04 t o 5 mg/kg, BMY 7378 was found t o have no e f f e c t upon l o r d o s i s b e h a v i o u r i n females primed w i t h e s t r o g e n and p r o g e s t e r o n e . I t i s p o s s i b l e , however, t h a t a t a h i g h e r dose i n h i b i t o r y e f f e c t s may have been o b s e r v e d . A l t h o u g h the 5-HT3 r e c e p t o r has been c h a r a c t e r i z e d as a p e r i p h e r a l r e c e p t o r , r e c e n t e v i d e n c e i n d i c a t e s the e x i s t e n c e of 5-HT3 b i n d i n g s i t e s i n b r a i n t i s s u e ( K i l p a t r i c k , Jones & T y e r s , 121 i n p r e s s , c i t e d i n T y e r s , 1988). The p o s s i b i l i t y t h a t t h e s e b i n d i n g s i t e s r e p r e s e n t f u n c t i o n a l 5-HT3 r e c e p t o r s i s suggested by the r e c e n t r e p o r t t h a t i n t r a h y p o t h a l a m i c a d m i n i s t r a t i o n of the s e l e c t i v e 5-HT3 a n t a g o n i s t ICS 205-930 f a c i l i t a t e s g a s t r i c emptying i n the g u i n e a - p i g ( C o s t a l l , K e l l y , N a y l o r , Tan & T a t t e r s a l l , 1986). In Experiment 9, the p e r i p h e r a l a d m i n i s t r a t i o n of 5 mg/kg ICS 205-930 was found t o f a c i l i t a t e l o r d o s i s i n e s t r o g e n - p r i m e d f e m a l e s . S t u d i e s employing c e n t r a l a d m i n i s t r a t i o n of ICS 205-930 a r e i n p r o g r e s s i n our l a b o r a t o r y . I n t e r e s t i n g l y , I have as y e t obs e r v e d no i n d i c a t i o n of f a c i l i t a t o r y e f f e c t s of the 5-HT3 a n t a g o n i s t MDL 72222 ( F o z a r d , 1984) . T h i s c o u l d be a r e f l e c t i o n of the d i f f e r e n t i a l e f f e c t i v e n e s s of these drugs on the subtypes of 5-HT3 r e c e p t o r s ( R i c h a r d s o n , E n g e l , Donatsch & S t a d l e r , 1985). However, pending the e v a l u a t i o n of o t h e r 5-HT3 s e l e c t i v e d r u g s , t h i s s u g g e s t i o n must be r e g a r d e d as h i g h l y s p e c u l a t i v e . S e r o t o n i n r e c e p t o r a g o n i s t s B e f o r e d i s c u s s i n g the e f f e c t s of drugs t h a t mimic 5-HT, I must note t h a t the a d m i n i s t r a t i o n of 5-HT i t s e l f i n t o p r e o p t i c and h y p o t h a l a m i c a r e a s i n h i b i t e d l o r d o s i s i n s t e r o i d - p r i m e d females (Foreman & Moss, 1978a; Clemens, 1978). However, the i n j e c t i o n of 10 /ig 5-HT i n t o the t h i r d v e n t r i c l e produced no e f f e c t , w h i l e i n j e c t i o n of 100 jug 5-HT i n t o the l a t e r a l v e n t r i c l e s i g n i f i c a n t l y f a c i l i t a t e d l o r d o s i s ( W i l s o n & Hunter, 1985) . These f i n d i n g s suggest t h a t 5-HT can e i t h e r i n h i b i t or f a c i l i t a t e l o r d o s i s , depending on which a r e a s of the b r a i n 122 r e c e i v e t r e a t m e n t . LSD was the f i r s t 5-HT a g o n i s t t o be e v a l u a t e d f o r e f f e c t s on l o r d o s i s . Iri v i t r o b i n d i n g d a t a i n d i c a t e t h a t the b i n d i n g of LSD t o the v a r i o u s subtypes of 5-HT r e c e p t o r s i s r e l a t i v e l y n o n s e l e c t i v e . I t b i n d s w i t h r o u g h l y e q u a l h i g h a f f i n i t i e s t o 5-HT 2, 5-HT,A and 5-HT,C r e c e p t o r s , and w i t h s l i g h t l y lower a f f i n i t y t o 5-HT,B s i t e s (Engel e t a l . , 1986). P e r i p h e r a l a d m i n i s t r a t i o n of LSD has i n h i b i t e d l o r d o s i s i n females t r e a t e d w i t h e s t r o g e n and p r o g e s t e r o n e ( E l i a s s o n , Michanek & Meyerson, 1972; Meyerson, C a r r e r & E l i a s s o n , 1974; E l i a s s o n & Meyerson, 1976; E l i a s s o n & Meyerson, 1977; S i e t n i e k s & Meyerson, 1980). A l t h o u g h one l a b o r a t o r y has r e p o r t e d i n h i b i t o r y e f f e c t s of LSD i n females t r e a t e d w i t h e s t r o g e n a l o n e ( E v e r i t t e t a l . , 1975), another f a i l e d t o c o n f i r m t h i s even w i t h r e l a t i v e l y h i g h doses of the drug ( S i e t n i e k s & Meyerson, 1980). The i n h i b i t o r y e f f e c t s of LSD have been taken as e v i d e n c e of s e r o t o n e r g i c i n h i b i t i o n of l o r d o s i s . However, t h i s i n t e r p r e t a t i o n i g n o r e s the f a c t t h a t LSD may a c t as e i t h e r an a g o n i s t or an a n t a g o n i s t , depending, perhaps, on the subtype of 5-HT r e c e p t o r . The a b i l i t y of LSD t o reduce t h e r a t e of f i r i n g of neurons i n the d o r s a l raphe ( H a i g l e r & A g h a j a n i a n , 1974b), and t o i n h i b i t the r e l e a s e of s e r o t o n i n from neuron t e r m i n a l s ( M i d d l e m i s s , 1982) sug g e s t s t h a t LSD may a c t as an a g o n i s t a t 5-HT,A and 5-HT,B r e c e p t o r s , r e s p e c t i v e l y . That the d i s c r i m i n a t i o n of LSD from s a l i n e can be b l o c k e d by s e l e c t i v e 5-HT2 a n t a g o n i s t s ( J a n s s e n , 1983) s u g g e s t s t h a t LSD may a c t as a t l e a s t a p a r t i a l a g o n i s t a t 5-HT2 r e c e p t o r s . However, LSD has been found t o b l o c k 123 the e x c i t a t o r y , and most l i k e l y , 5-HT2 mediated ( P e r o u t k a et a l . , 1981) e f f e c t s of s e r o t o n i n i n the c o r t e x ( R o b e r t s & St r a u g h n , 1967) and r e t i c u l a r f o r m a t i o n (Boakes, B r a d l e y , B r i g g s , & Dray, 1970). I su s p e c t t h a t the i n h i b i t o r y e f f e c t s of LSD a r e mediated p r i m a r i l y by p o s t s y n a p t i c 5-HT, r e c e p t o r s . However, i n view of the e f f e c t s of the c l a s s i c a l and s e l e c t i v e 5-HT2 a n t a g o n i s t s , i t i s t e m p t i n g t o suggest t h a t the l o r d o s i s -i n h i b i t i n g e f f e c t s of LSD may be p a r t i a l l y due t o bl o c k a d e of a c t i v i t y a t s p e c i f i c p o p u l a t i o n s of c e n t r a l 5-HT2 r e c e p t o r s . I t has been suggested t h a t the i n h i b i t i o n of l o r d o s i s by LSD i s due t o an i n c r e a s e i n a c t i v i t y a t 5-HT2 r e c e p t o r s ( S i e t n i e k s , 1985). T h i s c o n c l u s i o n was reached f o l l o w i n g the f i n d i n g t h a t the i n h i b i t o r y e f f e c t s of LSD were reduced by c i n a n s e r i n , c y p r o h e p t a d i n e , and p i r e n p e r o n e , and r e v e r s e d by the 5-HT2 a n t a g o n i s t a l t a n s e r i n . However, i n the same stu d y the 5-HT 2 a n t a g o n i s t s m e t e r g o l i n e , m e t h y s e r g i d e , and m i a n s e r i n had no e f f e c t on the i n h i b i t i o n of l o r d o s i s by LSD. M e t e r g o l i n e , m e t h y s e