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Serotonin receptor subtypes and sexual behaviour in the female rat Mendelson, Scott Douglas 1985

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zz * • SEROTONIN RECEPTOR SUBTYPES AND SEXUAL BEHAVIOUR IN THE FEMALE RAT by SCOTT DOUGLAS MENDELSON B.A. Sonoma State University, 1981 A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF Master of Arts in THE FACULTY OF GRADUATE STUDIES Department of Psychology We accept t h i s thesis as conforming to the required standard THE UNIVERSITY OF BRITISH COLUMBIA A p r i l 1985 © Scott Douglas Mendelson, 1985 In presenting t h i s thesis i n p a r t i a l f u l f i l m e n t of the requirements for an advanced degree at the University of B r i t i s h Columbia, I agree that the Library s h a l l make i t f r e e l y available for reference and study. I further agree that permission for extensive copying of t h i s thesis for scholarly purposes may be granted by the head of my department or by his or her representatives. I t i s understood that copying or publication of t h i s thesis for f i n a n c i a l gain s h a l l not be allowed without my written permission. Department of The University of B r i t i s h Columbia 1956 Main Mall Vancouver, Canada V6T 1Y3 DE - 6 (3/81) i i Abstract Recently, i t has been discovered that serotonin (5-HT) receptors exist as subtypes in the mammalian brain. At least two major subtypes that d i f f e r in their d i s t r i b u t i o n , and a f f i n i t y for serotonergic drugs, have now been described. These receptors have been labeled 5-HT, and 5~HT2 receptors. The purpose of this thesis is to determine what roles the 5-HT, and 5-HT2 receptors might play in the modulation of sexual behaviour in the female rat. The administration of the 5-HT2 receptor antagonist pirenperone inhibited sexual receptivity in adult, ovariectomized Sprague Dawley rats that had been primed either c h r o n i c a l l y with es t r a d i o l benzoate (EB), or.acutely with EB plus varying doses of progesterone (P). An i n h i b i t i o n occurred at peripherally administered doses of 50, 100 and 150, but not 25 jug/kg of pirenperone. Pirenperone also inhibited r e c e p t i v i t y when administered i n t r a v e n t r i c u l a r l y at a dose of 15 jug/kg, however t h i s dose of pirenperone was in e f f e c t i v e when administered peripherally. Increasing the dose of P did not attenuate the inhib i t o r y e f f e c t of pirenperone. The 5-HT2 antagonists ketanserin (2.5 mg/kg) and spiperone (250 yg/kg) also inhibited r e c e p t i v i t y in females that had been primed with EB plus P. The inhib i t o r y e f f e c t of pirenperone was attenuated by the 5-HT2 agonist quipazine , however the 5-HT precursor 5-hydroxytryptophan (5-HTP) (20 mg/kg), and the 5-HT, agonists 5-methoxy-N,N-dimethytryptamine (5MeODMT) (200 jug/kg) and tryptamine ( 2 mg/kg) d i d not attenuate the e f f e c t of pirenperone. Quipazine, 5-HTP, and 5 M e O D M T d i d not e f f e c t r e c e p t i v i t y in females that had been primed with EB plus P, however tryptamine i n h i b i t e d r e c e p t i v i t y . Whereas 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 methysergide ( 3 mg/kg) f a i l e d to have an e f f e c t on r e c e p t i v i t y in females that had been primed with EB, methysergide coadministered with q u i p a z i n e f a c i l i t a t e d r e c e p t i v i t y . Pirenperone a l s o i n h i b i t e d p r o c e p t i v i t y in females that had been primed with EB plus P. Although q u i p a z i n e d i d not attenuate the i n h i b i t o r y e f f e c t of pirenperone upon p r o c e p t i v i t y , q u i p a z i n e alone f a c i l i t a t e d p r o c e p t i v i t y in females that had been primed e i t h e r with EB, or with EB and P. Methysergide d i d not e f f e c t p r o c e p t i v i t y , and 5-HTP, 5 M e O D M T , and tryptamine were a l s o i n e f f e c t i v e with regards to p r o c e p t i v i t y . The r e s u l t s of the present s e r i e s of experiments are not e n t i r e l y c o n s i s t e n t with Meyerson's widely h e l d theory of s e r o t o n e r g i c i n h i b i t i o n , r a t h e r they suggest a dual r o l e f o r 5 -HT i n female sexual behaviour. T h e r e f o r e , a new theory r e g a r d i n g the r o l e of 5-HT i n sexual behaviour i s proposed. S p e c i f i c a l l y , i t i s proposed that i n h i b i t o r y e f f e c t s of 5-HT are mediated by a c t i v i t y at 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 are mediated by a c t i v i t y at 5-HT 2 r e c e p t o r s . i v TABLE OF CONTENTS ABSTRACT i i LIST OF TABLES v LIST OF FIGURES vi ACKNOWLEDGEMENTS v i i INTRODUCTION 1 GENERAL METHODS 7 EXPERIMENTS Experiment 1 ..8 Exper iment 2 15 Experiment 3 20 Experiment 4 31 Experiment 5 37 Experiment 6 45 GENERAL DISCUSSION 48 Is a reduction of 5-HT necessary for the expression of lordosis behaviour? 49 Does a general reduction of central 5-HT a c t i v i t y , per  se , f a c i l i t a t e lordosis behaviour in steroid-primed females? 58 Does progesterone f a c i l i t a t e lordosis by reducing serotonergic a c t i v i t y ? 66 Do low doses of 5-HT agonists f a c i l i t a t e lordosis behaviour through presynaptic inhibiton? 71 A new hypothesis: A dual role for 5-HT in lordosis behaviour 75 In what areas of the brain are the serotonergic effects upon lordosis manifested? 81 Questions and cautions 84 REFERENCES 94 V LIST OF TABLES 1. Serotonergic treatments and their effects upon lordosis behaviour 88 v i LIST OF FIGURES 1. The ef f e c t of pirenperone upon receptivity that was induced by the administration of e s t r a d i o l benzoate 14 2. The effect of pirenperone upon receptivity that was induced by the administration of e s t r a d i o l benzoate and progesterone..19 3. The ef f e c t s of pirenperone and 5-HT agonists upon rec e p t i v i t y that was induced by the administration of e s t r a d i o l benzoate and progesterone 28 4. The ef f e c t s of pirenperone and 5-HT agonists upon proceptivity that was induced by the administration of es t r a d i o l benzoate and progesterone. . . 30 5. The effect of c e n t r a l l y administered pirenperone upon rece p t i v i t y that was induced by the administration of e s t r a d i o l benzoate and progesterone 36 6. The ef f e c t s of quipazine and methysergide upon re c e p t i v i t y that was induced by the administration of e s t r a d i o l benzoate and progesterone . . .42 7. The effects of quipazine and methysergide upon proceptivity that was induced by the administration of e s t r a d i o l benzoate and progesterone .44 v i i ACKNOWLEDGEMENTS I would l i k e to express my appreciation to Dr. Boris Gorzalka, for without his insight, encouragement, and f a i t h in my a b i l i t y , this work would not have been possible. I would also l i k e to thank the members of my thesis committee, Dr. John Pinel and Dr. Jennifer Campbell, whose comments were helpful and astute. F i n a l l y , I would l i k e to express my hear t f e l t thanks to my wife Melissa, who, despite the many lonely nights, never f a i l e d to give me her love and support. This research was funded by a Natural Sciences and Engineering Research Council grant awarded to Dr. Boris Gorzalka. 1 INTRODUCTION It has been established that the ovarian steroid estrogen is required for the display of sexual behaviour in the female rat. Ovariectomized females deprived of natural estrogen do not display sexual a c t i v i t y . Furthermore, although single doses of estrogen are r e l a t i v e l y i n e f f e c t i v e , the chronic administration of low doses of estrogen restores sexual a c t i v i t y to ovariectomized females. (Boling & Blandau, 1939; Hemmington, 1932; Gray & Gorzalka, 1980). The ovarian steroid progesterone is not s u f f i c i e n t to stimulate sexual a c t i v i t y in ovariectomized females , however i t markedly f a c i l i t a t e s sexual a c t i v i t y in estrogen-primed, ovariectomized females (Beach, 1942; Boling & Blandau, 1939; Edwards, Whalen, & Nadler, 1968). A treatment regimen commonly employed to produce maximal sexual a c t i v i t y in ovariectomized females is the acute administration of estrogen, followed 48 hr later by progesterone. With this regimen, animals display vigorous sexual behaviour 4 to 6 hr after the administration of progesterone. With s u f f i c i e n t steroid priming, both proceptive and receptive behaviour can be observed, as is the case with estrous behaviour in intact, c y c l i n g females. Proceptive behaviour generally consists of hopping, darting, and rapid ear-wiggling, whereas receptive behaviour i s characterized by the display of lordosis. The r e f l e x i v e concavity of the back and l i f t i n g of the rump and t a i l , which i s e l i c i t e d by the mounting of a vigorous male, is referred to as lordosis, and serves to f a c i l i t a t e penetration by the male. The neurochemical mechanisms by which ovarian steroids 2 stimulate sexual behaviour in the female rat are not well understood. However, the discovery of the monoamine transmitters serotonin (5-HT), dopamine (DA), and noradrenalin (NA) in the mammalian brain, as well as the a v a i l a b i l i t y of drugs to manipulate their a c t i v i t i e s , has stimulated interest in how these neurotransmitters might ef f e c t the onset and maintainance of estrous behaviour. In 1964, Meyerson observed that female sexual r e c e p t i v i t y decreased following the administration of a variety of monoamine oxidase (MAO) i n h i b i t o r s in steroid-primed females. The several forms of MAO enzymes found in the brain serve to l i m i t the a c t i v i t y of the monoamine neurotransmitters by a l t e r i n g t h e i r molecular structures into inactive forms; consequently, the i n h i b i t i o n of the MAO enzymes acts to increase the levels of active monoamine neurotransmitters available in the brain. In Meyerson's study, the sexually inhibitory e f f e c t s of these MAO in h i b i t o r s were augmented by the coadministration of the 5-HT precursor 5-hydroxytryptophan (5-HTP); however, the precursors of DA and NA were i n e f f e c t i v e in t h i s regard. These results suggested that the inhib i t o r y e f f e c t s of the MAO i n h i b i t o r s were mediated primarily by an increase in 5-HT a c t i v i t y (Meyerson, 1964a). In a following experiment, he found that reserpine and tetrabenazine, drugs that reduce monoamine le v e l s , f a c i l i t a t e d lordosis behaviour. Moreover, i t appeared that these f a c i l i t a t o r y e f f e c t s were attenuated by restoring serotonergic a c t i v i t y . These and subsequent experiments led Meyerson to propose a theory of serotonergic i n h i b i t i o n of female sexual behaviour. 3 In the years following Meyerson's i n i t i a l papers; a substantial number of experiments has been performed in the e f f o r t to determine the role played by 5-HT in female sexual behaviour. For the most part, these experiments have consisted of various pharmacological manipulations of 5-HT a c t i v i t y in ovariectomized females primed with varying combinations of estrogen and progesterone. Table 1 presents the results of the many pharmacological experiments that , in large part, form the l i t e r a t u r e concerning 5-HT and female sexual behaviour. It is also intended to serve as a convenient reference for many of the experiments discussed throughout this paper. Table 1 is organized according to the type of agent used , and includes a description of the steroid priming in each experiment; whether the animal had been ovariectomized or adrenalectomized; and , when important, the dose of the drug used in treatment, and the latency from the time of treatment to the time of behavioural observat ion. An examination of the table suggests that there is considerable evidence to support Meyerson's theory of serotonergic i n h i b i t i o n . A variety of treatments that reduce 5-HT a c t i v i t y have been reported to f a c i l i t a t e female sexual behaviour, and even to mimic the a c t i v i t y of progesterone in estrogen-primed females. Among these treatments are the administration of the monoamine storage depletors reserpine and tetrabenazine ; the 5-HT synthesis i n h i b i t o r p-chlorophenylalanine (PCPA) ; and 5-HT antagonists, such as methysergide and cinanserin , which bind to 5-HT receptors and prevent 5-HT from acting upon target neurons . Neurotoxic 4 l e s i o n s produced by the c e n t r a l a d m i n i s t r a t i o n of 5,7-dihydroxytryptamine (5,7-DHT) have a l s o been r e p o r t e d to f a c i l i t a t e female sexual behaviour . T h i s drug decreases 5-HT a c t i v i t y by a c t u a l l y d e s t r o y i n g neurons that produce and r e l e a s e 5-HT. As would be expected from Meyerson's theory, treatments that i n c r e a s e 5-HT a c t i v i t y have been r e p o r t e d to i n h i b i t female sexual behaviour. Among these treatments are the a d m i n i s t r a t i o n of the 5-HT prec u r s o r 5-HTP ; 5-HT a g o n i s t s which mimic 5-HT at receptor s i t e s , such as LSD ; MAO i n h i b i t o r s i n c l u d i n g p a r g y l i n e and nialamide ; v a r i o u s 5-HT r e l e a s i n g agents such as fen f l u r a m i n e , which produce a r a p i d and s u s t a i n e d r e l e a s e of 5-HT from n e u r a l t e r m i n a l s ; and 5-HT reuptake b l o c k e r s , such as imipramine, which block the a b i l i t y of 5-HT neurons to gather up, and thus l i m i t the e f f e c t s of, p r e v i o u s l y r e l e a s e d 5-HT . Although there i s s u b s t a n t i a l evidence to suggest an i n h i b i t o r y r o l e for 5-HT in female sexual behaviour, the l i t e r a t u r e i s not e n t i r e l y c o n s i s t e n t with Meyerson's theory. Indeed, i t appears that data can be found to c o n t r a d i c t n e a r l y every f i n d i n g that has been o f f e r e d as evidence f o r s e r o t o n e r g i c i n h i b i t i o n of female sexual behaviour. I t i s reasonable to suggest that the numerous i n c o n s i s t e n c i e s i n the l i t e r a t u r e concerning 5-HT and female sexual behaviour may be due, at l e a s t in p a r t , to a lack of s p e c i f i c i t y of the drugs that have been adm i n i s t e r e d . For example, many reuptake b l o c k e r s that a f f e c t 5-HT a c t i v i t y have a l s o been shown to e f f e c t NA a c t i v i t y . PCPA has a l s o appeared to act i n a n o n s p e c i f i c manner by a f f e c t i n g a drenal a c t i v i t y , catecholamines, and p o s s i b l y amino a c i d 5 u t i l i z a t i o n , as well as i n h i b i t i n g 5-HT synthesis (Gorzalka & Whalen, 1975; F u l l e r , 1982). Similarly, i t has been demonstrated that reserpine and tetrabenazine deplete DA, NA, and 5-HT in a nonspecific manner (Meyerson, 1964a; Ahlenius, Engel, Eriksson, & Sodersten, 1972), whereas the neurotoxin 5,7-DHT is reported to affect noradrenergic, as well as serotonergic systems (Baumgarten, Bjorklund, Lachenmeyer, & Nobin, 1973). F i n a l l y , i t has been reported that the c l a s s i c a l 5-HT antagonists may even display a mixture of agonist and antagonist a c t i v i t y at 5-HT receptors (Colpaert & Janssen, 1983). Therefore, under some conditions these drugs may actually enhance serotonergic a c t i v i t y . The recent discovery of 5-HT receptor