r g i d e , and m i a n s e r i n , which f a i l e d t o b l o c k LSD, a l l p o s s e s s h i g h e r a f f i n i t y f o r 5-HT2 s i t e s than the e f f e c t i v e drug c i n a n s e r i n . Moreover, the a f f i n i t y of m e t e r g o l i n e f o r 5-HT2 s i t e s i s e q u a l t o , or g r e a t e r than those of the e f f e c t i v e drugs c y p r o h e p t a d i n e and p i r e n p e r o n e ( P e r o u t k a e t a l . , 1981; Leysen & T o l l e n a e r e , 1982; Hoyer e t a l . , 1985). F i n a l l y , l i k e LSD, c y p r o h e p t a d i n e , p i r e n p e r o n e , m e t h y s e r g i d e , m e t e r g o l i n e , and m i a n s e r i n i n h i b i t e d l o r d o s i s i n S i e t n i e k s ' (1985) s t u d y . Thus, i t seems u n l i k e l y t h a t S i e t n i e k s ' d a t a p r o v i d e e v i d e n c e t h a t LSD i n h i b i t s l o r d o s i s by i n c r e a s i n g a c t i v i t y a t 5-HT2 r e c e p t o r s . LSD i n v e r y low doses (5-20 uq/kq) appears t o f a c i l i t a t e 124 l o r d o s i s i n e s t r o g e n - t r e a t e d females ( E v e r i t t et a l . , 1975; S i e t n i e k s & Meyerson, 1983). These e f f e c t s of LSD have been a t t r i b u t e d t o i n h i b i t i o n of s e r o t o n e r g i c a c t i v i t y t h r o u g h a c t i o n upon a u t o r e c e p t o r s i n the d o r s a l raphe. However, whereas a r e d u c t i o n of n e u r o n a l a c t i v i t y i n the d o r s a l raphe might c o n t r i b u t e t o the l o r d o s i s - f a c i l i t a t i n g e f f e c t of LSD, the f a c i l i t a t i o n of l o r d o s i s by LSD cannot be due e n t i r e l y t o t h i s mechanism. The r e d u c t i o n of n e u r o n a l a c t i v i t y i n the raphe f o l l o w i n g LSD treatment i s a r e l a t i v e l y s h o r t - l i v e d phenomenon. Indeed, raphe neurons may b e g i n t o r e c o v e r t h e i r normal p a t t e r n s of f i r i n g w i t h i n 5 minutes a f t e r the i n t r a v e n o u s a d m i n i s t r a t i o n of LSD ( A g h a j a n i a n , Foote & Sheard, 1968). In c o n t r a s t , the f a c i l i t a t i o n of l o r d o s i s i n d u c e d by LSD may p e r s i s t u n d i m i n i s h e d f o r as l o n g as 3 hr a f t e r t r eatment ( S i e t n i e k s & Meyerson, 1983) . R e c e n t l y , i t has been found t h a t v e r y low doses of LSD (5-10 Mg/kg) enhance the a b i l i t y of s e r o t o n i n t o f a c i l i t a t e the g l u t a m a t e - i n d u c e d e x c i t a t i o n of motor neurons i n the r a t f a c i a l n u c l e u s ( M c C a l l & A g h a j a n i a n , 1980). T h i s e f f e c t of s e r o t o n i n appears t o be mediated by 5-HT2 r e c e p t o r s ( P e n i n g t o n & R e i f f e n s t e i n , 1986b). The enhancement of s e r o t o n e r g i c a c t i v i t y i n the f a c i a l n u c l e u s by LSD was found t o p e r s i s t f o r over 4 h r , a time c o u r s e s i m i l a r t o t h a t o b s e r v e d i n the f a c i l i t a t i o n of l o r d o s i s by LSD ( S i e t n i e k s & Meyerson, 1983). These d a t a suggest t h a t p o s t s y n a p t i c enhancement, r a t h e r than p r e s y n a p t i c i n h i b i t i o n of s e r o t o n e r g i c a c t i v i t y may be r e s p o n s i b l e f o r the p r o l o n g e d l o r d o s i s - f a c i l i t a t i n g e f f e c t of low doses of LSD. The h a l l u c i n o g e n i c p h e n y l a l k y l a m i n e s 2,5-dimethoxy-4-1 25 methylamphetamine (DOM), 2,4,5-trimethoxyamphetamine (TMA), 2,5-di m e t h o x y - 4 - m e t h y l p h e n y l e t h y l a m i n e (DOMPE), and m e s c a l i n e have a l s o been found t o f a c i l i t a t e l o r d o s i s a t low do s e s , and t o i n h i b i t l o r d o s i s a t h i g h e r doses ( E v e r i t t & Fuxe, 1977). As w i t h LSD, the f a c i l i t a t o r y e f f e c t s of the p h e n y l a l k y l a m i n e s have been a t t r i b u t e d t o r e d u c t i o n s i n s e r o t o n e r g i c a c t i v i t y ( E v e r i t t & Fuxe, 1977). However, n e i t h e r m e s c a l i n e ( H a i g l e r & A g h a j a n i a n , 1973) nor DOM ( P e n i n g t o n and R e i f f e n s t e i n , 1986a) has s i g n i f i c a n t e f f e c t s on s e r o t o n e r g i c a u t o r e c e p t o r s i n the d o r s a l raphe . I n t e r e s t i n g l y , l i k e LSD, m e s c a l i n e ( M c C a l l & A g h a j a n i a n , 1980) has been found t o enhance, and DOM ( P e n i n g t o n & R e i f f e n s t e i n , 1986b) t o mimic the 5-HT2 r e c e p t o r - m e d i a t e d e x c i t a t o r y e f f e c t of s e r o t o n i n on neurons of the f a c i a l motor n u c l e u s . Of f u r t h e r i n t e r e s t , the a f f i n i t i e s of DOM and TMA f o r 5-HT2 s i t e s have been found t o be 3 0 - f o l d h i g h e r (Shannon et a l . , 1984), and the a f f i n i t y of m e s c a l i n e 1 2 - f o l d h i g h e r (Leysen & T o l l e n a e r e , 1982) than t h e i r a f f i n i t i e s f o r 5-HT, s i t e s . The range of doses i n which t h e s e drugs produced f a c i l i t a t i o n and i n h i b i t i o n of l o r d o s i s ( E v e r i t t & Fuxe, 1977) seems t o r e f l e c t the drugs' r e l a t i v e a f f i n i t i e s f o r 5-HT2 and 5-HT, s i t e s . Low doses of the h a l l u c i n o g e n i c t r y p t a m i n e d e r i v a t i v e s N , N , d i m e t h y l t r y p t a m i n e (DMT), 5- m e t h o x y d i m e t h y l t r y p t a m i n e ( 5-MeODMT), and p s i l o c y b i n a l s o f a c i l i t a t e l o r d o s i s i n e s t r o g e n -primed f e m a l e s . High doses of these drugs a re i n h i b i t o r y i n females primed w i t h e s t r o g e n or w i t h e s t r o g e n and p r o g e s t e r o n e ( E v e r i t t & Fuxe, 1977). Tryptamine d e r i v a t i v e s have been thought t o b i n d w i t h h i g h e s t a f f i n i t y t o 5-HT, r e c e p t o r s ( P e r o u t k a e t a l . , 1981). W i t h i n t h i s c l a s s of r e c e p t o r s , 5-MeODMT and DMT 1 26 show a marked s e l e c t i v i t y f o r 5-HT,A s i t e s ( P e r o u t k a , 1986). Thus the f a c i l i t a t o r y and i n h i b i t o r y e f f e c t s of the N-methylated t r y p t a m i n e s c o u l d be a t l e a s t p a r t i a l l y due t o a c t i v i t y a t s o m a t o - d e n d r i t i c a u t o r e c e p t o r s and p o s t s y n a p t i c 5-HT,A r e c e p t o r s , r e s p e c t i v e l y . However, a t doses comparable t o those t h a t f a c i l i t a t e l o r d o s i s , p s i l o c i n ( the a c t i v e m e t a b o l i t e of p s i l o c y b i n ) enhances, and DMT mimics the n e u r a l e x c i t a t o r y e f f e c t of s e r o t o n i n i n the f a c i a l motor n u c l e u s ( M c C a l l & A g h a j a n i a n , 1980). Thus i t appears t h a t the l o r d o s i s -f a c i l i t a t i n g e f f e c t s of h a l l u c i n o g e n i c t r y p t a m i n e s c o u l d be a t l e a s t p a r t i a l l y due t o a c t i v i t y a t 5-HT2 r e c e p t o r s . The p i p e r a z i n e d e r i v a t i v e q u i p a z i n e b i n d s w i t h m o d e r a t e l y h i g h a f f i n i t y t o 5 - H T T C , 5 - H T T B , and 5-HT2 r e c e p t o r s , and w i t h s l i g h t l y lower a f f i n i t y t o 5-HT,A r e c e p t o r s (Hoyer e t a l . , 1985). Q u i p a z i n e was f i r s t r e p o r t e d t o i n h i b i t l o r d o s i s i n females primed w i t h e s t r o g e n and p r o g e s t e r o n e ( R o d r i g u e z - S i e r r a & D a v i s , 1979). However, i n l a t e r s t u d i e s comparable doses of q u i p a z i n e were found t o be i n e f f e c t i v e i n females t r e a t e d w i t h e s t r o g e n and p r o g e s t e r o n e (Arendash & G o r s k i , 1982; Mendelson & G o r z a l k a , 1985b) and t o f a c i l i t a t e l o r d o s i s i n females t r e a t e d w i t h e s t r o g e n a l o n e (Hunter et a l . , 1985). I n t e r e s t i n g l y , q u i p a z i n e has a l s o been found t o f a c i l i t a t e l o r d o s i s , t o a l i m i t e d degree, i n s p i n a l r a t s (Kow, Zemlan & P f a f f , 1979). I have s u b s e q u e n t l y o b s e r v e d t h a t low doses of q u i p a z i n e f a c i l i t a t e , whereas doses over 9 mg/kg may i n h i b i t l o r d o s i s i n e s t r o g e n - p r i m e d females (Mendelson & G o r z a l k a , u n p u b l i s h e d d a t a ) . Q u i p a z i n e i s a c t i v e a t s o m a t o - d e n d r i t i c 5-HT,A 127 a u t o r e c e p t o r s ( B l i e r & de Mon t i g n y , 1983) , thus i t may f a c i l i t a t e l o r d o s i s by r e d u c i n g t h e a c t i v i t y of l o r d o s i s -i n h i b i t i n g s e r o t o n e r g i c pathways. At h i g h e r doses, q u i p a z i n e may i n h i b i t l o r d o s i s by a c t i v a t i n g p o s t s y n a p t i c 5 - H T , A r e c e p t o r s , or by enhancing the r e l e a s e of 5 - H T i n c e r t a i n a r e a s t h r o u g h i t s a c t i o n as a weak a n t a g o n i s t a t p r e j u n c t i o n a l 5 - H T T B a u t o r e c e p t o r s ( M a r t i n & Sanders-Bush, 1982), However, q u i p a z i n e appears t o a c t p r i m a r i l y as a 5 - H T 2 a g o n i s t . Q u i p a z i n e e l e v a t e s serum c o r t i c o s t e r o n e l e v e l s , and t h i s i s r e v e r s e d by tr e a t m e n t w i t h the s e l e c t i v e 5 - H T 2 a n t a g o n i s t LY53857 (Cohen e t a l . , 1983). In s t i m u l u s g e n e r a l i z a t i o n s t u d i e s , a n i m a l s t r a i n e d t o respond t o the 5 - H T 2 a g o n i s t DOM w i l l a l s o respond t o q u i p a z i n e (Glennon, Young, & Rosencrans, 1983). Perhaps most i m p o r t a n t l y , q u i p a z i n e a t t e n u a t e s the l o r d o s i s - i n h i b i t i n g e f f e c t s of the 5-H T 2 a n t a g o n i s t s p i r e n p i r o n e , k e t a n s e r i n , m e t h y s e r g i d e , c y p r o h e p t a d i n e , and p i z o t e f i n (Mendelson & G o r z a l k a , 1985b, 1986a). These f i n d i n g s suggest t h a t q u i p a z i n e f a c i l i t a t e s l o r d o s i s by s t i m u l a t i n g 5-HT2 r e c e p t o r s , and a t t e n u a t e s the e f f e c t s of 5-HT2 a n t a g o n i s t s by r e s t o r i n g a c t i v i t y t o these r e c e p t o r s . In view of the much h i g h e r a f f i n i t y of a n t a g o n i s t s f o r 5-HT2 r e c e p t o r s , the s u g g e s t i o n t h a t q u i p a z i n e c o u l d compete e f f e c t i v e l y w i t h t h e s e drugs f o r 5-HT2 b i n d i n g s i t e s i s s u r p r i s i n g . I n t e r e s t i n g l y , r e c e n t d a t a i n d i c a t e t h a t a s u b p o p u l a t i o n of 5-HT2 b i n d i n g s i t e s p o s s e s s e s a c o n f o r m a t i o n a l s t a t e w i t h h i g h a f f i n i t y f o r 5-HT2 a g o n i s t s (Lyon, D a v i s & T i t e l e r , 1987). Q u i p a z i n e has been found t o b i n d w i t h q u i t e h i g h a f f i n i t y t o the a g o n i s t b i n d i n g s t a t e of the 5-HT2 r e c e p t o r (Lyon et a l . , 1987). At mod e r a t e l y h i g h doses, q u i p a z i n e might 128 be e x p e c t e d t o d i s p l a c e 5-HT2 a n t a g o n i s t s from th e s e s i t e s . I t i s worth n o t i n g t h a t DMT, 5-MeODMT, and p h e n y l a l k y l a m i n e s s i m i l a r t o DOM b i n d w i t h v e r y h i g h a f f i n i t y t o the a g o n i s t b i n d i n g ' s t a t e of the 5-HT2 r e c e p t o r (Lyon e t a l . , 1987). The p i p e r a z i n e MK 212 f a c i l i t a t e s l o r d o s i s , and t h i s e f f e c t has been a t t r i b u t e d t o s t i m u l a t i o n of 5-HT2 r e c e p t o r s ( W i l s o n & Hunt e r , 1985). MK 212 produces the h e a d - t w i t c h response ( C l i n e s c h m i d t , M c G u f f i n , & P f l u e g e r , 1977) i n a manner t y p i c a l of 5-HT2 a g o n i s t s and i t s u b s t i t u t e s f o r q u i p a z i n e i n drug d i s c r i m i n a t i o n s t u d i e s ( L u c o t , 1984). However, b i n d i n g s t u d i e s show a v e r y low a f f i n i t y of MK 212 f o r 5-HT2 and o t h e r 5-HT r e c e p t o r s ( E n g e l e t a l . , 1986). I t would be of i n t e r e s t t o determine the a f f i n i t y of MK 212 f o r the a g o n i s t b i n d i n g s t a t e of the 5-HT2 r e c e p t o r . R e c e n t l y , drugs w i t h v e r y h i g h s e l e c t i v i t y f o r 5-H^A r e c e p t o r s have become a v a i l a b l e . The h i g h l y s e l e c t i v e 5-HT,A a g o n i s t 8-OH-DPAT, and the s l i g h t l y l e s s s e l e c t i v e p a r t i a l a g o n i s t s b u s p i r o n e , i p s a p i r o n e , and g e p i r o n e i r f h i b i t l o r d o s i s i n females primed e i t h e r w i t h e s t r o g e n , or w i t h e s t r o g e n and p r o g e s t e r o n e ( A h l e n i u s , F e r n a n d e z - G u a s t i , H j o r t h & L a r s s o n , 1986; Mendelson & G o r z a l k a , 1986c,d). E x t r e m e l y s m a l l doses of the somewhat s e l e c t i v e 5-HT,A a g o n i s t l i s u r i d e ( P e r o u t k a , 1986) a l s o i n h i b i t l o r d o s i s i n females primed w i t h e s t r o g e n and p r o g e s t e r o n e ( S i e t n i e k s , 1985). At lower doses, i p s a p i r o n e and ge p i r o n e f a c i l i t a t e l o r d o s i s i n e s t r o g e n - p r i m e d females (Mendelson & G o r z a l k a , I986d). Because both drugs reduce the a c t i v i t y of s e r o t o n e r g i c neurons i n the d o r s a l raphe ( D o u r i s h , Hutson & Curzon, 1986; E i s o n , E i s o n , S t a n l e y & R i b l e t , 1986) the 129 l o r d o s i s - f a c i l i t a t i n g e f f e c t s