subtypes in the mammalian brain (Peroutka & Snyder,1979) further complicates the question of drug s p e c i f i c i t y . These receptor subtypes, conventionally labelled 5-HT, and 5-HT2, both bind and react to the 5-HT molecule; however, they appear to d i f f e r in location, function, and a f f i n i t y for s p e c i f i c drugs. The c l a s s i c a l serotonergic agents bind, in varying degrees, to both 5-HT, and 5-HT2 receptors (Peroutka, Lebovitz, & Snyder, 1981; Peroutka & Snyder, 1983); consequently, the use of these nonselective drugs has not allowed a precise evaluation of the effects that 5-HT might produce in acting upon each receptor subtype alone. At least one study has found i n h i b i t i o n of female sexual behaviour following the administration of the 5-HT agonists psilocybin, dimethyltryptamine (DMT), or 5-methoxy-N,N-dimethyltryptamine (5MeODMT). Moreover, i t has been reported that these derivatives of tryptamine have high 5-HT, s p e c i f i c i t y 6 ( P e r o u t k a & S n y d e r , 1 9 7 9 ) , t h u s i t i s r e a s o n a b l e t o s p e c u l a t e t h a t t h e 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 o f p h a r m a c o l o g i c a 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 m e d i a t e d v i a 5 - H T , r e c e p t o r s . The r e c e n t d e v e l o p m e n t o f a n t a g o n i s t s w i t h h i g h 5 - H T 2 a f f i n i t y h a s now made i t p o s s i b l e t o a s s e s s t h e r o l e o f t h e 5 -H T 2 r e c e p t o r i n f e m a l e s e x u a l b e h a v i o u r . I t i s a p p r o p r i a t e t o n o t e t h a t i n a r e c e n t s e r i e s o f e x p e r i m e n t s i n o u r l a b o r a t o r y , t h e 5 - H T 2 s p e c i f i c a n t a g o n i s t p i r e n p e r o n e ( C o l p a e r t & J a n s s e n , 1983; J a n s s e n , 1983) was f o u n d t o i n h i b i t s e x u a l b e h a v i o u r i n t h e m a l e r a t , s u g g e s t i n g t h a t a c o m p o n e n t o f 5 -HT a c t i v i t y may s e r v e t o f a c i l i t a t e t h e e x p r e s s i o n o f s e x u a l b e h a v i o u r i n t h e m a l e ( M e n d e l s o n & G o r z a l k a , i n p r e s s ) . T h i s e f f e c t a p p e a r s t o be s p e c i f i c , a s t h e i n h i b i t o r y e f f e c t s were a t t e n u a t e d by t h e 5 -HT a g o n i s t q u i p a z i n e . T h i s f i n d i n g i s p a r t i c u l a r l y i n t e r e s t i n g i n l i g h t o f t h e f a c t , t h a t i t h a s been h y p o t h e s i z e d t h a t 5 -HT i n h i b i t s s e x u a l b e h a v i o u r i n t h e m a l e ( T a g l i a m o n t e , T a g l i a m o n t e , G e s s a , & B r o d i e , 1 9 6 9 ) , a s w e l l a s t h e f e m a l e r a t . T h e r e f o r e , i n t h e f o l l o w i n g s e r i e s o f e x p e r i m e n t s t h e e f f e c t s of t h e 5 - H T 2 a n t a g o n i s t s p i r e n p e r o n e a n d k e t a n s e r i n upon f e m a l e s e x u a l b e h a v i o u r w i l l be e v a l u a t e d . M o r e o v e r , p o t e n t i a l a t t e n u a t i o n o f a n t a g o n i s t e f f e c t s w i l l be e x a m i n e d v i a t h e c o a d m i n i s t r a t i o n o f a v a r i e t y o f 5 -HT a g o n i s t s . 7 GENERAL METHODS Animals and Surgery Female Sprague-Dawley rats were obtained from Charles River Canada Inc., Montreal, at 60 days of age. At approximately 70 days of age, these females were b i l a t e r a l l y ovariectomized through lumbar i n c i s i o n s . Surgery was performed while the animals were under ether anesthesia. Immediately following surgery, these females were housed in groups of 4 to 6 in standard laboratory wire mesh cages, in a room maintained under a reversed 12 hr dark/12 hr l i g h t cycle at 21±1° C. Animals had free access to food and water. Drug Procedures E s t r a d i o l benzoate (EB) and progesterone (P) (Steraloids) were dissolved in peanut o i l . Steroids were administered subcutaneously in approximately 0.1 ml of the peanut o i l vehicle. Pirenperone and ketanserin were dissolved in warm, d i l u t e c i t r a t e solution, 5-HTP was brought into solution by the slow addition of HC1, and the remaining drugs were dissolved in warm saline. A l l peripheral injections of drugs were intraperitoneal (IP), and concentrations were adjusted such that a l l doses were delivered in approximately 0.05 ml of solvent. 8 Lordosis Testing Behavioural testing involved presentation of an experimental female to a sexually vigorous male rat in a c y l i n d r i c a l pyrex testing arena measuring 45 cm in height, and 29 cm in diameter. Immediately prior to sessions with the experimental females, these males had been given brief access to f u l l y receptive females that had each been given 10 M g EB 48 hr, and 500 M g P 4 hr e a r l i e r . Sessions were conducted 4 to 6 hr after commencement of the dark cycle. Each experimental female was placed with a single male u n t i l 10 mounts with pelvic thrusting had occurred. If a male would not mount, the female was placed in a d i f f e r e n t arena containing another male. A female's response to a mount was considered a lordosis response i f some degree of concavity of the back was observed. Lordosis quotients were calculated as the percentage of mounts with pelvic thrusting resulting in a lordosis response. Experiment 1 The effects of 5-HT antagonists upon female sexual behaviour have generally been assessed in ovariectomized females that have been acutely administered estrogen . In l i g h t of t h i s fact, a p i l o t experiment was performed in which 100 M g/kg of pirenperone, or the c i t r a t e vehicle, was administered to ovariectomized females that had e a r l i e r received 10 M g EB. This, and similar single doses of EB, generally produces minimal 9 s e x u a l r e c e p t i v i t y ; h o w e v e r , w h e n p r o g e s t e r o n e , o r v a r i o u s a g e n t s t h a t r e d u c e 5 - H T a c t i v i t y , a r e c o a d m i n i s t e r e d , r e c e p t i v i t y c a n b e s i g n i f i c a n t l y i n c r e a s e d . I n t h i s p i l o t e x p e r i m e n t , w e o b s e r v e d t h a t a l t h o u g h s o m e c o n t r o l a n i m a l s e x h i b i t e d l o r d o s i s b e h a v i o u r , r e c e p t i v i t y w a s n o t e x h i b i t e d b y t h o s e a n i m a l s t h a t h a d r e c e i v e d p i r e n p e r o n e . T h i s s u g g e s t e d t h a t i n f e m a l e s , a s w a s f o u n d t o b e t h e c a s e w i t h m a l e s , p i r e n p e r o n e m i g h t i n h i b i t s e x u a l b e h a v i o u r . A l t h o u g h t h e p i l o t s t u d y w a s s u g g e s t i v e , i t w a s i n c o n c l u s i v e , a s t h e r e c e p t i v i t y o f t h e c o n t r o l a n i m a l s w a s t o o l o w f o r a s t a t i s t i c a l l y s i g n i f i c a n t i n h i b i t i o n t o b e f o u n d . T h e r e f o r e i n t h e f i r s t e x p e r i m e n t , t h e e f f e c t s o f p i r e n p e r o n e w e r e e v a l u a t e d i n f e m a l e s t h a t h a d r e c e i v e d E B c h r o n i c a l l y r a t h e r t h a n a c u t e l y a s i n t h e p i l o t s t u d y . T h i s t r e a t m e n t p r o d u c e d a m o d e r a t e d e g r e e o f r e c e p t i v i t y i n c o n t r o l a n i m a l s , a n d t h u s a l l o w e d t h e e v a l u a t i o n o f p o t e n t i a l i n h i b i t o r y e f f e c t s o f p i r e n p e r o n e i n f e m a l e s t h a t h a d r e c e i v e d o n l y e s t r o g e n . M e t h o d I n E x p e r i m e n t 1 , 2 4 s e x u a l l y e x p e r i e n c e d , o v a r i e c t o m i z e d f e m a l e s r e c e i v e d 1 0 M g E B d a i l y f o r 4 d a y s . O n D a y 4 , t h e s e f e m a l e s w e r e p a i r e d w i t h s e x u a l l y v i g o r o u s m a l e s , a n d l o r d o s i s q u o t i e n t s w e r e r e c o r d e d . U s i n g t h e s e i n i t i a l d a t a , t w o g r o u p s o f 1 2 f e m a l e s m a t c h e d f o r r e c e p t i v i t y w e r e f o r m e d . O n e g r o u p o f a n i m a l s r e c e i v e d p i r e n p e r o n e , a n d t h e o t h e r g r o u p o f a n i m a l s r e m a i n e d a s c o n t r o l a n i m a l s t h r o u g h o u t t h e e x p e r i m e n t . O n D a y 5 , 1 h r 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 e e x p e r i m e n t a l a n i m a l s 1 0 received pirenperone in doses of either 25, 50, 100, or 150 Mg/kg, whereas control animals received an injec t i o n of the c i t r a t e vehicle. The procedure of the administration of 10 Mg EB on days 1, 2, 3, and 4; behavioural testing on Day 4; and behavioural testing following treatment on Day 5 was repeated to allow the assessment of each of the four pirenperone doses. A single dose of pirenperone was administered to a l l experimental animals on Day 5 of each procedure. The order in which the four doses were given was derived from a table of random numbers. The interval between each complete procedure was 1 week. Results and Discussion An examination of F i g . 1 suggests that the peripheral administration of pirenperone inh i b i t e d sexual r e c e p t i v i t y . Furthermore, these data provide no indication of any cumulative effects of chronic EB treatment, or residual effects of repeated administration of pirenperone. This suggests that the apparent i n h i b i t i o n of r e c e p t i v i t y can be attributed to the acute e f f e c t s of pirenperone. The apparent i n h i b i t i o n of sexual r e c e p t i v i t y was confirmed by a 2x2x4 analysis in which the factors were: group, that i s , control versus experimental; day, that i s , Day 4 with no treatment versus Day 5 with pirenperone treatment; and week, that i s , which of the four complete weekly testing procedures. In the case of the experimental animals, week was confounded with pirenperone dose. The lordosis quotients of the animals receiving pirenperone 11 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 animals, F ( 1 , 20 ) = 6 . 592 , }D<.0M6. Furthermore, Day 5 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 than those of Day 4 , F(1,20) =26.646, P_<.0001. The a n a l y s i s a l s o r e v e a l 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 of group with day of t e s t i n g , F(1,20)=39.804,£<.0001. Subsequent use of the Newman-Keuls method of m u l t i p l e comparison demonstrated that the l o r d o s i s q u o t i e n t s of the experimental animals on Day 5 were s i g n i f i c a n t l y lower than those on Day 4, and a l s o lower than those of the c o n t r o l animals on both Day 4 and 5 (2<.05). The Day 4 values of the experimental animals, and the Day 4 and 5 values of the c o n t r o l animals were not, among themselves, s i g n i f i c a n t l y d i f f e r e n t . There was no s i g n i f i c a n t main e f f e c t of week, however a s i g n i f i c a n t i n t e r a c t i o n of week with day of t e s t i n g was evident, F(3,60)=4. 182, p_<.0094. The Newman-Keuls method r e v e a l e d that in weeks in which experimental animals r e c e i v e d 50, 100, or 150 Mg/kg pirenperone, the combined Day 5 scores were s i g n i f i c a n t l y lower than those of the combined Day 4 scores (p_<.05). There was no such d i f f e r e n c e i n the week in which 25 jug/kg was admin i s t e r e d , r a t h e r the Day 4 and Day 5 scores of t h i s week d i d not s i g n i f i c a n t l y d i f f e r from any of the other week/day combinations. The simple e f f e c t s of the Group/Day and Week/Day i n t e r a c t i o n s c l e a r l y i n d i c a t e d that s i g n i f i c a n t i n h i b i t i o n of r e c e p t i v i t y was manifest on only Day 5, the day of pirenperone treatment. Therefore, to determine the c h a r a t e r i s t i c s of the pirenperone dose response curve, the Day 5 data were analyzed s e p e r a t e l y . The a n a l y s i s of Day 5 data i n d i c a t e d an i n t e r a c t i o n 1 2 of group with week, F(3,60)= 2 . 791 ,p_< . 047 . Use of the Newman-Keuls method revealed that 50, 100, and 150 M g / k g pirenperone s i g n i f i c a n t l y inhibited r e c e p t i v i t y , whereas lordosis behaviour of animals receiving 25 M g / k g was not s i g n i f i c a n t l y d i f f e r e n t from that of control animals. The receptivity observed after 50 and 100 M g/kg was not s i g n i f i c a n t l y lower than that following 25 M g/kg; however, whereas the eff e c t of 150 M g/kg did not d i f f e r s i g n i f i c a n t l y from the effects of either 50 or 100 M g / k g , lordosis quotients were s i g n i f i c a n t l y lower after 150 M g / k g than after 25 M g / k g pirenperone. It can be concluded from Experiment 1, that pirenperone i n h i b i t s lordosis behaviour in ovariectomized female rats that have been chronically administered estrogen. The finding that the 5-HT2 s p e c i f i c antagonist pirenperone i n h i b i t s sexual r e c e p t i v i t y challenges the notion of a simple inhibitory role for 5-HT in female sexual behaviour. It further suggests that inconsistencies in the l i t e r a t u r e may be due, in part, to d i f f e r e n t i a l roles of 5-HT receptor subtypes in the modulation of female sexual behaviour. However, the questions remain as to whether pirenperone i n h i b i t s r e c e p t i v i t y by acting as a 5-HT2 antagonist, or i f i t s ef f e c t s are produced via a nonspecific mechanism, for example i l l n e s s or sedation. 1 3 F i g . 1. Mean l o r d o s i s q u o t i e n t s ± S.E.M. of f e m a l e r a t s p r i m e d w i t h 4 d a i l y i n j e c t i o n s of e s t r a d i o l b e n z o a t e ( E B ) . On EB Day 4, a n i m a l s r e c e i v e d no a d d i t i o n a l t r e a t m e n t p r i o r t o t e s t i n g . On Day 5 a n i m a l s r e c e i v e d p i r e n p e r o n e or t h e c i t r a t e v e h i c l e 1 h r p r i o r t o t e s t i n g . LORDOSIS QUOTIENT ('<*;) 1 5 Experiment 2 In Experiment 1, the 5-HT2 antagonist pirenperone inhibited lordosis behaviour in ovariectomized females chronically administered estrogen. This finding challenged the notion that 5-HT simply i n h i b i t s female sexual behaviour. Moreover, i t challenged the proposal that progesterone f a c i l i t a t e s female sexual behaviour in estrogen-primed females by reducing central 5-HT a c t i v i t y (Kow, Malsbury, & Pfaff, 1974). Therefore, i t was of interest to determine what, i f any, interaction pirenperone might have with progesterone. In Experiment 2, pirenperone was administered to determine i t s e f f e c t s upon r e c e p t i v i t y induced by acutely administered estrogen and progesterone. Method In a repeated measures design, 12 ovariectomized females received 10 M g EB, followed 48 hr later by progesterone in a dose of either 75, 150, 250, or 500 M g . The administration of progesterone was followed 3 hr la t e r by either 100 M g / k g pirenperone or the c i t r a t e vehicle. After an additional hr, the females were placed with males for behavioural t e s t i n g . The sequence of treatments was randomized for each animal, and the int e r v a l between successive tests was 1 week. 1 6 Results and Discussion An examination of F i g . 