of thes e drugs may be due t o a c t i v i t y a t s o m a t o - d e n d r i t i c 5-HT,A a u t o r e c e p t o r s . I t i s of i n t e r e s t t o note t h a t doses of b u s p i r o n e , i p s a p i r o n e , and g e p i r o n e t h a t e i t h e r f a c i l i t a t e l o r d o s i s or are i n e f f e c t i v e i n females primed w i t h e s t r o g e n a l o n e i n h i b i t l o r d o s i s i n females primed w i t h b o t h e s t r o g e n and p r o g e s t e r o n e (Mendelson & G o r z a l k a , I986d). The l o r d o s i s - i n h i b i t i n g e f f e c t s of the s e l e c t i v e 5-HT,A a g o n i s t s 8-OH DPAT (Mendelson & G o r z a l k a , u n p u b l i s h e d data) and l i s u r i d e ( H l i n a k , 1987; S i e t n i e k s , 1985), the 5-HT,A a c t i v e a g o n i s t LSD ( S i e t n i e k s & Meyerson, 1980) and the u n c h a r a c t e r i z e d 5-HT a g o n i s t a m e t h y l t r y p t a m i n e ( E s p i n o , Sano & Wade, 1975) a l s o appear t o be e i t h e r enhanced by or dependent upon t r e a t m e n t w i t h p r o g e s t e r o n e . These d a t a support our r e c e n t s u g g e s t i o n t h a t p r o g e s t e r o n e enhances the e f f e c t s of a c t i v i t y at 5-HT,A r e c e p t o r s (Mendelson & G o r z a l k a , I986d). The 5-HT a g o n i s t 1 - ( 3 - t r i f l u o r o m e t h y l p h e n y l ) p i p e r a z i n e (TFMPP) has a s e r o t o n e r g i c b i n d i n g p r o f i l e s i m i l a r t o t h a t of q u i p a z i n e . However, TFMPP appears t o a c t p r i m a r i l y as an a g o n i s t a t 5 - H T T B r e c e p t o r s . U n l i k e q u i p a z i n e , TFMPP i n h i b i t s the K +-indu c e d r e l e a s e of 5-HT from h y p o t h a l a m i c synaptosomes ( M a r t i n & Sanders-Bush, 1982). In s t i m u l u s g e n e r a l i z a t i o n s t u d i e s , a n i m a l s t r a i n e d t o respond t o TFMPP w i l l respond t o the 5 - H T T B a g o n i s t s m - c h l o r o p h e n y l p i p e r a z i n e (MCPP) and RU24969, but not t o q u i p a z i n e , the 5-HT2 a g o n i s t DOM, or the s e l e c t i v e 5-HT,A a g o n i s t 8-OH DPAT (Cunningham & A p p e l , 1986; Glennon, McKenny & Young, 1984). P e r i p h e r a l a d m i n i s t r a t i o n of TFMPP f a c i l i t a t e s l o r d o s i s i n e s t r o g e n - p r i m e d f e m a l e s ( E x p e r i m e n t 8 ) . In a d d i t i o n , 1 30 I have v e r y r e c e n t l y o b s e r v e d t h a t 0.03 mg/kg of the p u t a t i v e 5-HT,B a g o n i s t CGS 12066B ( N e a l e , F a l l o n , Boyar, Wasley, M a r t i n , S tone, G l a e s e r , S i n t o n & W i l l i a m s , 1987) f a c i l i t a t e s l o r d o s i s i n e s t r o g e n - p r i m e d females ( Mendelson & G o r z a l k a , u n p u b l i s h e d d a t a ) . T o g e t h e r , th e s e d a t a suggest t h a t p r e j u n c t i o n a l S-H^B a u t o r e c e p t o r s mediate l o r d o s i s - f a c i l i t a t i n g e f f e c t s of 5-HT. In apparent c o n t r a d i c t i o n t o t h i s p o s s i b i l i t y , RU 24969 has been r e p o r t e d t o i n h i b i t l o r d o s i s (Hunter & W i l s o n , 1985). However, whereas RU 24969 has o f t e n been c h a r a c t e r i z e d as a s e l e c t i v e 5-HT,B a g o n i s t , the drug b i n d s w i t h n e a r l y e q u a l h i g h a f f i n i t y t o 5-HT,A r e c e p t o r s ( T r i c k l e b a n k , M i d d l e m i s s & N e i l l , 1986). Indeed, a t doses t h a t i n h i b i t l o r d o s i s ( W i l s o n & Hunter, 1985), RU 24969 mimics the hypothermic e f f e c t of the 5-HT,A s e l e c t i v e a g o n i s t 8-OH DPAT ( T r i c k l e b a n k e t a l . , 1986). Recent e v i d e n c e s u g g e s t s t h a t 5-HT,B r e c e p t o r s may e x i s t p o s t - as w e l l as p r e -s y n a p t i c a l l y ( K e n n e t t , D o u r i s h & Curzon, 1987). T h e r e f o r e , t h e r e i s the p o s s i b i l i t y t h a t h i g h e r doses of 5-HT,B a g o n i s t s c o u l d produce l o r d o s i s - i n h i b i t i n g e f f e c t s t h r o u g h a c t i o n at c e r t a i n p o s t s y n a p t i c 5-HT,B s i t e s . However, the f a c t t h a t TFMPP f a c i l i t a t e d l o r d o s i s a t doses t h a t appeared t o produce p o s t s y n a p t i c s e r o t o n e r g i c s t i m u l a t i o n t e n d s t o argue a g a i n s t t h i s p o s s i b i l i t y . C o n c l u s i o n s In r e v i e w i n g the e f f e c t s of 5-HT a n t a g o n i s t s and a g o n i s t s i t becomes apparent t h a t s e r o t o n i n can e i t h e r i n h i b i t or f a c i l i t a t e the e x p r e s s i o n of l o r d o s i s b e h a v i o u r i n the female 131 r a t . I t appears t h a t the l o r d o s i s - i n h i b i t i n g e f f e c t s of s e r o t o n i n a r e mediated p r i m a r i l y by p o s t - s y n a p t i c 5-HT,A r e c e p t o r s . I t i s t e m p t i n g t o suggest t h a t the 5-HT!A r e c e p t o r s t h a t mediate these e f f e c t s e x i s t p r i m a r i l y i n the f o r e b r a i n . T h i s c o n c l u s i o n i s c o n s i s t e n t w i t h the v a r i e t y of r e p o r t s ( c i t e d i n Mendelson & G o r z a l k a , 1985b) i n d i c a t i n g t h a t s i m p l e d e p l e t i o n of f o r e b r a i n s e r o t o n i n l e v e l s , by e i t h e r c h e m i c a l or s u r g i c a l means, f a c i l i t a t e s l o r d o s i s . On the b a s i s of p r e l i m i n a r y e v i d e n c e , I f u r t h e r suggest t h a t f o r e b r a i n 5-HT3 r e c e p t o r s may mediate some of the l o r d o s i s - i n h i b i t i n g e f f e c t s of s e r o t o n i n . The l o r d o s i s - f a c i l i t a t i n g e f f e c t s of s e r o t o n i n appear t o be mediated p r i m a r i l y by 5 - H T 2 r e c e p t o r s . Moreover, i t i s tempting t o suggest t h a t the s u b p o p u l a t i o n of 5 - H T 2 r e c e p t o r s p o s s e s s i n g a h i g h a f f i n i t y a g o n i s t b i n d i n g s t a t e may p l a y a p a r t i c u l a r l y i m p o r t a n t r o l e i n m e d i a t i n g t h e s e e f f e c t s . Of c o u r s e , I might a g a i n note t h a t drugs s e l e c t i v e f o r 5 - H T 2 r e c e p t o r s t e n d a l s o t o b i n d w i t h h i g h a f f i n i t y t o 5 - H T T C r e c e p t o r s . I t h e r e f o r e cannot e l i m i n a t e the p o s s i b i l i t y t h a t a c t i v i t y a t c e r t a i n p o p u l a t i o n s of 5 - H T , C r e c e p t o r s enhances l o r d o s i s . There i s e v i d e n c e t h a t s t i m u l a t i o n of the m e d u l l a r y r e t i c u l a r f o r m a t i o n f a c i l i t a t e s l o r d o s i s ( Cohen, Schwartz-G i b l i n & P f a f f , 1987). Moreover, i t appears t h a t 5-HT2 r e c e p t o r s mediate n e u r a l e x c i t a t o r y e f f e c t