2 suggests that pirenperone inhibited lordosis behaviour in females that had been acutely administered estrogen and progesterone. Furthermore, i t appears that the inhibitory effect of pirenperone was not attenuated by increasing doses of progesterone. In the absence of pirenperone, receptivity increased with progesterone dose, however when animals had received pirenperone, their lordosis quotients were uniformly low across a l l levels of progesterone dose. A 2x4 analysis of variance for repeated measures confirmed that pirenperone inhibited sexual re c e p t i v i t y , F(1,11)=75.705, D<.0001. A s i g n i f i c a n t main eff e c t of progesterone dose was also indicated, F(3 , 33)= 4.542 , p_<.009. The Newman-Keuls method confirmed an increase in lordosis behaviour as progesterone dose increased. Lordosis quotients following 75 and 150 jug did not s i g n i f i c a n t l y d i f f e r , nor was there a difference among the lordosis quotients when animals received either 150, 250 , or 500 Mg; however, lordosis quotients following administration of 250, or 500 nq were s i g n i f i c a n t l y higher than those following the administration of 75 Mg progesterone. The analysis of variance further revealed a s i g n i f i c a n t interaction of pirenperone with progesterone , F(3,33)=3.576, p_<.0239. Because of the s i g n i f i c a n t interaction, the Newman-Keuls method was used to evaluate a l l pairwise comparisons. No s i g n i f i c a n t difference was indicated among the levels of progesterone when pirenperone had been administered. In the absence of pirenperone, lordosis quotients were s i g n i f i c a n t l y 17 higher at 250 and 500 Mg than at 75 and 150 Mg progesterone (p<.05), though 250 was not s i g n i f i c a n t l y d i f f e r e n t from 500 Mg, nor was 75 s i g n i f i c a n t l y d i f f e r e n t from 150 Mg progesterone. At every dose of progesterone, lordosis quotients were s i g n i f i c a n t l y higher when c i t r a t e rather than pirenperone had been administered (p<.05). Although these data c l e a r l y indicate an i n h i b i t o r y effect of pirenpeorne upon female sexual behavior, t h i s e f f e c t may have been produced via a nonspecific mechanism. To diminish this p o s s i b i l i t y , the effect of pirenperone upon wheel-running a c t i v i t y was evaluated in females that had been acutely administered estrogen and progesterone. Animals that received 100 Mg/kg pirenperone 1 hr prior to testing did not d i f f e r s i g n i f i c a n t l y from control animals in th e i r wheel-running a c t i v i t y , with each group making 157.0±54.2 and 18 7.7 ± 31.5 revolutions in 1 hr, respectively. This result is consistent with a report that pirenperone does not disturb lever pressing a b i l i t y (Janssen, 1983), or exploratory behaviour in an open f i e l d paradigm (Mendelson & Gorzalka, in press). Therefore, i t remains possible that a nonspecific mechanism mediated the inhibitory e f f e c t of pirenperone, however i t appears unlikely that this e f f e c t was due to i l l n e s s , sedation, or motor impai rment. 18 F i g . 2. Mean lordosis quotients ± S.E.M. of female rats primed with e s t r a d i o l benzoate and varying doses of progesterone following the administration of 100 nq/kg pirenperone or the c i t r a t e vehicle 1 hr prior to testing. IOOI • O i r e n p e r o n e v C i t r a t e 75 LU o Z) O 50r GO o Q DC o 25 f 75 150 250 500 PROGESTERONE DOSE (gg) 20 Experiment 3 In Experiment 1, pirenperone inhibited sexual re c e p t i v i t y in ovariectomized female rats that had been chronically administered estrogen. In Experiment 2, i t was demonstrated that pirenperone inhibited receptivity in ovariectomized females that had been acutely administered estrogen and progesterone. However, questions have remained concerning the mechanism by which pirenperone produced i t s e f f e c t . Although pirenperone has been considered to be a s p e c i f i c 5-HT2 antagonist, i t i s possible that a mechanism other than the blockade of 5-HT 2 receptors was responsible for the inhibitory effects of the drug. However, i f pirenperone did indeed produce i t s e f f e c t s through the blockade of 5-HT 2 a c t i v i t y , then the coadministration of a 5-HT agonist with high a f f i n i t y for the 5-HT2 receptor should attenuate these e f f e c t s . Therefore, in Experiment 3 the 5-HT agonists 5-HTP, 5MeODMT, quipazine, and tryptamine, which d i f f e r in their a f f i n i t i e s for the 5-HT 2 receptor, were each coadministered with pirenperone prior to behavioural testing. It was expected that quipazine, which binds s e l e c t i v e l y to the 5-HT 2 receptor, would attenuate the e f f e c t s of pirenperone, whereaa the other, less selective agonists were expected to be i n e f f e c t i v e . Method In a repeated measures design, 20 ovariectomized females 21 received 10 M g EB followed 48 hr later by 500 M g progesterone. The administration of progesterone was followed 3 hr later by either 100 M g / k g pirenperone or the c i t r a t e vehicle, as well as the coadministration of either 5-HTP (20 m g / k g ) , quipazine (3 mg/kg), tryptamine (2 mg/kg), 5~MeODMT(200 M g/kg), or saline. After an additional hr, females were placed with males for behavioural testing, and the recording of lordosis quotients. The sequence of drug treatments was randomized for each animal, and the interval between successive tests was 1 week. In Experiment 3, proceptive behaviour was also recorded. A score of 0 was assigned when no proceptive behaviour was observed; a score of 1 was assigned when earwiggling was weak, infrequent, and not accompanied by crouching, hopping, or darting behaviour; a score of 2 was assigned when occasional, yet strong earwiggling was.observed, as well as instances of hopping and darting; and a score of 3 was assigned when earwiggling was persistent, vigorous, and accompanied by f u l l and frequent displays of crouching, hopping ,and darting behaviour. Earwiggling served as the basis of this rating system because i t has been reported that i t may be the most e a s i l y e l i c i t e d component of proceptive behaviour (Zemlan & Adler, 1977). Consistent with this report, no instances of crouching, hopping, or darting were observed in the absence of earwiggling behaviour. Results and Discussion In F i g . 3 i t can be observed that pirenperone inhibited sexual behaviour in a manner consistent with the results of 22 Experiments 1 and 2. Although no 5-HT agonist prevented the inhibi t o r y e f f e c t s of pirenperone, sexual r e c e p t i v i t y appeared .to be less inhibited by pirenperone when animals were coadministered quipazine. When administered alone, 5-HTP, 5MeODMT, and quipazine did not effect lordosis behaviour; however, lo r d o s i s quotients were reduced following the administration of tryptamine. Data were evaluated in a 2x5 analysis of variance for repeated measures, with the factors being pirenperone, and the type of 5-HT agonist coadministered. This analysis confirmed a s i g n i f i c a n t main effect of pirenperone, F(1,19)=229.015, P_<.0001. A s i g n i f i c a n t main effect of the type of 5-HT agonist coadministered was also indicated, F ( 4 , 76 ) = 4 . 9 1 3 ,p_< . 00 1 5 . The Newman-Keuls method further revealed that following the administration of tryptamine, lordosis quotients were s i g n i f i c a n t l y lower than those which followed the administration of either 5-HTP or quipazine (p_<. 05) . Lordosis quotients recorded after._t.he administration of 5MeODMT or saline did not d i f f e r s i g n i f i c a n t l y from those following either tryptamine, 5-HTP, or quipaz ine A s i g n i f i c a n t interaction of pirenperone with the 5-HT agonists was also indicated in th i s analysis, F(4,76)=2.9132,2<.027. -Due to the significance of th i s interaction, pairwise comparisons were evaluated by means of the Newman-Keuls method. It was revealed that pirenperone inhibited sexual r e c e p t i v i t y under every drug condition (g<.05); however, when animals had received both quipazine and pirenperone, lordosis quotients were s i g n i f i c a n t l y higher than when animals 23 had received pirenperone and saline (p_<.05). Furthermore, when animals had received pirenperone, the lordosis quotients observed- following the administration of quipazine were higher than those observed following the administration of tryptamine (p_<.05). In the presence of pirenperone, quipazine was not s i g n i f i c a n t l y d i f f e r e n t from 5-HTP, or 5MeODMT. There were no si g n i f i c a n t differences among 5-HTP, 5MeODMT, tryptamine, or saline when coadministered with pirenperone. When administered without pirenperone, 5-HTP, 5MeODMT, quipazine, and saline did not d i f f e r in their effect upon lordosis behaviour. In the absence of pirenperone, tryptamine s i g n i f i c a n t l y reduced lordosis behaviour in comparison to saline, 5-HTP, and quipazine (£<.05), though i t did not d i f f e r from 5MeODMT in i t s effect upon rec e p t i v i t y in the absence of pirenperone. Proceptivity data are displayed in F i g . 4. These data indicate that pirenperone inhibited proceptivity, and that this i n h i b i t i o n was not attenuated by any of the four 5-HT agonists. Furthermore, although 5-HTP, DMT, and tryptamine alone did not a l t e r proceptive behavior, quipazine did appear to f a c i l i t a t e proceptive behavior. Proceptive data were subjected to an analysis of variance for repeated measures. This analysis confirmed that pirenperone inhi b i t e d proceptivity, F(1,19)=73.80,p<.0001. The analysis also indicated a s i g n i f i c a n t main effect of the 5-HT agonists, F(4,76)=5.67,p<.0005. Use of the Newman-Keuls method confirmed that 5-HTP, DMT, and tryptamine did not d i f f e r from saline, or among themselves in their e f f e c t s upon proceptive behaviour, however quipazine 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 24 proceptivity in comparison with saline and the other 5-HT agonists (p<.05). There was no s i g n i f i c a n t interaction of pirenperone with the coadministered 5-HT agonists. Experiment 3 i s consistent with Experiments 1 and 2 in demonstrating inhibitory e f f e c t s of pirenperone upon lordosis behaviour. Furthermore, the attenuation by quipazine of the pirenperone i n h i b i t i o n of re c e p t i v i t y supports the notion that pirenperone i n h i b i t s r e c e p t i v i t y via an antagonism of a c t i v i t y at 5-HT2 receptors. Although Experiment 3 c l e a r l y suggests a f a c i l i t a t o r y role for 5-HT2 receptors, tryptamine, which binds primarily to 5-HT, receptors (Peroutka & Snyder, 1979) was found to i n h i b i t sexual behaviour. However, these data are not contradictory, but merely suggest that the type of serotonergic a c t i v i t y , ' that i s , 5-HT, or 5-HT2, may be c r i t i c a l in determining the effect of a 5-HT agonist upon sexual behaviour. Although 5MeODMT was found to be in e f f e c t i v e , others have reported f a c i l i t a t i o n at doses lower than used in the present experiment, and i n h i b i t i o n at s t i l l higher doses. Therefore, the apparent ineffectiveness of the drug may have simply been due to the choice of dose. Experiment 3 also suggests that 5-HTP does not af f e c t lordosis behaviour, a finding contrary to the reports of others. However, t h i s inconsistency may be due to methodological differences. For example, in the present experiment 5-HTP was administered either alone, or with pirenperone. However, in those experiments in which ef f e c t s of 5-HTP upon sexual behaviour had been observed, the drug had been coadministered with the peripheral decarboxylase i n h i b i t o r benserazide. 25 Decarboxylases are the enzymes that convert 5-HTP to 5-HT, and are considered necessary for the effectiveness of 5-HTP administration. The eff e c t s of a peripheral decarboxylase inhi b i t o r can be appreciated in the fact that 5-HTP can pass freely from the blood into the brain, however 5-HT cannot do so; therefore, 5-HT converted from 5-HTP outside of the brain can have no direc t central e f f e c t s . By coadministering benserazide, and thereby preventing the conversion of 5-HTP to 5-HT in the periphery, more 5-HTP remains availabe to pass into the brain, and the effectiveness of 5-HTP is greatly enhanced. The apparent inconsistencies between the present results and e a r l i e r reports may therefore have been due to the use of benserazide by others. It i s apparent from the results of Experiment 3 that pirenperone i n h i b i t s proceptive as well as receptive behaviour. However, the results of the present experiment are unusual in that they also provide evidence of a dissociation of the regulation of proceptive behavior from that of receptive behavior. Although pirenperone was found to i n h i b i t proceptivity, 8 of 20 females did display proceptive behavior after receiving pirenperone alone, even though th i s treatment produced an extremely low mean lordosis quotient of 9.5±3.0. Of these 8 females, 3 displayed proceptive behavior in the complete absence of lordosis behavior. This dissociation i s not unprecedented, as similar e f f e c t s have been observed following lesions of the dorsomedial pontine tegmentum (Yamanouchi & Arai, 1982). It has been suggested that the neural substrate for proceptive behavior is less sensitive to hormonal stimulation than is the neural substrate for receptive behavior (Zemlan & 2 6 Adler, 1977). However, i t can be concluded from the present data that the observation of receptive behaviour being accompanied by proceptive behaviour only at higher doses of steroids does not necessarily r e f l e c t a continuum of steroid e f f e c t s upon a single neural mechanism. The results of Experiment 3 also indicate that quipazine stimulates proceptive behaviour in females that have been acutely administered estrogen and progesterone. However, i t cannot be established from the present data whether quipazine merely enhances the a b i l i t y of progesterone to f a c i l i t a t e proceptive behavior, or i f quipazine can mimic the effect of progesterone in producing proceptive behavior in the estrogen-primed female. 27 F i g . 3. Mean lordosis quotients ± S.E.M. of female rats primed with e s t r a d i o l benzoate and progesterone following the administration of 100 /ng/kg pirenperone or the c i t r a t e vehicle, plus 20 mg/kg 5-HTP, 3 mg/kg quipazine, 2 mg/kg tryptamine, 200 Mg/kg 5-MeODMT, or saline 1 hr prior to testing. 28 100i o O I/) i/> O cc O 75 50-25-_L ////. '''///, O • • v.-•y,y •///. Legend ez: PI-ENFERONE cr CONTROL ;0NT 5-HTP 5DMT OUIP 5 -HT AGONISTS CO-ADM'MISTERED TRYP 29 F i g . 4. Proceptivity scores ± S.E.M. of female rats primed with es t r a d i o l benzoate and progesterone following the administration of 100 Mg/kg pirenperone or the c i t r a t e vehicle, plus 20 mg/kg 5-HTP, 3 mg/kg quipazine, 2 mg/kg tryptamine, 200 Mg/kg 5-MeODMT, or saline 1 hr prior to testing. The c r i t e r i a for scoring proceptive behaviour have been described in the method section of Experiment 4 . 30 'A 7/7A v. y/A r,y/A/ y>y yyy. Legend ?z PIRENPERONE fZ3 CONTROL CONT 5-HTP 5DMT QUIP 5-HT AGONISTS CO-ADMINISTERED TRYP 31 Experiment 4 In Experiments 1 and 2, pirenperone was shown to i n h i b i t lordosis behaviour in the female rat, and the results of Experiment 3 suggested that the mechanism of i t s action may involve a c t i v i t y at 5~HT2 receptors. However, the question remains as to where pirenperone acted to produce i t s inhib i t o r y e f f e c t . Though pirenperone is r e l a t i v e l y soluble in l i p i d s , and thus l i k e l y to enter the brain, d i r e c t central a c t i v i t y of pirenperone could not be established from the i n i t i a l experiments. Therefore, to begin to determine the si t e of action of pirenperone, the drug was was administered, via a cannula, d i r e c t l y into the right l a t e r a l v e n t r i c l e of the brain of steroid-primed females prior to observation of their sexual behaviour. Surgery Animals were anesthetized with 40 mg/kg sodium pentobarbitol (M.T.C.), and chronic intraventricular guide cannulae were implanted. Surgery involved inc i s i o n and retraction of the scalp, i n s t a l l a t i o n of four stainless steel anchor screws, d r i l l i n g of a small burr hole through the s k u l l , and f i x i n g of the guide cannula into place with a c r y l i c cement. The guide cannulae (23 ga sta i n l e s s steel) were stereot a x i c a l l y positioned according to the atla s of Pellegrino, Pellegrino, and Cushmah (1979), with co-ordinates 0.2 mm 32 posterior to the skull landmark bregma, 1.75 mm to the right of the midline of the s k u l l , and 3.0 mm ventral to the surface of the brain. These co-ordinates placed the t i p of the cannulae just within the dorsal boundary of the l a t e r a l v e n t r i c l e . Injection needles ( 3 0 ga sta i n l e s s steel) extended 0.5 mm beyond the lumen of the guide cannula. When not in use, the guide cannulae were protected by 30 ga stainless steel obdurators. Method Following f u l l recovery from surgery, 10 cannulated, ovar iectomized females received 10 j u g EB, followed 48 hr later by 500 / u g progesterone. Progesterone was followed 3 hr later by the central administration of 10, 5, or 1 M g of pirenperone, or the c i t r a t e vehicle. The average weight of these animals was 340 gm, making these doses approximately 30, 15, 3, and 0 M g /kg pirenperone, respectively. The results of Experiment 1 suggested that none of these doses of pirenperone would i n h i b i t r e c e p t i v i t y following peripheral administration. A l l central injections were 5 M1 in volume, and an e l e c t r i c a l l y - d r i v e n syringe pump (Sage Instruments, model 341 A), was used to administer the drug d i r e c t l y into the right l a t e r a l v e n t r i c l e at the rate of 5 M l/min. In 1 hr following central administration, the females were placed with males for behavioural observation. 33 Results and Discussion The data collected in Experiment 4 are displayed in F i g . 5 , and indicate that c e n t r a l l y administered pirenperone inhibited lordosis behaviour in females that had been acutely administered estrogen and progesterone. These data were analyzed in a one-factor analysis of variance for repeated measures that confirmed the inhi b i t o r y effect of c e n t r a l l y administered pirenperone, F ( 3 , 24 ) =4 1 . 57 ,p_< . 000 1 . Subsequent use of the Newman-Keuls method of pairwise comparison indicated that 1 uq pirenperone did not i n h i b i t lordosis in comparison with the c i t r a t e control; however, 5 jug pirenperone s i g n i f i c a n t l y inhibited lordosis behaviour in contrast to both 1 Mg pirenperone and the c i t r a t e vehicle (p_<.05). Furthermore, s i g n i f i c a n t l y less lordosis behaviour was observed following 10 Mg than was observed following 5 Mg of centrally administered pirenperone (p_<.05). In Experiment 1, 25 M g / k g of pirenperone was i n e f f e c t i v e when administered peripherally , however in Experiment 4, 5 Mg, or approximately 15 Mg/kg of pirenperone, inhibited lordosis when administered c e n t r a l l y . This suggested that pirenperone inhibited lordosis behaviour by acting d i r e c t l y on the brain. However, differences in steroid treatments, that i s , chronic administration of estrogen in Experiment 1, versus acute administration of estrogen and progesterone in Experiment 4, precluded d i r e c t comparison of these two doses. Therefore, 15 M g / k g pirenperone, or the c i t r a t e vehicle, was administered IP to 20 females that were acutely administered estrogen and progesterone, after which lordosis behaviour was observed. Under 34 these conditions, 15 Mg/kg pirenperone did not s i g n i f i c a n t l y d i f f e r from the c i t r a t e vehicle in i t s effect upon lordosis behaviour, with lordosis quotients for the two treatment groups being 93±2.1 and 97±1.5, respectively. These additional data c l e a r l y suggest that pirenperone acts at a central s i t e . 35 F i g . 5. Mean lordosis quotients ± S.E.M. of females primed with e s t r a d i o l benzoate and progesterone, following the central administration of either 0, 1, 5, or 10 uq pirenperone. L O R D O S I S QUOT IENT (%) ro cn o cn 1 1 m z TJ m 13 w o m CD I • — i ON 37 Experiment 5 In Experiments 1, 2, 3, and 4, pirenperone was consistently found to i n h i b i t lordosis behaviour. Furthermore, i t was concluded from the results of Experiments 3 and 4 that pirenperone produced i t s effect by acting upon central 5-HT receptors. These findings challenged the theory of a simple inhibitory a c t i v i t y of 5-HT, and suggested that some component of 5-HT a c t i v i t y served to f a c i l i t a t e sexual behaviour. Finding that the s p e c i f i c 5-HT2 antagonist pirenperone inhibited sexual r e c e p t i v i t y c a l l e d into question the rel a t i o n between pirenperone and those 5-HT antagonists that had been reported to f a c i l i t a t e . female sexual behaviour, for example , methysergide. It was reasonable to suspect that the effects of pirenperone and methysergide upon sexual behaviour have been mediated by di f f e r e n t receptors. It may have been that pirenperone blocked hypothetical f a c i l i t a t o r y 5-HT receptor s i t e s , whereas methysergide primarily blocked those 5-HT receptors responsible for i n h i b i t i o n of sexual behaviour. If such were the case, the administration of quipazine, which was shown in Experiment 3 to attenuate the inhibitory effects of pirenperone, would be expected- to augment any f a c i l i t a t o r y e f f e c t s of methysergide in the ovariectomized, estrogen-primed female. A synergistic increase in sexual behaviour would be consistent with a dual role for 5-HT in the modulation of female sexual behaviour. Therefore, in Experiment 5 the interactive effects of quipazine and methysergide were evaluated in 38 ovariectomized, estrogen-primed females. Methods In a repeated measures design, ovariectomized females received 10 jug EB, followed 51 hr later by either 3 mg/kg methysergide, 3 mg/kg quipazine, methysergide plus quipazine, or saline. After an additional hr, females were placed with males for behavioural testing. The sequence of treatments was randomized for each animal, and the interval between successive tests was 1 week. Results and Discussion Mean lordosis quotients are displayed in Fig. 6. It appears that neither methysergide nor quipazine alone f a c i l i t a t e d r e c e p t i v i t y , whereas the combination of methysergide plus quipazine did f a c i l i t a t e sexual receptivity in ovariectomized, estrogen-primed females. A 2x2 analysis of variance for repeated measures revealed a s i g n i f i c a n t main effect of quipazine, F (1 , 1 0 ) =22 . 52 , p_<.008, no s i g n i f i c a n t main effect of methysergide, and a s i g n i f i c a n t interaction between methysergide and quipazine, F{1,10)=13.07, p_<.0047. Use of the Newman-Keuls method revealed that methysergide, quipazine, and saline did not d i f f e r in their effect upon rec e p t i v i t y , however methysergide plus quipazine s i g n i f i c a n t l y f a c i l i t a t e d r e c e p t i v i t y in comparison to the other 39 three treatments ( p _ < . 0 5 ) . Proceptivity data are displayed in F i g . 7 and indicate that quipazine, either alone or in combination with methysergide, increased proceptive behavior in ovariectomized, estrogen-primed females. Methysergide, when administered alone, reduced proceptivity scores and the proportion of animals displaying proceptive behavior. Proceptivity data were analyzed in a 2 x 2 analysis of variance for repeated measures . This analysis confirmed that quipazine s i g n i f i c a n t l y increased proceptive behavior in ovariectomized, estrogen-primed females, F ( 1 , 1 0 ) = 3 1 . 1 5 , p_<.0003. There was no main effect of methysergide, nor was there any s i g n i f i c a n t interaction of methysergide with quipazine. The results of Experiment 5 demonstrate that neither quipazine nor methysergide alone a l t e r s lordosis behavior in estrogen-primed females. These data are contrary to the theory of a simple inhibitory role for 5-HT in female sexual behavior. The observation of the f a c i l i t a t i o n of lordosis behavior following the combined administration of quipazine and methysergide i s consistent with a dual role for 5-HT in female sexual behavior. A comparison of the e f f e c t s of quipazine on proceptivity in Experiment 3 with those of Experiment 5 suggests that the agonist does more than merely enhance the a b i l i t y of progesterone to f a c i l i t a t e proceptive responses. Whereas both estrogen and progesterone were injected in Experiment 3, only estrogen was administered in the present study. Therefore, quipazine appears capable of mimicking the effect of 40 progesterone on proceptivity, but not on r e c e p t i v i t y . It seems unlikely that the f a c i l i t a t i o n of proceptivity was due to quipazine releasing progesterone or other adrenal steroids known to f a c i l i t a t e r e c e p t i v i t y (Gorzalka & Whalen, 1977) , as quipazine was e n t i r e l y without effect on lordosis behaviour. Furthermore, quipazine e l i c i t e d proceptivity in Experiment 3 where the quantity of exogenous progesterone would have masked any e f f e c t of adrenal steroids. The present data cannot eliminate the p o s s i b i l i t y that quipazine f a c i l i t a t e s proceptive behavior v i a a dopaminergic mechanism. Although DA may i n h i b i t r e c e p t i v i t y (Meyerson & Lewander, 1970), there is evidence to suggest that DA f a c i l i t a t e s proceptive behavior (Caggiula, Herndon, Scanlon, Greenstone, Bradshaw, & Sharp, 1979). Moreover, quipazine does appear to enhance DA a c t i v i t y (Rokosz-Pelc, Antkiewicz-Michaluk, & Vetulani, 1980). 41 Fig. 6. Mean lordosis quotients ± S.E.M. of females primed with estr a d i o l benzoate following the administration of 3 mg/kg quipazine, 3 mg/kg methysergide, quipazine plus methysergide, or the saline vehicle 1 hr prior to testing. 42 100r o\° LU 75 § 5 0 | -O co O 25|-Q DC O Hiij methysergide | | saline s a l i n e q u i p a z i n e 43 Fig. 7. Proceptivity scores ± S.E.M. of female rats primed with estr a d i o l benzoate following the administration of 3 mg/kg quipazine, 3 mg/kg methysergide, quipazine plus methysergide, or the saline vehicle 1 hr prior to te s t i n g . The c r i t e r i a • for scoring proceptive behaviour have been described in the method section of Experiment 4. 44 LU cr O o CO >-Q_ LU o o cr a. 3 r 0 I I tfjij methyserg ide [ | sa l ine s a l i n e q u i p a z i n e 45 Experiment 6 Although pirenperone has been characterized as a r e l a t i v e l y s p e c i f i c 5-HT2 antagonist (Janssen, 1983), a recent paper has suggested that i t may also act as an antagonist at DA receptors (Meltzer, Simonovic, & Gudelsky, 1983). This conclusion was based on the finding that pirenperone increases release of prol a c t i n from the anterior p i t u i t a r y . The tonic i n h i b i t i o n by DA has been considered to be a major factor in the regulation of prol a c t i n release (MacLeod, 1976). Ketanserin, a s i s t e r compound highly similar in structure to pirenperone, provided an opportunity to assess the p o s s i b i l i t y of a dopaminergic mechanism of pirenperone i n h i b i t i o n of sexual behavior. Although both drugs have a similar high a f f i n i t y for 5-HT2 receptors, ketanserin has been found not to raise p r o l a c t i n levels (Meltzer et a l . , 1983), and thus i t can be considered as r e l a t i v e l y inactive at DA receptors. Therefore, i f the inhibitory e f f e c ts of pirenperone were due to the blockade of 5-HT2 receptors rather than DA receptors , then ketanserin should produce an i n h i b i t i o n of lordosis similar to that observed following the administration of pirenperone. This hypothesis i s tested in Experiment 6. Method In a repeated measures design, 12 ovariectomized females received lOjug EB, followed 48 hr later by progesterone, and 3 hr 46 later by the IP administration of either 2.5 mg/kg ketanserin, or .05 ml of the c i t r a t e vehicle. After an additional hr, females were placed with males for behavioral testing. One week la t e r , treatments were reversed, and animals were retested for lordosis behavior. Results and Discussion Experiment 6 demonstrated that ketanserin inhibited lordosis behaviour in females that had been acutely administered estrogen and progesterone. Following the administration of c i t r a t e and ketanserin, lordosis quotients averaged 91.7±3.4 and 25.8±9.1 , respectively. These data were evaluated using a student's t-test for dependent groups, which confirmed that lordosis quotients were s i g n i f i c a n t l y reduced by ketanserin, t(22)=4.569,p_<.005. The present experiment demonstrates that ketanserin, l i k e pirenperone, i n h i b i t s lordosis behaviour. These results are consistent with the p o s s i b i l i t y that the i n h i b i t i o n of lordosis behavior produced by ketanserin and pirenperone was due to the antagonism of a c t i v i t y at 5-HT2 receptors. However, i f the blockade of 5-HT2 receptors had indeed been responsible for the inhibitory e f f e c t s of pirenperone and ketanserin, then other 5-HT2 antagonists should also i n h i b i t lordosis behaviour. Spiperone has been found to bind with high a f f i n i t y to both DA and 5-HT2 receptors, acting as an antagonist at these receptors (Peroutka & Snyder, 1980). Therefore, the eff e c t s of spiperone on lordosis behaviour were assessed. Two groups of 11 animals 47 each received 10 Mg EB followed 48 hr later by 500 Mg P. Three hr after the administration of P , one group received 0.25 mg/kg spiperone and the other group received the saline vehicle. After an additional hr, the females were placed with males for behavioural testing. The females that had received spiperone displayed s i g n i f i c a n t l y less lordosis behavior than those that received the saline vehicle. The mean lordosis quotients for the experimental and control animals were 2 7 . 3 ± 6 . 6 and 9 7 . 3 ± 1 . 4 , respectively, t O 0 ) = l 0 . 3 5 , p _ < . 0 0 l . The role of DA in female sexual behaviour remains controversial, and thus i t is possible that the inhibitory e f f ects of pirenperone and spiperone may have been , at least p a r t i a l l y mediated by a dopaminergic mechanism. However pimozide, a DA antagonist with low a f f i n i t y for 5-HT2. receptors (Leysen, Niemegeers, Van Nueten, & Laduron, 1 9 8 2 ) has been reported to f a c i l i t a t e female sexual behaviour ( E v e r i t t , Fuxe, & Hokfelt, 1 9 7 4 ) . Therefore, i t is reasonable to speculate that spiperone, l i k e pirenperone and ketanserin, i n h i b i t s lordosis through the antagonism of 5-HT2 receptors, an action common to a l l three drugs. 