s of s e r o t o n i n i n t h i s a r e a ( H a i g l e r & A g h a j a n i a n , 1974a; P e r o u t k a e t a l . , 1981). Very r e c e n t l y I have found t h a t the a d m i n i s t r a t i o n of s m a l l doses of the 5-HT2 a n t a g o n i s t LY 53857 d i r e c t l y i n t o the m e d u l l a r y r e t i c u l a r f o r m a t i o n i n h i b i t s l o r d o s i s , whereas the a d m i n i s t r a t i o n of q u i p a z i n e i n t o t h i s a r e a i s f a c i l i t a t o r y 132 ( u n p u b l i s h e d d a t a ) . In view of these r e s u l t s , and of the many r e p o r t s of f a c i l i t a t i o n of l o r d o s i s f o l l o w i n g d e p l e t i o n of f o r e b r a i n s e r o t o n i n , I h y p o t h e s i z e t h a t the l o r d o s i s -f a c i l i t a t i n g e f f e c t s of s e r o t o n i n a re mediated p r i m a r i l y by n e u r a l e x c i t a t o r y a c t i v i t y a t 5-HT2 r e c e p t o r s i n the b r a i n s t e m . I t i s t e m p t i n g t o o f f e r an a d d i t i o n a l mechanism by which a c t i v i t y a t 5-HT2 r e c e p t o r s might f a c i l i t a t e l o r d o s i s . I t has been suggested t h a t i n a r e a s of the b r a i n where 5-HT, and 5-HT2 r e c e p t o r s c o - e x i s t , 5-HT2 r e c e p t o r s may se r v e t o modulate the a c t i v i t y of 5-HT, r e c e p t o r s . I n some a r e a s , a c t i v i t y a t 5-HT2 appears t o d i m i n i s h the e f f e c t s of a c t i v i t y a t 5-HT, r e c e p t o r s ( A g h a j a n i a n , Sprouse & Rasmussen, 1987). I t may be t h a t s e l e c t i v e s t i m u l a t i o n of 5-HT2 r e c e p t o r s can f a c i l i t a t e l o r d o s i s i n d i r e c t l y by a t t e n u a t i n g the l o r d o s i s - i n h i b i t i n g e f f e c t s of a c t i v i t y a t a d j a c e n t 5-HT,A r e c e p t o r s i n the f o r e b r a i n . C o n v e r s e l y , 5-HT2 a n t a g o n i s t s would i n h i b i t l o r d o s i s by f r e e i n g f o r e b r a i n 5-HT,A r e c e p t o r s from t h e m o d u l a t i n g e f f e c t s of a c t i v i t y a t 5-HT2 r e c e p t o r s . I t i s i n t e r e s t i n g t o c o n s i d e r t h a t by t h i s mechanism, the apparent e f f e c t i v e n e s s of 5-HT2 a g o n i s t s and a n t a g o n i s t s i n a f f e c t i n g l o r d o s i s might v a r y as a f u n c t i o n of b a s e l i n e l e v e l s of s e r o t o n e r g i c a c t i v i t y . E v i d e n c e suggests t h a t a c t i v i t y a t s o m a t o - d e n d r i t i c 5-HT,A a u t o r e c e p t o r s may a l s o f a c i l i t a t e l o r d o s i s b e h a v i o u r . O s t e n s i b l y , t h i s would be due t o r e d u c t i o n s i n the a c t i v i t y of l o r d o s i s - i n h i b i t i n g s e r o t o n e r g i c pathways a s c e n d i n g t o the f o r e b r a i n . I f u r t h e r suggest t h a t a c t i v i t y a t p r e j u n c t i o n a l a u t o r e c e p t o r s of the 5-HT,B type f a c i l i t a t e s l o r d o s i s a c t i v i t y . As w i t h the a c t i v a t i o n of a u t o r e c e p t o r s of the 5-HT,A t y p e , the 133 a c t i v a t i o n of p r e j u n c t i o n a l 5-HT,B r e c e p t o r s would r e s u l t i n the r e d u c t i o n of a c t i v i t y i n c e r t a i n l o r d o s i s - i n h i b i t i n g s e r o t o n e r g i c pathways. In summary, I h y p o t h e s i z e t h a t s e r o t o n i n can e i t h e r i n h i b i t or f a c i l i t a t e l o r d o s i s b e h a v i o u r . I suggest t h a t the i n h i b i t o r y e f f e c t s of s e r o t o n i n a r e mediated p r i m a r i l y by p o s t - s y n a p t i c 5-HT,A r e c e p t o r s i n the f o r e b r a i n , whereas the f a c i l i t a t o r y e f f e c t s a r e mediated by 5-HT2 r e c e p t o r s i n the b r a i n s t e m . I f u r t h e r suggest t h a t a c t i v i t y a t s o m a t o - d e n d r i t i c 5-HT,A a u t o r e c e p t o r s i n the raphe n u c l e i may f a c i l i t a t e l o r d o s i s . F i n a l l y , on the b a s i s of p r e l i m i n a r y e v i d e n c e , I suggest t h a t 5-HT 3 r e c e p t o r s may mediate i n h i b i t o r y , and p r e j u n c t i o n a l S-HT^B a u t o r e c e p t o r s f a c i l i t a t o r y e f f e c t s of s e r o t o n i n on l o r d o s i s b e h a v i o u r . IMPLICATIONS FOR UNDERSTANDING EFFECTS OF SEROTONERGIC DRUGS ON HUMAN BEHAVIOUR The r e p r o d u c t i v e b i o l o g y of the female r a t i s c o n s i d e r a b l y d i f f e r e n t from t h a t of the human female. For example, as noted e a r l i e r , the s e x u a l b e h a v i o u r of the female r a t i s e n t i r e l y dependent on exposure t o e s t r o g e n . In c o n t r a s t , whereas the magnitude and na t u r e of her s e x u a l m o t i v a t i o n may v a r y somewhat th r o u g h her m e n s t r u a l c y c l e , the s e x u a l a c t i v i t y of the human female appears t o be l a r g e l y independent of f l u c t u a t i o n s i n e s t r o g e n l e v e l s . There are a l s o d i s t i n c t d i f f e r e n c e s i n the p h y s i c a l e x p r e s s i o n of s e x u a l b e h a v i o u r i n the female r a t and the human female. For example, the r e f l e x i v e l o r d o s i s response 134 has no o b v i o u s c o u n t e r p a r t i n the human female. Moreover, i t might be noted t h a t the s t i m u l a t i o n r e c e i v e d by the female r a t i n c o p u l a t i o n , which might i n c l u d e s i x t o ten w e l l - s p a c e d and s h o r t - l i v e d ( g e n e r a l l y l e s s than 2 or 3 seconds i n d u r a t i o n ) i n s e r t i o n s of the male's p e n i s , would be d e c i d e d l y u n c h a r a c t e r i s t i c of t h a t e x p e r i e n c e d (or a t l e a s t expected!) by the human fema l e . F i n a l l y , of c o u r s e , i t s h o u l d be emphasized t h a t the g r e a t e s t d i f f e r e n c e s between the s e x u a l b e h a v i o u r of the female r a t and t h a t of the human female l i e i n the e x t r e m e l y r i c h e m o t i o n a l , s o c i a l , and c o g n i t i v e components of human s e x u a l b e h a v i o u r . In view of the extreme d i f f e r e n c e s i n the s e x u a l b e h a v i o u r s of the female r a t and the human female , one might q u e s t i o n the r e l e v a n c e the p r e s e n t d a t a might h o l d f o r the u n d e r s t a n d i n g of the r o l e of s e r o t o n i n i n the m o d u l a t i o n of human female s e x u a l b e h a v i o u r . However, d e s p i t e t h e s e o b v i o u s d i f f e r e n c e s I b e l i e v e t h a t t h e r e a r e a t l e a s t t h r e e ways i n which the p r e s e n t d a t a may be of r e l e v a n c e t o the u n d e r s t a n d i n g of the r o l e of s e r o t o n i n and the e