48 GENERAL DISCUSSION The results of the present series of experiments demonstrate an inhibitory effect of the 5-HT 2 antagonist pirenperone upon proceptive and receptive behaviour in the female rat. The p a r t i a l attenuation of the i n h i b i t o r y e f fects of pirenperone on re c e p t i v i t y by the 5-HT agonist quipazine appears to confirm the serotonergic mediation of the pirenperone e f f e c t . It is unlike l y that the inhibitory effects of pirenperone were merely a t y p i c a l effects of that drug, as the 5-HT 2 antagonists ketanserin and spiperone also produced a profound i n h i b i t i o n of sexual behaviour. Furthermore, though according to Meyerson's theory of serotonergic i n h i b i t i o n of female•sexual behaviour the 5-HT agonist quipazine would have been expected to i n h i b i t sexual behaviour, no i n h i b i t i o n of re c e p t i v i t y was observed. Quipazine in fact appeared to f a c i l i t a t e proceptive behaviour, and, in combination with methysergide, mimicked the effects of progesterone by producing vigorous proceptive and receptive behaviour in estrogen-primed females. Many of the results of the present study are at variance with a general inhi b i t o r y role for 5-HT in female sexual behaviour, and suggest the need for a reevaluation of Meyerson's theory. Although proceptive behaviour has been evaluated by a number of researchers, the vast majority of studies of female sexual behaviour in the rat have been concerned exclusively with the lordosis response as a measure of sexual r e c e p t i v i t y . Therefore in the following discussion, the basic implications of Meyerson's theory with regards to lordosis behaviour w i l l be 49 challenged. F i r s t , i s a general reduction of central 5-HT a c t i v i t y necessary for the expression of lordosis behaviour? Second, i s the reduction of central 5-HT a c t i v i t y per se s u f f i c i e n t to f a c i l i t a t e lordosis behaviour in steroid-primed females? Third, does progesterone f a c i l i t a t e lordosis in estrogen-primed females by reducing serotonergic a c t i v i t y ? Although such a theory has been proposed, there is evidence to suggest that progesterone does not act simply as an antiserotonergic agent. Fourth, i s the f a c i l i t a t i o n of lordosis sometimes observed following the administration of low doses of 5-HT agonists due to the presynaptic i n h i b i t i o n of 5-HT release? Such a mechanism would be consistent with Meyerson's theory, however there is evidence to suggest that more complex mechanisms may be operating. F i n a l l y , in l i g h t of t h i s c r i t i q u e of Meyerson's theory, an attempt w i l l be made to integrate the results of the present study with Meyerson's theory. In thi s e f f o r t , a dual role for 5-HT in female sexual behaviour w i l l be hypothesized. S p e c i f i c a l l y , i t w i l l be proposed that 5-HT serves both f a c i l i t a t o r y and in h i b i t o r y roles in female sexual behaviour, r e f l e c t i n g d i f f e r e n t i a l roles of the 5-HT2 and 5-HT, receptors , respectively. Is a reduction of 5-HT necessary for the expression of lordosis  behaviour? Between 1964 and 1966, Meyerson performed a series of studies that led him to suggest an inhib i t o r y role for serotonin in female sexual behaviour. Meyerson f i r s t reported that the 50 administration of the MAO inh i b i t o r s nialamide, pargyline, and JB 516 inhibited sexual behaviour in female rats primed with estrogen and progesterone (Meyerson,.1964a) . He observed in his second paper of 1964, that the monoamine storage depletors reserpine and tetrabenazine appeared to f a c i l i t a t e lordosis behaviour in estrogen-primed females (Meyerson, 1964b). In his t h i r d paper of 1964, Meyerson reported that the serotonin synthesis i n h i b i t o r a-propyldopacetamide prevented the inhibitory effect of the MAO i n h i b i t o r pargyline, and in this paper he suggested that increases in serotonergic a c t i v i t y i nhibited female sexual behaviour. However, he also volunteered that " the existence of special serotonergic heat inhibitory receptors i s s t i l l uncertain" (Meyerson, 1964c). In 1966, Meyerson published the results of a study in which he observed that the sexually f a c i l i t a t o r y e f f e c t s of reserpine and tetrabenazine were attenuated by the monoamine reuptake blocker imipramine, ostensibly by sparing serotonergic a c t i v i t y (Meyerson, 1966a). Meyerson did not e x p l i c i t l y propose inhibitory serotonergic pathways in t h i s paper of 1966, however in the introduction of a following paper he stated that, " Our working hypothesis i s that there exist serotonergic pathways mediating i n h i b i t i o n of the copulatory response in the female rat" (Meyerson, 1968). It is noted, that at this time Meyerson remained reluctant to propose a tonic serotonergic inhibiton of sexual behaviour. In neurophysiological terms, a tonic process is one that is steadily maintained, whereas a phasic process is engaged intermittently or merely in response to s t i m u l i . Thus, i f serotonergic i n h i b i t i o n were a phasic process, then 51 serotonergic pathways would merely be available to block the expression of sexual behaviour. However i f serotonergic i n h i b i t i o n were tonic, then some serotonergic pathways would be continuously active in suppressing sexual behaviour. Although he c l e a r l y suggested tonic mechanisms in early papers, Meyerson did not e x p l i c i t l y discuss tonic serotonergic i n h i b i t i o n of female sexual behaviour u n t i l as recently as 1983 (Seitnieks & Meyerson, 1983). The most fundamental implication of a theory of serotonergic i n h i b i t i o n of sexual behaviour, either tonic or phasic, is that central serotonergic a c t i v i t y i s incompatible with lordosis behaviour. Indeed, in the years subsequent to Meyerson's i n i t i a l papers, a variety of authors have reported that treatments that increase 5-HT a c t i v i t y i n h i b i t female sexual behaviour. For example, the serotonin precursor 5-HTP (Seitnieks & Meyerson, 1982b; Seitnieks & Meyerson , 1983b), and the 5-HT agonists LSD (Meyerson et a l . , 1974; E v e r i t t , Fuxe, Hokfelt, & Jonsson, 1975; Eliasson & Meyerson, 1977; Seitnieks & Meyerson, 1980; Seitnieks & Meyerson, 1983), DMT, ps i l o c y b i n (Fuxe et a l . , 1975), and 5MeODMT (Fuxe et a l . , 1975; Rodriguez-Sierra & Davis, 1979) have been shown to i n h i b i t lordosis behaviour. Moreover, drugs such as fenfluramine ( E v e r i t t , Fuxe, Hokfelt, & Jonsson, 1975; Michanek & Meyerson, 1977) and PCA (Michanek & Meyerson, 1977; Zemlan et a l . , 1977) that release 5-HT from the terminals of serotonergic neurons have also been reported to i n h i b i t lordosis. F i n a l l y , i t must be noted that in at least two cases, serotonin i t s e l f has been reported to i n h i b i t , though not eliminate lordosis behaviour in females 52 primed with estrogen and progesterone when administered d i r e c t l y into the medial preoptic nucleus (Clemens, 1978; Foreman & Moss, 1978), or the arcuate or ventromedial nuclei (Foreman & Moss, 1978) of the hypothalamus. Although there has been substantial evidence to suggest an inhib i t o r y role for 5-HT, the l i t e r a t u r e has not been e n t i r e l y consistent with this conclusion . Indeed, in many cases pharmacological increases in serotonergic a c t i v i t y have not been found to suppress the expression of lordosis behaviour. For example, inconsistencies can be found among the reports concerning the e f f e c t s of 5-HT reuptake blockers upon lordosis behaviour. These drugs enhance 5-HT a c t i v i t y , and in the context of a theory of serotonergic i n h i b i t i o n , they would be expected to i n h i b i t l o r d o s i s . In an early study, Meyerson did observe i n h i b i t i o n following the administration of a variety of t r i c y c l i c antidepressants, including imipramine, desmethylimipramine, amytriptyline, n o r t r i p t y l i n e , and protr i p t y l i n e (Meyerson...... 1966a). Because these drugs were believed to act by blocking reuptake of 5-HT, these results were offered as evidence of sexually inhibitory serotonergic pathways. However, a more recent study has indicated that these drugs may be more e f f e c t i v e in enhancing noradrenergic rather than serotonergic a c t i v i t y (Fuller & -Wong, 1977). Indeed, desmethylimipramine, the drug Meyerson found to be most e f f e c t i v e in eliminating sexual behaviour, was reported as being v i r t u a l l y inactive with regards to the reuptake of 5-HT. Contrary to the e a r l i e r reports of inhi b i t o r y e f f e c t s of 5-HT reuptake blockers, the administration of the r e l a t i v e l y s p e c i f i c 53 5-H'T reuptake blockers Org 6582, femoxitine, or chlorimipramine has been reported to f a c i l i t a t e sexual behaviour (Hamburger-Bar, Rigter & Dekker, 1978) , Moreover, though the 5-HT selective reuptake blocker zimelidine inhibited lordosis in sexually active females, i t was reported to f a c i l i t a t e lordosis behaviour in a population of females that were r e l a t i v e l y unresponsive to ovarian steroids (Hunter & Wilson, cited in Tucker and F i l e , 1982). In one report, the 5-HT reuptake blockers Org 6582, GEA 654, and the less selective H102/09 were found to i n h i b i t lordosis behaviour ( E v e r i t t , 1977), however these apparent inconsistencies in the effects of 5-HT re-uptake blockers may have been due to differences in steroid doses or temporal parameters. Other examples can be found in the l i t e r a t u r e to suggest that increased serotonergic a c t i v i t y i s not necessarily incompatible with lordosis a c t i v i t y . For example, the acute, administration of large doses of the 5-HT agonist LSD has been reported to i n h i b i t lordosis behaviour, however the chronic administration of LSD did not appear to reduce mating behaviour (Meyerson et a l . , 1974). The present study has also demonstrated that increased serotonergic a c t i v i t y does not necessarily reduce lordosis behaviour, as the administration of the 5-HT agonist quipazine did not i n h i b i t r e c e p t i v i t y in females that had been primed either with estrogen, or with estrogen and progesterone. These results are consistent with an e a r l i e r report of the ineffectiveness of quipazine i n females administered estrogen and progesterone (Arendash & Gorski, 1983). In an e a r l i e r study, quipazine was found to i n h i b i t lordosis behaviour in females 54 primed with estrogen and progesterone (Rodriguez-Sierra & Davis, 1979). Moreover, this i n h i b i t i o n was observed following a dose of quipazine that was comparable to that of the present study. One methodological difference that may have been responsible for this inconsistency is that a 68 hr post-estrogen interval was employed when inhibitory e f fects of quipazine were observed, whereas a 48 hr post-estrogen i n t e r v a l was employed throughout the present study. However, i t is not obvious how t h i s difference in post-estrogen interval might have resulted in a d i f f e r e n t i a l response to quipazine. Nonetheless, the results of research now being performed in our laboratory remain consistent with those of the present study with regards to quipazine. We have yet to observe i n h i b i t i o n of lordosis behaviour following the administration of quipazine. Indeed, quipazine alone appears to f a c i l i t a t e lordosis behaviour under some conditions. It has been noted that fenfluramine and PCA, drugs that produce a rapid release of central 5-HT, have been reported to i n h i b i t l o r d osis. Such results would be consistent with an in h i b i t o r y effect of 5-HT. However, one study has openned the p o s s i b i l i t y that a transient release of 5-HT is at least p a r t i a l l y responsible for the f a c i l i t a t o r y e f f e c ts of the 5-HT synthesis i n h i b i t o r PCPA. It appears that a portion of PCPA introduced into the rat is metabolized into the related compound p-chlorophenylethylamine (PCPEA). PCPEA, l i k e fenfluramine and PCA, releases central 5-HT. However the prevention of the conversion of PCPA to PCPEA blocked the f a c i l i t a t o r y e f f e c ts of PCPA, and therefore i t was suggested that an increase, rather than a decrease in 5-HT a c t i v i t y mediates the f a c i l i t i t o r y 55 ef f e c t s of PCPA. (Wilson et a l . , 1982). Perhaps the most serious weakness in the notion that a reduction in 5-HT is necessary for the expression of female sexual behaviour i s the lack of evidence that the combined administration of estrogen and progesterone actually reduces central 5-HT a c t i v i t y . Indeed, in 1964, Meyerson found that the administration of estrogen and progesterone to ovariectomized female rats did not a l t e r the concentration, or turnover of central 5-HT (Meyerson, 1964c), even though assays were performed at a time when sexual r e c e p t i v i t y would have been expected to be maximal. The turnover of 5-HT is a measure of the rate of change of 5-HT levels in brain tissue, and is considered to be a more accurate indication of actual 5-HT a c t i v i t y than a simple assay of 5-HT content. Meyerson's conclusion has been well supported in the l i t e r a t u r e by other reports that have indicated few, i f any, effects of either ovariectomy or the combined administration of estrogen and progesterone upon central 5-HT l e v e l s or turnover (Bapna, Neff, & Costa, 1971; Fuxe, Schubert, Hokfelt, & Jonsson, 1974; Hyyppa & C a r d i n a l i , 1975). In the few studies that have demonstrated effects of combined steroid treatment upon the turnover of central 5-HT, these e f f e c t s have actually been increases in 5-HT turnover in the median eminence (Crowley, O'Donohue, Muth, & Jacobowitz, 1979), thalamus (Sietnieks,Anden, & Grabowska-Anden, 1983), and dorsal raphe (Cone, Davis, & Goy 1981). Increases of 5-HT turnover following the combined administration of estrogen and progesterone would be consistent with a f a c i l i t a t o r y , rather than an i n h i b i t o r y role for 5-HT in female sexual behaviour. 56 Although MAO i n h i b i t o r s have been reported to i n h i b i t lordosis r e c e p t i v i t y , several studies have indicated that in ovariectomized females, chronic administration of estrogen reduces the a c t i v i t y of type A MAO (Chevillard, Barden, & Saavedra, 1981; Luine,Khylchevskaya, & McEwen, 1975; Luine & McEwen, 1977), the type of MAO believed to be most responsible for the deactivation of 5-HT (Johnson, 1968). Thus, these data suggest that chronic estrogen administration, a treatment known to enhance lordosis behaviour, may actually increase 5-HT a c t i v i t y in some areas of the brain. In the intact, c y c l i n g female, both 5-HT uptake and MAO a c t i v i t y in the hypothalamus have been reported to f a l l in the afternoon just prior to the onset of estrous behaviour (Kamberi & Kobayashi, 1970; Meyer & Quay, 1976.; Meyer, Singh, & Jimenez, 1983), suggesting that in the intact female, 5-HT a c t i v i t y may be increasing with the appearance of lordosis a c t i v i t y . However, similar patterns of 5-HT uptake and MAO a c t i v i t y are seen at points of the estrous cycle when females are not sexually receptive, indicating that these changes may not be correlated with changes in either ovarian ster o i d l e v e l s , or lordosis a c t i v i t y . There may be neuronal mechanisms by which the ovarian steroids could, in e f f e c t , reduce serotonergic a c t i v i t y without d i r e c t l y a f f e c t i n g the levels or metabolism of 5-HT. For example, the ovarian steroids could f a c i l i t a t e lordosis behaviour by down-regulating the number or a c t i v i t y of 5-HT receptors. A recent report has indicated that chronic administration of estrogen and progesterone decreases the number of 5-HT,, but not 5-HT2 receptors in rat cortex (Biegon, Reches, 57 Snyder, & McEwen, 1983). Moreover, the authors of this report have suggested that these data might i l l u s t r a t e the means by which the ovarian steroids f a c i l i t a t e lordosis behaviour. However, chronic administration of estrogen and progesterone does not normally induce sexual r e c e p t i v i t y . Whereas the acute administration of progesterone enhances lordosis behaviour in estrogen-primed females, the repeated administration of progesterone has been reported to in h i b i t lordosis behaviour (Powers & Moreines, 1976), a phenomenon known as the biphasic effect of progesterone. Thus i t appears unlikel y that the regimen of steroid treatment that was found to reduce the number of c o r t i c a l 5-HT, receptors would actually enhance lordosis behaviour. Of more relevance to the present discussion is the report in the same study that the chronic administration of estrogen, a treatment known to f a c i l i t a t e lordosis behaviour, reduces the number of 5-HT, receptors, but increases the number of 5-HT2 receptors in the rat cortex (Biegon et a l . , 1983). Such results would be consistent with a dual role for 5-HT in female sexual behaviour. Although inhibitory e f fects of serotonergic stimulation have been reported, the necessity of a reduction in central 5-HT a c t i v i t y for the expression of sexual behaviour has not been demonstrated. Moreover, the increases in 5-HT a c t i v i t y reported to produce i n h i b i t i o n of lordosis behaviour may be too extreme to be considered physiological. For example, in one report a 90% i n h i b i t i o n of MAO, and a 100% increase in preoptic-hypothalamic 5-HT was required to i n h i b i t lordosis in females primed with estrogen and progesterone (Luine & Paden, 1981). In fact, i t 58 appears that r e l a t i v e l y small increases in 5-HT a c t i v i t y may not be e n t i r e l y incompatible with lordosis behaviour, and may, in some cases, even enhance i t . The present series of experiments may provide an explanation for these apparent inconsistencies. It may be that the type of stimulation, that i s , 5-HT2 versus 5-HT,, is c r i t i c a l in determining the effect of serotonergic treatment upon lordosis behaviour. Does a general reduction of central 5-HT a c t i v i t y , per se, fa c i 1 i t a t e lordosis behaviour in steroid-primed females? Although a general reduction in 5-HT a c t i v i t y does not appear to be necessary for the expression of lordosis behaviour, treatments known to reduce central serotonergic a c t i v i t y have been reported to f a c i l i t a t e lordosis behaviour in estrogen-primed females, and, in some cases, in females that had been primed with both estrogen and progesterone. Such results have been offered as evidence that the reduction of central serotonergic a c t i v i t y per se f a c i l i t a t e s lordosis behaviour in steroid-primed females. Although many antiserotonergic treatments have been reported to f a c i l i t a t e lordosis behaviour in steroid-primed females, the results of the studies concerning the effects of these treatments have been markedly inconsistent. Indeed, numerous examples can be found in the l i t e r a t u r e to suggest that the reduction of 5-HT has no eff e c t on lordosis behaviour in steroid-primed females. Meyerson found the 5-HT synthesis i n h i b i t o r a -propyldopacetamide to be e f f e c t i v e in reducing 59 central 5-HT l e v e l s , but i n e f f e c t i v e in f a c i l i t a t i n g lordosis behaviour in estrogen-primed females (Meyerson & Lewander, 1970). However in another study, a-propyldopacetamide was found to f a c i l i t a t e lordosis behaviour in estrogen-primed females (Everi t t , Fuxe, Hokfelt, & Jonsson, 1975). The 5-HT synthesis i n h i b i t o r PCPA reduces central 5-HT le v e l s (Koe & Weissman, 1966), however results have been inconsistent with regards to i t s effect upon lordosis behaviour. Moreover, when f a c i l i t a t i o n has been reported, no clear r e l a t i o n can be found between th i s f a c i l i t a t i o n and the degree of reduction of central 5-HT. In v i r t u a l l y every published account of experiments in which lordosis behaviour has been observed 2 to 4 hr after the acute administration of PCPA in ovariectomized females, authors have reported f a c i l i t a t i o n (Meyerson & Lewander, 1970; Ahlenius, Engel, Eriksson, Modigh, & Sodersten, 1972; Eriksson & Sodersten, 1973; E v e r i t t , Fuxe, Hokfelt, & Jonsson, 1975; Wilson, Bonney, Everard, Parrot, & Wise, 1982). At these times, PCPA has been reported to reduce central 5-HT l e v e l s by approximately 20% (Koe & Weissman, 1966). However, i f the reduction of 5-HT lev e l s were primarily responsible for the f a c i l i t a t o r y e f f e c ts of PCPA, then f a c i l i t a t i o n of lordosis behaviour would also be expected 24 to 72 hours after acute administration, or after several days of chronic administration, when central 5-HT is reduced by over 80% (Koe & Weissman, 1966). Although some studies have demonstrated f a c i l i t a t o r y e f f e c t s in ovariectomized females (Davis & Kohl, 1978; Emery & Larsson, 1979; E v e r i t t , Fuxe, Hokfelt, & Jonsson, 1975), PCPA has more often been found to be i n e f f e c t i v e at these times ( Segal & 6 0 Whalen, 1970; Ahlenius et a l . , 1972b; Sodersten et a l . , 1976; Eliasson & Meyerson, 1977; Emery & Larsson, 1979). There have in fact, been reports of i n h i b i t i o n of lordosis behaviour in ovariectomized (Segal & Whalen, 1970; Hamburger-Bar et a l . , 1978), and intact (Al S a t l i & Aron, 1981) females at those times when PCPA i s most e f f e c t i v e in reducing levels of central 5-HT. Inconsistencies are also apparent in the reports of the effects of the 5-HT depleting drug PCA on lordosis behaviour. The i n i t a l e f f e c t of PCA is the release of central 5-HT, and i n h i b i t i o n of lordosis has been reported within several hours of administration (Michanek & Meyerson, 1978). However, several days after PCA treatment, central 5-HT levels are depleted, and thus , according to the theory of serotonergic i n h i b i t i o n , f a c i l i t a t i o n of sexual behaviour would be expected at t h i s time. However, though one study has described f a c i l i t a t o r y e f f e c ts of PCA (Zemlan, Trulson, Howell, & Hoebel, 1977), the results of the study are d i f f i c u l t to interpret within a simple model of serotonergic i n h i b i t i o n . In t h i s study of 1977, f a c i l i t a t o r y e f f e c t s of PCA were observed in females that had been acutely administered estrogen and progesterone, however none were observed in animals that had received estrogen only. Furthermore, 10 mg/kg PCA , which depleted central 5-HT by 66%, f a c i l i t a t e d r e c e p t i v i t y , whereas 20 mg/kg PCA, which depleted central 5-HT by 80%, did not f a c i l i t a t e lordosis a c t i v i t y . F i n a l l y , one group of authors found PCA to be i n e f f e c t i v e in females primed either with estrogen and progesterone, or with estrogen alone (Sodersten, Berge, & Hole, 1978) . The administration of the serotonergic neurotoxin 5,7-DHT 61 has also f a i l e d to consistently produce f a c i l i t a t i o n of lordosis behaviour in estrogen-primed females. In several studies, neurotoxic lesions produced by the administration of 5,7-DHT d i r e c t l y into 5-HT pathways ascending from the mesencephalon to the hypothalamus have been found to f a c i l i t a t e lordosis behaviour. (Everitt, Fuxe, & Jonsson 1975; Luine, Frankfurt, Rainbow, Biegon, & Azmita, 1983). In one such study (E v e r i t t , Fuxe, & Jonsson, 1975), a f a c i l i t a t o r y effect was observed 1 to 7, but not 7 to 13 days after treatment with 5,7-DHT. However, because central 5-HT levels remain low for considerably longer than 2 weeks after treatment with 5,7-DHT (Baumgarten et a l . , 1973), these results are d i f f i c u l t to explain in terms of a simple inhibitory role for 5-HT. Moreover, one study has found serotonergic lesions produced by 5,7-DHT to be in e f f e c t i v e in estrogen-primed females (Sodersten et a l . , 1978). Whereas some authors have depleted central 5-HT by the administration of neurotoxins, others have performed e l e c t r o l y t i c lesions to destroy the serotonergic neurons of the dorsal and median raphe nuclei, the primary sources of forebrain 5-HT. However, the three reports existing in the l i t e r a t u r e concerning e l e c t r o l y t i c lesions of the dorsal and median raphe are consistent in indicating that damage to these areas does not f a c i l i t a t e lordosis behaviour (Herndon, 1976; E v e r i t t , 1978; Arendash & Gorski, 1983). Although 5-HT antagonists have been reported to enhance lordosis behaviour, f a c i l i t a t i o n has not been consistently observed following their administration. Of the three published studies evaluating the effects of the antagonist cinanserin in 62 estrogen-primed females, two studies demonstrated f a c i l i t a t o r y e f f e c t s of the drug (Zemlan, Ward, Crowley, , & Margules,1973; Ward, Crowley, Zemlan, & Margules, 1975), whereas a t h i r d study found the drug to be i n e f f e c t i v e ( E v e r i t t , Fuxe, Hokfelt, & Jonsson, 1975). The 5-HT antagonist methysergide has been found to f a c i l i t a t e lordosis behaviour after either central (Zemlan et al.,1973; Ward et a l . , 1975; Foreman & Moss, 1978; Franck & Ward, 1981) or peripheral administration (Zemlan et a l . , 1973; Henrik & G e r a l l , 1976; Rodriguez-Sierra & Davis, 1979). However, the f a i l u r e in the present study of methysergide to f a c i l i t a t e r e c e p t i v i t y in estrogen-primed females is consistent with the report of the ineffectiveness of methysergide when administered d i r e c t l y into the pre-optic areas of the hypothalamus of estrogen-primed females (Clemens, 1978) . Moreover, there are at least two reports in the l i t e r a t u r e of i n h i b i t i o n of lordosis following the administration of methysergide ( Meyerson & Eliasson, 1977; Clemens, 1978). Although very small doses of the 5-HT antagonist metergoline has been found to f a c i l i t a t e l o r d o s i s behaviour , when administered in moderate doses i t i n h i b i t e d lordosis behaviour in females chronically receiving estrogen (Fuxe, et a l . , 1976). It was suggested by the authors that the large doses of metergoline inhibited lordosis behaviour by antagonizing the process of presynaptic i n h i b i t i o n . In t h i s phenomenon, a small proportion of neurotransmitter released at the synapse returns to bind at special receptor si t e s on the neurons of o r i g i n , there i n h i b i t i n g further release of neurotransmitter in a process of negative feedback. Thus in e f f e c t , metergoline would 63 have been acting as a 5-HT agonist. However, such an explanation is untenable, as doses even higher than those required to i n h i b i t lordosis behaviour were used by the same authors to successfully block the serotonergic e f f e c t s of the 5-HT agonist LSD, thus demonstrating antiserotonergic a c t i v i t y of metergoline at high doses. The inconsistency in the l i t e r a t u r e concerning possible f a c i l i t a t o r y effects of antiserotonergic treatments is further complicated by evidence suggesting that at least some of the effects that have been observed following antiserotonergic treatments may have been the result of adrenal stimulation. The adrenal glands, l i k e the ovaries, produce a variety of steroid hormones, including s i g n i f i c a n t quantities of progesterone and deoxycorticosterone, both of which have been shown to f a c i l i t a t e lordosis r e c e p t i v i t y in estrogen-primed, ovariectomized rats (Gorzalka & Whalen, 1977). Decreases in central monoaminergic a c t i v i t y have in fact been reported to stimulate adrenal steroid production in the rat (Maickel, Westerman, & Brodie, 1961). Unfortunately, the results of studies designed to examine the question of adrenal mediation have not been consistent. For example, the f a c i l i t a t o r y e f f e c t s of reserpine have been reported to be blocked by the prior administration of dexamethasone ( Paris, Resko, & Goy, 1971), a drug known to prevent the release of adrenal steroids; however in an e a r l i e r study, reserpine was found to be e f f e c t i v e in adrenalectomized females (Meyerson, 1964c). A single study has also found tetrabenazine to be i n e f f e c t i v e in ovariectomized-adrenalectomized females ( Larsson, Feder, & Komisurak, 1974), 64 however both methysergide and cinanserin have been reported to f a c i l i t a t e lordosis behaviour in females without adrenals ( Zemlan et a l . , 1973). The p o s s i b i l i t y that the adrenal glands may, at least p a r t i a l l y , mediate the effects of PCPA on lordosis behaviour also remains controversial. PCPA has been reported by some authors to f a c i l i t a t e lordosis behaviour in ovariectomized-adrenalectomized females (Zemlan et a l . , 1973; E v e r i t t , Fuxe, Hokfelt, & Jonsson, 1975) , however others have reported that the f a c i l i t a t o r y effect of PCPA was abolished by the removal of the adrenal glands (Eriksson & Sodersten, 1973; Gorzalka & Whalen, 1975) or by the administration of dexamethasone (Emery & Larsson,1979). Along with the p o s s i b i l i t y of adrenal mediation, there is evidence that a reduction in central catecholamines rather than 5-HT may be responsible for the f a c i l i t a t o r y e f f e c ts of what have been considered to be antiserotonergic treatments. Such a mechanism would be consistent with evidence that the reduction of DA a c t i v i t y f a c i l i t a t e s r e c e p t i v i t y ( E v e r i t t , Fuxe, Hokfelt, & Jonsson, 1975). Although PCPA has generally been reported to f a c i l i t a t e lordosis behaviour 2 to 8 hr after administration, when 5-HT, DA and NA levels are reduced, some authors have reported that PCPA does not f a c i l i t a t e lordosis behaviour 24 or more hours after administration. At these times 5-HT le v e l s remain reduced, but catecholamines have returned to nearly normal l e v e l s (Ahlenius et a l . , 1972). Furthermore, i t has been reported that the administration of the 5-HT precursor 5-HTP does not prevent the f a c i l i t a t o r y effect of PCPA (Wilson et a l . , 1982 ). If a reduction of 5-HT were responsible for the 65 f a c i l i t a t o r y e f f e c t , the restoration of 5-HT level s would have been expected to attenuate the PCPA ef f e c t . The dopamine hypothesis is also consistent with the results of an experiment designed to evaluate the eff e c t s of tetrabenazine on lordosis behaviour. In t h i s experiment, tetrabenazine was found to f a c i l i t a t e lordosis behaviour in estrogen-primed females in doses of either 2 or 