f f e c t s of s e r o t o n e r g i c drugs on human female s e x u a l b e h a v i o u r and human b e h a v i o u r i n g e n e r a l . F i r s t , the p r e s e n t e v a l u a t i o n of the e f f e c t s of s e r o t o n e r g i c drugs on l o r d o s i s may c o n t r i b u t e d i r e c t l y t o our u n d e r s t a n d i n g of the neuropharmacology of human female s e x u a l b e h a v i o u r . Indeed, a thorough u n d e r s t a n d i n g of the e f f e c t s of s e r o t o n e r g i c drugs on l o r d o s i s c o u l d p o s s i b i l y l e a d t o the development of an a n i m a l model of the of s e r o t o n e r g i c m o d u l a t i o n of s e x u a l b e h a v i o u r i n women. In view of the s e r i o u s l a c k of i n f o r m a t i o n c o n c e r n i n g the neuropharmacology of human, p a r t i c u l a r l y female, s e x u a l 135 b e h a v i o u r , a s u c c e s s f u l a n i m a l model would be of s u b s t a n t i a l v a l u e . Second, the p r e s e n t d a t a may p r o v i d e a b a s i s f o r the u n d e r s t a n d i n g of p o t e n t i a l i n t e r a c t i o n s between s e r o t o n e r g i c drugs and the gonadal s t e r o i d hormones i n humans. T h i r d , t h e s e d a t a may a l l o w f u r t h e r i n s i g h t i n t o p o t e n t i a l sex d i f f e r e n c e s i n humans i n the responses t o s e r o t o n e r g i c drugs. A l t h o u g h g r e a t s t r i d e s have been made i n u n d e r s t a n d i n g the neuropharmacology of a f f e c t i v e b e h a v i o u r , v e r y l i t t l e i s known about the neuropharmacology of human s e x u a l b e h a v i o u r . Moreover, i t appears t h a t most of what i s known about the e f f e c t s of drugs on human s e x u a l b e h a v i o u r i s known i n r e g a r d s t o the somewhat m e c h a n i c a l a s p e c t s of male s e x u a l b e h a v i o u r , e r e c t i o n and e j a c u l a t i o n . R e l a t i v e l y l i t t l e i s known about the e f f e c t s of drugs on s e x u a l m o t i v a t i o n or s a t i s f a c t i o n i n e i t h e r males or fem a l e s . In s p i t e of a r e l a t i v e l a c k of i n f o r m a t i o n on drug e f f e c t s , t h e r e i s e v i d e n c e t o suggest t h a t the s e x u a l b e h a v i o u r of human females i s a t l e a s t p a r t i a l l y under s e r o t o n e r g i c i n f l u e n c e . For example, women r e c e i v i n g the monoamine o x i d a s e (MAO) i n h i b i t o r s p h e n e l z i n e , t r a n y l c y p r o m i n e , and i s o c a r b o x i d e as t r e a t m e n t s f o r d e p r e s s i o n have f r e q u e n t l y been r e p o r t e d t o e x p e r i e n c e l o s s of l i b i d o and anorgasmia, t h a t i s , the l o s s of a b i l i t y t o e x p e r i e n c e orgasm (Shen & S a t a , 1983). MAO i n h i b i t o r s a r e thought t o produce t h e i r t h e r a p e u t i c e f f e c t s by p r e v e n t i n g the enzymatic breakdown of s e r o t o n i n and the c a t e c h o l e a m i n e n e u r o t r a n s m i t t e r s . F o l l o w i n g t r e a t m e n t w i t h MAO i n h i b i t o r s , t he e f f e c t i v e n e s s of thes e n e u r o t r a n s m i t t e r s i s enhanced. These f a c t s suggest t h a t the s e x u a l l y i n h i b i t o r y e f f e c t s of thes e 1 36 drugs may be a t l e a s t p a r t i a l l y be due t o i n c r e a s e s i n c e r t a i n t y p e s of s e r o t o n e r g i c a c t i v i t y . Women r e c e i v i n g t r i c y c l i c a n t i d e p r e s s a n t d r u g s , i n c l u d i n g a m i t r i p t y l i n e , i m i p r a m i n e , n o r t r i p t y l i n e and c l o m i p r a m i n e , have a l s o f r e q u e n t l y been r e p o r t e d t o e x p e r i e n c e d e c r e a s e s i n l i b i d o and anorgasmia (Buffurn, 1986). These t r i c y l i c a n t i d e p r e s s a n t s have l o n g been thought t o produce t h e i r t h e r a p e u t i c e f f e c t s by p r e v e n t i n g neurons from r e c o v e r i n g s e r o t o n i n (and t o some degree n o r a d r e n a l i n ) a f t e r i t s r e l e a s e . When the r e c o v e r y ( r e - u p t a k e ) of s e r o t o n i n i s b l o c k e d , h i g h e r c o n c e n t r a t i o n s of s e r o t o n i n remain i n c o n t a c t w i t h t a r g e t neurons and the e f f e c t s of the n e u r o t r a n s m i t t e r a re enhanced. More r e c e n t l y i t has become known t h a t t h e s e drugs a l s o b i n d w i t h r e l a t i v e l y h i g h a f f i n i t y t o 5-HT 2 r e c e p t o r s , where they appear t o a c t as a n t a g o n i s t s (Tang & Seeman, 1980; S t o l z , Marzden & M i d d l e m i s s , 1983). In view of the ways i n which these drugs i n t e r a c t w i t h s e r o t o n e r g i c systems, i t i s t e m p t i n g t o suggest t h a t the i n h i b i t i o n of s e x u a l b e h a v i o u r i n human females t h a t o c c u r s w i t h the a d m i n i s t r a t i o n of t r i c y c l i c a n t i d e p r e s s a n t s i s due t o i n c r e a s e s of a c t i v i t y a t 5-HT, r e c e p t o r s and b l o c k a d e of a c t i v i t y a t 5-HT2 r e c e p t o r s . I n t e r e s t i n g l y , the t r i c y c l i c a n t i d e p r e s s a n t d e s i p r a m i n e , a drug w i t h l i t t l e a b i l i t y t o b l o c k r e u p t a k e of s e r o t o n i n and w i t h r a t h e r low a f f i n i t y f o r 5-HT2 r e c e p t o r s , appears t o produce l i t t l e , i f any, s e x u a l impairment (Buffum, 1986). Of f u r t h e r i n t e r e s t i s the f a c t t h a t the substa n c e MDA, which has been known on the s t r e e t as a ' l o v e drug ' (Gawin, 1978) and has been c o n s i d e r e d by some r e s e a r c h e r s t o a c t as a s e x u a l s t i m u l a n t ( N a r a n j o , S h u l g i n & S a r g e n t , 1967), a l s o b i n d s 137 w i t h r e l a t i v e l y h i g h a f f i n i t y t o 5-HT2 r e c e p t o r s (Glennon St Rosencrans, 1982). However, u n l i k e the t r i c y c l i c a n t i d e p r e s s a n t s , MDA appears t o a c t as an a g o n i s t a t 5-HT2 s i t e s (Glennon & Rosencrans, 1982; Shannon, 1980). The m i l d l y h a l l u c i n o g e n i c harmala a l k a l o i d s , d e r i v e d from the Perqanum  harmala shrub , have a l s o been used as a p h r o d i s i a c s i n the f o l k m e d i c i n e s of I n d i a and the M i d d l e E a s t (Gawin, 1978). Moreover, some harmala a l k a l o i d s have been found t o b i n d w i t h m o d e r a t e l y h i g h a f f i n i t y t o 5-HT2 r e c e p t o r s (Rommelspacher, B r u n i n g , S u s i l o , N i c k & H i l l , 1985). In view of the t h e o r y t h a t i n d o l e a m i n e and p h e n y l a l k y l a m i n e h a l l u c i n o g e n s produce t h e i r e f f e c t s t h r o u g h s t i m u l a t i o n of 5-HT2 r e c e p t o r s (Glennon, Young & Rosencrans, 1983), i t i s c o n c e i v a b l e t h a t the a l l e g e d s e x u a l l y s t i m u l a t i n g e f f e c t s of the harmala a l k a l o i d s a r e a t l e a s t p a r t i a l l y due t o s t i m u l a t i o n of 5-HT2 r e c e p t o r s . I n t h i s c o n t e x t i t must be noted t h a t the harmala a l k a l o i d harmine has been r e p o r t e d t o f a c i l i a t e l o r d o s i s b e h a v i o u r i n the female r a t and t o r e v e r s e the l o r d o s i s - i n h i b i t i n g e f f e c t s of the 5-HT2 a n t a g o n i s t s p i r e n p i r o n e and k e t a n s e r i n (Mendelson & G o r z a l k a , I986e). A l t h o u g h h i g h l y s p e c u l a t i v e , i t i s t e m p t i n g t o suggest from the above d a t a t h a t i n the human female, as i n the female r a t , s e r o t o n i n s e r v e s a d u a l r o l e i n the m o d u l a t i o n of s e x u a l b e h a v i o u r . I f t h i s i s indeed the c a s e , then the model of s e r o t o n e r g i c c o n t r o l of l o r d o s i s b e h a v i o u r i n the female r a t proposed i n t h i s d i s s e r t a t i o n may be of some v a l u e i n u n d e r s t a n d i n g and p r e d i c t i n g the e f f e c t s of s e r o t o n e r g i c drugs on human female s e x u a l b e h a v i o u r . The p r e s e n t s e r i e s of s t u d i e s may a l s o be of r e l e v a n c e i n 138 u n d e r s t a n d i n g the e f f e c t s of s e r o t o n e r g i c drugs on human be h a v i o u r by opening the p o s s i b i l i t y of i n t e r a c t i o n s between s e r o t o n e r g i c drugs and the hormones e s t r o g e n and p r o g e s t e r o n e . I t i s common knowledge t h a t the e f f e c t s of drugs d e s t i n e d f o r use i n humans a r e f i r s t e v a l u a t e d i n e x p e r i m e n t a l a n i m a l s . However, what i s r a r e l y c o n s i d e r e d i s the f a c t t h a t t h e a n i m a l s used i n the s e e v a l u a t i o n s a re almost i n v a r i a b l y male a n i m a l s . I t seems t h a t the f l u c t u a t i o n s i n hormone l e v e l s t h a t c h a r a c t e r i z e the e s t r o u s c y c l e s of fe m a l e s , and the b e h a v i o u r a l changes t h a t accompany the s e f l u c t u a t i o n s , a r e l o o k e d upon as unwelcome s o u r c e s of v a r i a n c e i n s t a n d a r d b e h a v i o u r a l paradigms. U n f o r t u n a t e l y , t h i s b i a s e l i m i n a t e s the p o s s i b i l i t y of e v a l u a t i n g p o t e n t i a l i n t e r a c t i o n s between drugs and the o v a r i a n hormones. Because the f u l l e x p r e s s i o n of l o r d o s i s b e h a v i o u r i s dependent upon exposure t o the female sex hormones, the e v a l u a t i o n of the e f f e c t s of drugs on l o r d o s i s b e h a v i o u r p r o v i d e s an i d e a l o p p o r t u n i t y t o e v a l u a t e p o t e n t i a l drug/hormone i n t e r a c t i o n s . In Experiment 6 i t was found t h a t h i g h doses of the s e l e c t i v e 5-HT,A a g o n i s t s b u s p i r o n e , i p s a p i r o n e and g e p i r o n e i n h i b i t e d l o r d o s i s b e h a v i o u r . However, low doses of t h e s e d r u g s , which e i t h e r f a c i l i t a t e d l o r d o s i s or were i n e f f e c t i v e i n females primed w i t h e s t r o g e n a l o n e , i n h i b i t e d l o r d o s i s i n females primed w i t h both e s t r o g e n and p r o g e s t e r o n e . From these d a t a i t was suggested t h a t the l o r d o s i s - i n h i b i t i n g e f f e c t s of t h e s e drugs a r e enhanced by p r o g e s t e r o n e . With t h e s e p o s s i b i l i t i e s i n mind i t s h o u l d be noted t h a t s e r o t o n e r g i c drugs a r e now p r e s c r i b e d i n the t r e a t m e n t of a v a r i e t y of a f f e c t i v e d i s o r d e r s . Indeed, the 139 s e l e c t i v e 5-HT,A a g o n i s t b u s p i r o n e has j u s t r e c e n t l y become a v a i l a b l e i n Canada as a tr e a t m e n t t o r e l i e v e a n x i e t y . I f p r o g e s t e r o n e does enhance the e f f e c t s of a g o n i s t s a t 5-HT,A s i t e s , then i t i s c o n c e i v a b l e t h a t i t might a l s o a l t e r t he a n x i o l y t i c e f f e c t s of the s e d r u g s . The p o s s i b i l i t y t h a t the p s y c h o t h e r a p e u t i c e f f e c t i v e n e s s of the s e drugs might v a r y t h r o u g h the m e n s t r u a l c y c l e as a f u n c t i o n of ch a n g i n g l e v e l s of e s t r o g e n and p r o g e s t e r o n e l e v e l s s h o u l d be of c o n s i d e r a b l e c o n c e r n t o the m e d i c a l community. However, t o the be s t of my knowledge t h i s p o s s i b i l i t y has not been a d d r e s s e d i n the l i t e r a t u r e . I t may a l s o be r e c a l l e d t h a t 5-HT,A a g o n i s t s produce t h e i r e f f e c t s on be h a v i o u r by m i m i c k i n g the e f f e c t s of s e r o t o n i n . I f e s t r o g e n and p r o g e s t e r o n e do modulate the e f f e c t s of 5-HT,A a g o n i s t s , then i t i s r e a s o n a b l e t o suggest t h a t t h e s e hormones modulate the a c t i v i t i e s of s e r o t o n i n i t s e l f a t 5-HT,A r e c e p t o r s . T h e r e f o r e , i n view of the e v i d e n c e t h a t a c t i v i t y a t 5-HT,A r e c e p t o r s may i n some way be i n v o l v e d i n the e x p e r i e n c e of a n x i e t y ( D o u r i s h et a l . , 1986), the r e s u l t s of Experiment 6 a l s o l e a d t o the s u g g e s t i o n t h a t a b n o r m a l i t i e s i n the m o d u l a t i o n of 5-HT,A r e c e p t o r s by p r o g e s t e r o n e may be i n v o l v e d i n the p a t h o g e n e s i s of mood d i s o r d e r s a s s o c i a t e d w i t h the p r e m e n s t r u a l syndrome. F i n a l l y , when taken t o g e t h e r w i t h the r e s u l t s of ex p e r i m e n t s now i n p r o g r e s s , the p r e s e n t d a t a r a i s e t he p o s s i b i l i t y t h a t t h e r e may be sex d i f f e r e n c e s i n the responses t o s e r o t o n e r g i c drugs. As w i t h female r a t s , s t u d i e s on the e f f e c t s of r e c e p t o r subtype s e l e c t i v e drugs on the s e x u a l 140 b e h a v i o u r of male r a t s have o n l y r e c e n t l y begun. However, i n s e v e r a l c a s e s t h e r e have appeared t o be d r a m a t i c d i f f e r e n c e s i n the e f f e c t s - of c e r t a i n s u b t y p e - s e l e c t i v e s e r o t o n e r g i c drugs on the s e x u a l b e h a v i o u r of male and female r a t s . The f a c t t h a t the 5-HT,A a g o n i s t 8-OH DPAT i n h i b i t s l o r d o s i s b e h a v i o u r i n females (Experiment 8) but f a c i l i t a t e s s e x u a l b e h a v i o u r i n male r a t s (as w e l l as t h e male s e x u a l b e h a v i o u r of t e s t o s t e r o n e t r e a t e d female r a t s ; Experiment 8) s u g g e s t s t h a t i n humans t h e r e may a l s o be sex d i f f e r e n c e s i n the responses t o the newly a v a i l a b l e 5 - H T T A s e l e c t i v e a n x i o l y t i c s . E v i d e n c e a l s o s u g gests t h a t t h e r e a r e sex d i f f e r e n c e s i n the e f f e c t s of 5 - H T T B - s e l e c t i v e drugs on the s e x u a l b e h a v i o u r of r a t s . Whereas TFMPP and o t h e r 5-HT,B a g o n i s t s f a c i l i t a t e l o r d o s i s b e h a v i o u r i n females (Experiment 8 and u n p u b l i s h e d data) , t h e s e drugs i n h i b i t the e x p r e s s i o n of s e x u a l b e h a v i o u r i n males (Mendelson & G o r z a l k a , u n p u b l i s h e d d a t a ) . Indeed, i n the case of TFMPP, f a c i l i t a t i o n of l o r d o s i s b e h a v i o u r o c c u r s a t doses a t l e a s t 5 times h i g h e r than those s u f f i c i e n t t o c o m p l e t e l y e l i m i n a t e the e x p r e s s i o n of s e x u a l b e h a v i o u r i n male r a t s . I t must be noted t h a t the 5 - H T T B r e c e p t o r does not occur i n human b r a i n t i s s u e . However, an analago u s r e c e p t o r , the S-H^D r e c e p t o r , i s found i n dense c o n c e n t r a t i o n s i n areas throughout the human b r a i n ( P a l a c i o s , 1987) At p r e s e n t , the f u n c t i o n of the 5-HT,D r e c e p t o r i n humans remains unknown. However, i t i s r e a s o n a b l e t o assume t h a t the f u n c t i o n of the s e r e c e p t o r s w i l l be e l u c i d a t e d , and t h a t drugs w i l l be d e v e l o p e d t o a l t e r t h e i r a c t i v i t y f o r s p e c i f i c t h e r a p e u t i c p urposes. In view of what appear t o be d r a m a t i c sex d i f f e r e n c e s i n the responses t o 5-H^B a g o n i s t s i n the r a t , i t 141 i s r e a s o n a b l e t o su s p e c t t h a t t h e r e c o u l d a l s o be sex d i f f e r e n c e s i n the responses t o 5 - H T , D - s e l e c t i v e drugs t h a t may become a v a i l a b l e i n the f u t u r e . Summary In t h i s d i s s e r t a t i o n I have e v a l u a t e d the e f f e c t s on l o r d o s i s b e h a v i o u r of drugs t h a t a c t s e l e c t i v e l y a t the known subtypes of c e n t r a l s e r o t o n i n r e c e p t o r s . By e v a l u a t i n g the e f f e c t s of t h e s e drugs I was a b l e b oth t o c o n f i r m and t o e x t e n d the d u a l r o l e h y p o t h e s i s of s e r o t o n e r g i c m o d u l a t i o n of l o r d o s i s b e h a v i o u r (Mendelson & G o r z a l k a , 1985b). In the o r i g i n a l statement of the d u a l r o l e h y p o t h e s i s i t was proposed t h a t 5-HT, r e c e p t o r s mediate the l o r d o s i s - i n h i b i t i n g e f f e c t s of s e r o t o n i n , whereas 5-HT2 r e c e p t o r s mediate l o r d o s i s - f a c i l i t a t i n g e f f e c t s of s e r o t o n e r g i c a c t i v i t y . From e v i d e n c e g a t h e r e d i n the p r e s e n t s e r i e s of e x p e r i m e n t s i t was c o n c l u d e d t h a t the l o r d o s i s -i n h i b i t i n g e f f e c t s of s e r o t o n i n a r e mediated p r i m a r i l y by the 5-HT,A subtype of r e c e p t o r . I t was f u r t h e r suggested t h a t a c t i v i t y a t c e n t r a l 5-HT3 s i t e s might a l s o i n h i b i t l o r d o s i s b e h a v i o u r . The p r e s e n t d a t a tended t o c o n f i r m the h y p o t h e s i s t h a t a c t i v i t y a t 5-HT2 r e c e p t o r s f a c i l i t a t e s l o r d o s i s . However, th e s e d a t a i n d i c a t e d t h a t s t i m u l a t i o n of s o m a t o - d e n d r i t i c 5-HT,A a u t o r e c e p t o r s and 5-HT,B p r e j u n c t i o n a l a u t o r e c e p t o r s might a l s o f a c i l i t a t e l o r d o s i s b e h a v i o u r . O s t e n s i b l y , the l o r d o s i s -f a c i l i t a t i n g e f f e c t s of s t i m u l a t i o n of the 5-HT,A and 5-HT,B subtypes of a u t o r e c e p t o r s would be due t o d e c r e a s e s i n the a c t i v i t y of l o r d o s i s - i n h i b i t i n g s e r o t o n e r g i c pathways. The 142 q u e s t i o n of what, i f any r o l e might be p l a y e d by p o s t - s y n a p t i c 5 - H T T B r e c e p t o r s remains t o be de t e r m i n e d . The e v a l u a t i o n of l o r d o s i s b e h a v i o u r i n the p r e s e n t s e r i e s was performed w i t h a n i m a l s a d m i n i s t e r e d v a r y i n g c o m b i n a t i o n s of the female sex hormones e s t r o g e n and p r o g e s t e r o n e . E v a l u a t i o n s of drug e f f e c t s under d i f f e r i n g s t e r o i d t r e a t m e n t s p r o v i d e d the o p p o r t u n i t y t o e v a l u a t e p o t e n t i a l i n t e r a c t i o n s between the e f f e c t s of the s e r o t o n e r g i c drugs and the e f f e c t s of the s t e r o i d s . From the d a t a g a t h e r e d i n these e x p e r i m e n t s , and by i n t e r p r e t a t i o n of e x i s t i n g r e p o r t s i n the l i t e r a t u r e i t was c o n c l u d e d t h a t the e f f e c t s of some s e r o t o n e r g i c d r u g s , p a r t i c u l a r l y those a c t i v e as a g o n i s t s a t 5-HT,A s i t e s , may be enhanced by exposure t o p r o g e s t e r o n e . F i n a l l y , i n the c l o s i n g s e c t i o n I d i s c u s s e d some i m p l i c a t i o n s f o r human b e h a v i o u r s of the e v a l u a t i o n of the e f f e c t s of s e r o t o n e r g i c drugs on l o r d o s i s b e h a v i o u r . I suggested t h a t the model of s e r o t o n e r g i c c o n t r o l of s e x u a l b e h a v i o u r i n the female r a t may be of some use i n u n d e r s t a n d i n g and even p r e d i c t i n g the e f f e c t s of s e r o t o n e r g i c drugs on the s e x u a l b e h a v i o u r of women. I f u r t h e r s uggested t h a t the e v a l u a t i o n of the e f f e c t s of s e r o t o n e r g i c drugs on the s e x u a l b e h a v i o u r of r a t s may p r o v i d e a model t o examine i n t e r a c t i o n s between s e r o t o n e r g i c drugs and the s t e r o i d sex hormones as w e l l as sex d i f f e r e n c e s i n the res p o n s e s t o s e r o t o n e r g i c d r u g s . 143 REFERENCES A g h a j a n i a n , G.K., W.E. F o o t e , , and M.H. Sheard. (1968). L y s e r g i c a c i d d i e t h y l a m i d e : S e n s i t i v e n e u r o n a l u n i t s i n the m i d b r a i n raphe. S c i e n c e , 161,706-708. A g h a j a n i a n , G.K., J.S. Sprouse, and K. 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