10 mg/kg. However, whereas 10 mg/kg tetrabenazine produced a s i g n i f i c a n t reduction in brain DA, 5-HT, and NA levels, the lower dose of 2 mg/kg reduced only levels of DA , while having no s i g n i f i c a n t e f f e c t s upon levels of 5-HT or NA (Ahlenius et a l . , 1972). F i n a l l y , the physiological relevance of many studies that have evaluated the effects of 5-HT agonists must be questioned. In contrast to the apparent lack of effect of estrogen and progesterone, many of the serotonergic manipulations described in the l i t e r a t u r e are known to dramatically a l t e r 5-HT a c t i v i t y . For example, the administration of 150 mg/kg PCPA, a dose representative of those found in the l i t e r a t u r e , has been reported to produce a 76% decrease in central 5-HT levels within 24 hr (Ahlenius et a l . , 1972). Si m i l a r l y , the int r a v e n t r i c u l a r administration of 5,7-DHT has been reported to reduce central 5-HT levels of some areas of the brain by 80% (Baumgarten et al.,1973). Clearly, the p o s s i b i l i t y remains that _the ovarian steroids e l i c i t lordosis behaviour by producing very s l i g h t reductions of 5-HT a c t i v i t y in highly l o c a l i z e d areas of the brain. Drugs such as PCPA and 5,7-DHT , by virtue of reducing whole brain 5-HT, may also reduce 5-HT a c t i v i t y in these s p e c i f i c areas, thereby releasing lordosis behaviour. However, 66 i t may be that any large or rapid decline in 5-HT a c t i v i t y i n i t i a t e s neuroendocrine processes that would in themselves f a c i l i t a t e lordosis behaviour, regardless of 5-HT a c t i v i t y . The f a i l u r e of some antiserotonergic treatments to f a c i l i t a t e sexual r e c e p t i v i t y in adrenalectomized animals is consistent with t h i s p o s s i b i l i t y . Although Meyerson's theory would predict that antiserotonergic treatments f a c i l i t a t e lordosis behaviour in steroid-primed females, i t is clear that f a c i l i t a t i o n does not always follow such treatment. The l i t e r a t u r e i s in fact extremely inconsistent in thi s regard, making interpretation d i f f i c u l t . This inconsistency might be explained by the p o s s i b i l i t y that progesterone, adrenal a c t i v i t y , and catecholaminergic effects may be c r i t i c a l factors in determining the e f f e c t s of treatment with s p e c i f i c drugs. However, in l i g h t of the present data, i t is not unreasonable to suggest that the ineffectiveness, and occasional i n h i b i t i o n that has been observed following some antiserotonergic treatments may have been due to an in s u f f i c i e n c y of some pa r t i c u l a r type of 5-HT a c t i v i t y . The i n h i b i t i o n of lordosis observed in the present series of experiments following the administration of the 5-HT 2 s e l e c t i v e antagonists pirenperone, spiperone, or ketanserin is consistent with this p o s s i b i l i t y . Does progesterone f a c i 1 i t a t e lordosis by reducing serotonergic  act i v i t y ? It was noted early by Meyerson that reserpine and 67 tetrabenazine appeared to replace progesterone in the f a c i l i t a t i o n of lordosis behaviour in estrogen-primed females (Meyerson, 1966a). In subsequent papers, he suggested the p o s s i b i l i t y that progesterone might f a c i l i t a t e lordosis behaviour by reducing central monoamines in estrogen-primed females. However, i t was not u n t i l 1974 that a formal theory appeared proposing that progesterone f a c i l i t a t e d lordosis behaviour by reducing central 5-HT a c t i v i t y (Kow, Malsbury, & Pfaff, 1974). Although the administration of estrogen and progesterone has not produced demonstrable effects on 5-HT levels or turnover, there i s , somewhat paradoxically, evidence to suggest that progesterone might interact with 5-HT to modulate lordosis behaviour in- estrogen-primed females. However, these apparent interactions cannot be f u l l y explained by a simple antiserotonergic effect of progesterone. Under some conditions, the presence of progesterone may reverse the f a c i l i t a t o r y e f f e c t s of some antiserotonergic treatments. For example methysergide has been reported to f a c i l i t a t e l o r d o s i s behaviour in estrogen-primed females, however there are at least two reports that methysergide i n h i b i t s lordosis behaviour in females primed with both estrogen and progesterone (Meyerson & Eliasson, 1977; Clemens, 1978) . Furthermore, although some authors have reported PCPA to f a c i l i t a t e lordosis behaviour in estrogen-primed females, there are at least two reports of PCPA i n h i b i t i n g lordosis behaviour in females receiving both estrogen and progesterone ( Gorzalka & Whalen, 1975; Hamburger-Bar et a l . , 1978). Unfortunately, the e f f e c t s of 5-HT antagonists have, 68 for the most part, been evaluated in females receiving estrogen only. Therefore, i t can not be said whether 5-HT antagonists , in general, i n h i b i t lordosis behaviour in the presence of progesterone. Similar to the apparent interactions of progesterone with 5-HT antagonists, progesterone may be a factor in determining the effects of treatments that enhance 5-HT a c t i v i t y . For example, the 5-HT agonist a methyltryptamine has been reported to i n h i b i t lordosis behaviour in females primed with estrogen and progesterone, but not in females made receptive by the chronic administration of estrogen alone (Espino, Sano, & Wade, 1975). Similar data can found with regard to the eff e c t s of LSD. Although an acutely administered dose of 100 jug/kg of LSD eliminated sexual re c e p t i v i t y in females administered estrogen and progesterone, this large dose of LSD was i n e f f e c t i v e in females made receptive with estrogen alone (Seitnieks & Meyerson, 1980). There is also evidence to suggest that the time of administration of 5-HT reuptake blockers in rel a t i o n to the time of progesterone administration may be a factor in determining the effect of these drugs upon lordosis behaviour. When administered 24 hr prior to testing and 2 hr after progesterone, Org 6582 f a c i l i t a t e d lordosis behaviour; however when administered 24 hr prior to testing but 14 hr after progesterone, the drug was i n e f f e c t i v e (Hamburger-Bar et a l . , 1978). The reuptake blockers femoxitine and chlorimipramine also f a c i l i t a t e d lordosis behaviour when administered 2 hr before progesterone, and 24 hr prior to testing (Hamburger-Bar et a l . , 1978). A variety of 5-HT reuptake blockers, including Org 6582, 69 have been reported to i n h i b i t lordosis behaviour when administered at the same time as, or several hours after progesterone; however in these cases, the drugs were administered 2 to 4 hr prior to testing (Everitt, 1977). Given that the majority of 5-HT agonists have been evaluated in females primed with both estrogen and progesterone, the possible progesterone-dependence of their e f f ects remains to be determined. However, i t must be mentioned that several tryptamine-derived 5-HT agonists have been reported to i n h i b i t lordosis behaviour in females primed with estrogen only (Fuxe et a l . , 1976), suggesting that the inhibitory effects of at least some 5-HT agonists are not progesterone-dependent. If progesterone and 5-HT do in fact interact, the behavioural evidence suggests that i t is unlikely that progesterone simply reduces serotonergic a c t i v i t y . Indeed, recent reports from Meyerson's laboratory have suggested that progesterone may in some cases f a c i l i t a t e serotonergic a c t i v i t y . As would be expected from Meyerson's theory, high, acutely administered doses of LSD or 5-HTP i n h i b i t lordosis behaviour; however, small doses appear to f a c i l i t a t e lordosis behaviour. To remain consistent with the theory of a simple inhibitory role for 5-HT, the f a c i l i t a t o r y effect of small doses of these drugs has been explained as being due to presynaptic i n h i b i t i o n . However, Sietnieks and Meyerson (1983) have recently reported that doses of LSD or 5-HTP too small to f a c i l i t a t e lordosis in females primed with estrogen and moderate doses of progesterone, did f a c i l i t a t e when progesterone doses were increased Moreover, they observed that doses of LSD or 5-HTP too small to 70 i n h i b i t l o r d o s i s i n f e m a l e s r e c e i v i n g b o t h e s t r o g e n a n d p r o g e s t e r o n e d i d i n h i b i t when p r o g e s t e r o n e d o s e s w e r e i n c r e a s e d . T h e s e d a t a s u g g e s t t h a t p r o g e s t e r o n e e n h a n c e d t h e b i n d i n g o f 5-HT t o p r e s y n a p t i c r e c e p t o r s i t e s . H o w e v e r , t h e s e d a t a a l s o s u g g e s t t h a t p r o g e s t e r o n e e n h a n c e d t h e b i n d i n g o f 5-HT t o p o s t s y n a p t i c s i t e s , t h o u g h S i e t n i e k s a n d M e y e r s o n n e g l e c t e d t o i n c l u d e t h i s p o i n t i n t h e i r d i s c u s s i o n . T h e e n h a n c e m e n t o f p r e s y n a p t i c b i n d i n g o f 5-HT b y t h e s e x u a l l y f a c i l i t a t o r y s t e r o i d p r o g e s t e r o n e i s c o n s i s t e n t w i t h M e y e r s o n ' s t h e o r y o f s e r o t o n e r g i c i n h i b i t i o n o f l o r d o s i s b e h a v i o u r ; h o w e v e r , t h e e n h a n c e m e n t o f 5-HT a c t i v i t y a t t a r g e t c e l l s i s n o t e a s i l y r e c o n c i l e d w i t h a s i m p l e m o d e l o f s e r o t o n e r g i c i n h i b i t i o n o f l o r d o s i s b e h a v i o u r . T h e s e d a t a a r e , i n f a c t , c o n s i s t e n t w i t h t h e p o s s i b i l i t y t h a t some s p e c i f i c t y p e o f 5-HT 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 . I n some c a s e s , p r o g e s t e r o n e c a n r e v e r s e t h e f a c i l i t a t o r y e f f e c t o f a n t i s e r o t o n e r g i c t r e a t m e n t . M o r e o v e r , i t a p p e a r s t h a t t h e i n h i b i t o r y e f f e c t s o f some 5-HT a g o n i s t s may b e p r o g e s t e r o n e d e p e n d e n t . S u c h f i n d i n g s c h a l l e n g e t h e n o t i o n t h a t p r o g e s t e r o n e 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 s i m p l y b y r e d u c i n g 5-HT a c t i v i t y . M o r e o v e r , t h e s e f i n d i n g s a l s o i l l u s t r a t e t h e e r r o r o f e v a l u a t i n g t h e e f f e c t s o f a s e r o t o n e r g i c a g e n t w i t h t h e u s e o f o n l y o n e t y p e o f s t e r o i d t r e a t m e n t . I t h a s b e e n a common p r a c t i c e t o e v a l u a t e t h e e f f e c t s o f 5-HT a n t a g o n i s t s i n a n i m a l s p r i m e d w i t h e s t r o g e n a l o n e , a n d t h e e f f e c t s o f 5-HT a g o n i s t s i n a n i m a l s a d m i n i s t e r e d b o t h e s t r o g e n a n d p r o g e s t e r o n e . T h e r a t i o n a l e h a s b e e n t h a t t h e m i n i m a l l e v e l o f r e c e p t i v i t y p r o d u c e d b y e s t r o g e n a l o n e w o u l d a l l o w a n y f a c i l i t a t o r y e f f e c t s o f a n t i s e r o t o n e r g i c 71 treatment to be observed. S i m i l a r l y , i t has been reasoned that any i n h i b i t o r y effects of 5-HT agonists would be most ea s i l y demonstrated in animals administered both estrogen and progesterone, as this treatment would o r d i n a r i l y produce high levels of r e c e p t i v i t y . Unfortunately, i t appears that in some cases results that have been interpreted as evidence for an inhibi t o r y role of serotonin, may have been e n t i r e l y dependent upon an a r b i t r a r y choice of steroid treatment. Do low doses of 5-HT agonists f a c i l i t a t e lordosis behaviour  through presynaptic inhibition? Although 5-HT agonists have generally been reported to i n h i b i t lordosis behaviour, many of these drugs have f a c i l i t a t e d lordosis behaviour when administered in lower doses. Among the serotonergically active drugs that have been reported to f a c i l i t a t e r e c e p t i v i t y at low doses are LSD (Everitt, Fuxe, Hokfelt, & Jonsson, 1975; Seitnieks & Meyerson, 1983), 5-HTP (Seitnieks & Meyerson, 1983) , DMT, 5MeODMT, psilocybin, mescaline, 2,5-dimethoxy-4-methylamphetamine (DOM),2,5-dimethoxy-4-methylphenylethylamine , and 2,4,5-trimethoxyamphetamine (Fuxe et a l . , 1975). To remain consistent with Meyerson's theory of serotonergic i n h i b i t i o n , the process of presynaptic i n h i b i t i o n has routinely been offered to explain the f a c i l i t a t o r y e f f e c ts of 5-HT agonists. In other words, given that presynaptic i n h i b i t i o n reduces serotonergic a c t i v i t y , i t is suggested that these drugs may, in e f f e c t , be acting as 5-HT antagonists when administered in low doses. 72 There i s substantial evidence to show that peripherally administered 5-HT agonists can indeed reduce the a c t i v i t y of serotonergic neurons . In early studies of the effects of LSD, i t was demonstrated that extremely small doses of the drug completely eliminated the f i r i n g of serotonergic neurons in the dorsal raphe of the rat when administered d i r e c t l y onto the c e l l bodies of those neurons. However when the same small doses of LSD were administered onto neurons that were targets of serotonergic pathways, the drug appeared to be i n e f f e c t i v e (Aghajanian & Haigler, 1975). Thus i t was concluded that the reduction of serotonergic neural a c t i v i t y by LSD was due to the direct presynaptic i n h i b i t i o n of serotonergic neurons, rather than a feedback . system i n i t i a t e d by a c t i v i t y at target neurons. Moreover, i t was suggested that LSD bound p r e f e r e n t i a l l y to receptors mediating presynaptic i n h i b i t i o n , over those mediating postsynaptic e f f e c t s . Presynaptic i n h i b i t i o n , assumed to be the mechanism by which low doses of LSO produce effects on central serotonergic systems, was subsequently used as a model to explain the effects of a variety of 5-HT agonists upon lordosis behaviour. However, although presynaptic i n h i b i t i o n may explain the f a c i l i t a t o r y e f f e c t s of 5-HT agonists in a manner consistent with Meyerson's theory, there are reasons to believe that t h i s explanation is not e n t i r e l y correct. For example, mescaline and DOM are both reported to f a c i l i t a t e lordosis behaviour at low dose l e v e l s , however neither drug produces presynaptic i n h i b i t i o n of serotonergic a c t i v i t y (McCall, 1982). Clearly, i t could be argued that the f a c i l i t a t o r y e f f e c ts of mescaline and DOM are 73 mediated by a non-serotonergic mechanism, however there is substantial evidence to suggest that these drugs have s i g n i f i c a n t serotonergic a c t i v i t y . In a discrimination paradigm, DOM was found to generalize as a stimulus to mescaline, quipazine, LSD, and 5-OMeDMT, and t h i s stimulus-generalization was blocked by the 5-HT2 antagonist pirenperone (Glennon, Young, & Rosencrans, 1983). Furthermore, DOM, LSD, quipazine, and l i s u r i d e produced similar disturbances in the responses of rats on f i x e d - r a t i o schedules of food presentation, and these effects were attenuated by the the 5-HT antagonists metergoline, p i z o t e f i n , or cinanserin (Mokler, Commissaris, Warner, & Rech, 1983). The administration of 5-HT antagonists also reduced the discriminative stimulus properties of mescaline (Browne & Ho, 1975), while the e l i c i t a t i o n by mescaline of the head-twitch response, an effect that has been used as an assay of 5-HT2 receptor stimulation, has further demonstrated the serotonergic a c t i v i t y of the drug (Leysen et a l . , 1982). Contrary to e a r l i e r reports, recent evidence has suggested that the effects of low doses of LSD may not be limited to presynaptic i n h i b i t i o n of serotonergic neural a c t i v i t y Although small quantities of LSD may have no direct effect upon postsynaptic target membranes, these same small quantities appear to enhance the excitatory effects of serotonin at .postsynaptic sites (Aghajanian, Foote, & Sheard, 1970). This enhancement of postsynaptic serotonergic excitation has also been observed following the administration of mescaline, DMT, and psilocyn, a c e n t r a l l y active non-esterified form of psilocybin . These results lead to the speculation that a 74 p a r t i c u l a r type of postsynaptic enhancement, rather than a general presynaptic i n h i b i t i o n of 5-HT a c t i v i t y could be a common factor among 5-HT agonists that f a c i l i t a t e lordosis behaviour. However, before such thoughts can be developed further, a number of questions must be answered. For example, i t remains to be determined whether other sexually f a c i l i t a t o r y 5-HT agonists, such as DOM and 5-HTP, enhance postsynaptic, serotonergic a c t i v i t y . Furthermore, there have been no reports concerning the effects upon lordosis behaviour of drugs such as l i s u r i d e , that produce presynaptic i n h i b i t i o n of serotonergic neurons , but do not enhance postsynaptic serotonergic a c t i v i t y at low le v e l s (McCall, 1982). If simple presynaptic i n h i b i t i o n were s u f f i c i e n t to f a c i l i t a t e lordosis behaviour in estrogen-primed females, then l i s u r i d e , a drug reported to be as much as ten times more potent than LSD in producing presynaptic i n h i b i t i o n (Rowgawski & Aghajanian, 1979), would be expected to be f a c i l i t a t o r y at very small doses. However, the p o s s i b i l i t y remains that both presynaptic i n h i b i t i o n , and postsynaptic enhancement of serotonergic a c t i v i t y can contribute to the f a c i l i t a t i o n of lordosis behaviour. Such might be the case i f the serotonergic modulation of lordosis behaviour consisted of f a c i l i t a t o r y and inhibitory components. F i n a l l y , i t is noted that quipazine has been reported to stimulate presynaptic 5-HT receptors (B l i e r & de Montigny, 1983), therefore i t is possible that quipazine contributes to the f a c i l i t a t i o n of sexual behaviour v i a the presynaptic i n h i b i t i o n of 5-HT release. However, t h i s issue remains controversial, as another report suggests that quipazine antagonizes presynaptic i n h i b i t i o n 75 (Martin & Sanders-Bush, 1982). Notwithstanding this controversy, the attenuation by quipazine of the inhibitory effect of pirenperone could not ea s i l y be explained by the mechanism of presynaptic i n h i b i t i o n . Pirenperone, which binds to 5-HT2 receptors, has l i t t l e a f f i n i t y for the 5-HT, receptor that is believed to mediate presynaptic i n h i b i t i o n . Therefore, quipazine most l i k e l y attenuated the effect of pirenperone by restoring a c t i v i t y at postsynaptic 5-HT2 receptors. A new hypothesis: A dual role for 5-HT in lordosis behaviour There is substantial evidence in the l i t e r a t u r e to suggest that Meyerson's theory of tonic serotonergic i n h i b i t i o n f a i l s to f u l l y describe the role of 5-HT in lordosis behaviour. It appears that 5-HT a c t i v i t y i s not e n t i r e l y incompatible with lordosis behaviour in the female rat, and that a reduction in central 5-HT a c t i v i t y i s neither necessary nor s u f f i c i e n t for the expression of lordosis behaviour. Furthermore, the complexities of the interactions of progesterone with serotonergic drugs do not r e f l e c t a simple reduction of 5-HT a c t i v i t y by progesterone. Indeed, both agonists and antagonists have been reported to i n h i b i t mating behaviour in females administered estrogen and progesterone. By providing evidence of a f a c i l i t a t o r y role for 5-HT in female sexual behaviour, the present series of experiments has further demonstrated the inadequacy of Meyerson's theory. Therefore, in an e f f o r t to more accurately describe the role of serotonin in the modulation of female sexual behaviour, a new theory w i l l be proposed. 76 S p e c i f i c a l l y , i t w i l l be proposed that 5-HT serves both a f a c i l i t a t o r y and an inhibitory role in the modulation of lordosis , and that these roles are mediated by 5-HT2 and 5-HT, receptor subtypes, respectively. In the present series of experiments, the 5-HT2 s p e c i f i c antagonists pirenperone, ketanserin, and spiperone were found to in h i b i t lordosis behaviour, thus c l e a r l y suggesting a f a c i l i t a t o r y role for 5-HT2 receptors. However, i f the blockade of 5-HT2 receptors i n h i b i t s lordosis behaviour, then some degree of i n h i b i t i o n should also be observed following the administration of the c l a s s i c a l 5-HT antagonists. Although they are not selective for 5-HT2 receptors, these drugs are considered to have s i g n i f i c a n t 5-HT2 a c t i v i t y . The 5-HT antagonist metergoline, with high a f f i n i t y for both 5-HT, and 5-HT2 receptors (Peroutka, Lebovitz, & Snyder, 1981), has been reported to f a c i l i t a t e lordosis behaviour in low doses; however when administered in a higher dose, metergoline inhibited the lordosis response ( Fuxe et a l . , 1975). This inhib i t o r y effect of metergoline, which has recently been confirmed in our own laboratory, is consistent with the present hypothesis. Inhibition of lordosis has also been reported following the administration of chlorpromazine (Meyerson, 1966b), a r e l a t i v e l y potent antagonist of 5-HT2 a c t i v i t y (Leysen & Tollenaere, 1982). F i n a l l y , although there have been no published studies concerning the eff e c t s of the c l a s s i c a l 5-HT antagonists cyproheptadine, metitepine, and p i z o t e f i n on female sexual behaviour, i n i t i a l results of research currently being performed in our laboratory suggest that these drugs also 77 i n h i b i t lordosis behaviour. A l l three of these drugs have been shown to have moderately high a f f i n i t y for 5-HT2 receptors (Leysen & Tollenaere, 1982), and thus the apparent inhibitory e f f e c t s of these drugs are consistent with the present hypothesis. Interestingly, the LSD l i t e r a t u r e may also provide evidence in support of the present hypothesis. In those studies evaluating the eff e c t s of LSD upon female sexual behaviour, the drug i s consistently referred to as a 5-HT agonist; however, there have been reports to suggest that LSD may, in some cases, antagonize serotonergic a c t i v i t y . For example in the cat, moderate doses of LSD have been reported to block the excitatory e f f e c t s of 5-HT in the cortex and brain stem (Boakes, Bradley, Briggs, & Dray, 1970). The postsynaptic excitatory effects of 5-HT are believed to be mediated by 5~HT2 receptors (Peroutka, Lebovitz, & Snyder, 1981), thus the sexually inh i b i t o r y e f f e c t s of large doses of LSD may be due, at least in part, to a decrease of 5-HT2 a c t i v i t y . It i s noted that i f thi s i s indeed the case, then the sexually i n h i b i t o r y e f fects of LSD would not be expected to be ameliorated simply by the coadministration of a 5-HT antagonist, but rather some type of 5-HT2 agonist might , in addition, be required to restore lordosis behaviour. The 5-HT antagonist methysergide i s active at both 5-HT, and 5-HT2 receptor s i t e s , thus the present hypothesis suggests that under some conditions, methysergide may i n h i b i t lordosis behaviour. Consistent with the present hypothesis are at least two reports of i n h i b i t i o n following the administration of methysergide. 78 A factor that may be c r i t i c a l in determining the effect of methysergide on lordosis behaviour i s the length of time between the administration of the drug and behavioural testing. It has been reported that the maximal f a c i l i t a t o r y e f f e c t of systemically administered methysergide occurs 2 to 4 hours after administration. Indeed, in every case where f a c i l i t a t i o n has been reported following peripherally administered methysergide, post-administration intervals of 2 to 8 hours were employed. However, there is evidence to suggest that methysergide is ef f e c t i v e as a central 5-HT antagonist as early as 30 to 60 minutes after administration (Green, H a l l , & Rees; Browne, & Ho, 1975). Moreover, when administered intravenously, methysergide has been shown to block the 5-HT2 mediated f a c i l i t a t o r y effect of 5-HT on neurons of the f a c i a l motor nucleus within 1 to 2 minutes (McCall & Aghajanian, 1980). A similar antagonism of the excitatory e f f e c t s of 5-HT was observed after the intravenous administration of metergoline; however, whereas the blocking ef f e c t of metergoline lasted for at least 6 hours, the blocking effect of intravenous methysergide dissappeared within 30 minutes (McCall & Aghajanian, 1980). Taken together, the appearance and disappearance of a 5-HT2 mediated ef f e c t within 30 minutes of administration of methysergide, and the f a c i l i t a t i o n of lordosis being observed as late as 8 hours after administration suggest the p o s s i b i l i t y of biphasic effects of methysergide on female sexual behaviour. S p e c i f i c a l l y , i t is suggested that methysergide i n h i b i t s lordosis behaviour early after peripheral administration, although t h i s i n h i b i t i o n may be followed by f a c i l i t a t i o n after 79 several hours. This p o s s i b i l i t y was recently tested in our laboratory, and i t was found that in estrogen-primed ovariectomized females, methysergide inhibited the lordosis reflex 35 to 40 minutes after IP administration. These results are consistent with a f a c i l i t a t o r y role for 5~HT2 a c t i v i t y . Unfortunately, the majority of 5-HT agonists bind p r e f e r e n t i a l l y to 5-HT, receptors, thus there is r e l a t i v e l y l i t t l e data from which conclusions can be drawn with regards to the e f f e c t s of selective 5-HT2 stimulation on female sexual behaviour. However in the present series of experiments, quipazine, which binds p r e f e r e n t i a l l y to 5-HT2 receptors {Leysen & Tollenaere, 1982), was found to attenuate the inhibitory e f f ects of pirenperone, thus c l e a r l y suggesting a f a c i l i t a t o r y effect of 5-HT2 agonists. Such a conclusion i s also consistent with reports of the sexually f a c i l i t a t o r y e f f e c t s of mescaline and DOM, as both drugs are active at 5-HT2 receptors (Leysen & Tollenaere, 1982). Although no 5-HT, s p e c i f i c antagonists are presently available, the c l a s s i c a l antagonists are reported to have varying degrees of a f f i n i t y for 5-HT, receptors (Peroutka & Snyder, 1979). Therefore, i f the present hypothesis is correct, any sexually f a c i l i t a t o r y e f f e c ts of the c l a s s i c a l 5-HT antagonists may be mediated, at least in part, by the blockade of 5-HT, receptors. Consistent with this hypothesis i s the report of f a c i l i t a t i o n of lordosis behaviour following the administration of methysergide d i r e c t l y into the hippocampus, an area in which the serotonergic a c t i v i t y i s mediated almost e n t i r e l y by 5-HT, receptors (Peroutka & Snyder ,1981). 80 In the present study, the 5-HT agonist tryptamine was found to i n h i b i t lordosis behaviour in females primed with both estrogen and progesterone. Tryptamine i s reported to bind p r e f e r e n t i a l l y to 5-HT, receptors (Peroutka & Snyder, 1979), thus these results are consistent with the present hypothesis. A variety of modified forms of tryptamine also appear to act as r e l a t i v e l y s p e c i f i c 5-HT, agonists (Peroutka & Snyder, 1979). Consistent with the present hypothesis, the 5-HT, sel e c t i v e tryptamine derivatives psilocybin , DMT, and 5MeODMT have been reported to i n h i b i t lordosis behaviour, when administered in moderate doses (Fuxe et a l . , 1975). F i n a l l y , i t must be noted that while the f a c i l i t a t o r y e f f e c t s of antiserotonergic treatment may be mediated by the release of adrenal steroids, i t is unlikely that the inhibitory e f f e c t s of some 5-HT, agonists could be due to decreases in adrenal a c t i v i t y . Indeed, i t has been demonstrated that some 5-HT agonists , including the r e l a t i v e l y selective 5-HT, agonists 5MeODMT and trifluoromethylphenylpiperazine , stimulate the release of adrenal steroids (Fuller & Snoddy, 1979). Although quipazine attenuated the inhib i t o r y effect of pirenperone on lordosis, i t did not effect lordosis when administered alone, thus suggesting that quipazine does not simply f a c i l i t a t e lordosis behaviour. Receptor binding studies have in fact indicated that quipazine is primarily a 5-HT2 agonist, however i t does have a f f i n i t y for the 5-HT, receptor (Leysen & Tollenaere, 1982). The 5-HT, a c t i v i t y of quipazine might therefore l i m i t the f a c i l i t a t o r y effects of the drug. Such an explanation would be consistent with the dramatic 81 f a c i l i t a t i o n of lordosis behaviour observed following the coadministration of quipazine and methysergide. Thus, methysergide may have blocked the inhibitory 5-HT, component of quipazine, while only weakly antagonizing quipazine a c t i v i t y at f a c i l i t a t o r y 5-HT2 receptor s i t e s . Methysergide has in fact been reported to be potent in preventing the serotonin syndrome, a const e l l a t i o n of behavioural effects believed to be due to 5-HT, receptor stimulation; however, in comparison with ketanserin, i t is r e l a t i v e l y weak in preventing head twitch, a behavioural effect believed to be due to 5-HT2 receptor stimulation (Lucki, Nobler, & Frazer, 1984). As i s the case with other 5-HT agonists, quipazine also stimulates the release of adrenal steroids (Fuller & Snoddy, 1979), however , i t i s unlikely that the release of adrenal steroids could be e n t i r e l y responsible for the ef f e c t s of the drug. In the present series of experiments, quipazine was ef f e c t i v e in females administered both estrogen and progesterone, whereas any effect of quipazine due to the release of adrenal progesterone would almost ce r t a i n l y have been masked by the quantity of exogenous st e r o i d . In what areas of the brain are the serotonergic e f f e c t s upon  lordosis manifested? In the present series of experiments, pirenperone was found to be e f f e c t i v e following intraventricular administration at doses that were i n e f f e c t i v e when administered peripherally. Moreover, a variety of reports have demonstrated that the central administration of serotonergic agents with high 5-HT, 82 a c t i v i t y i s e f f e c t i v e in a l t e r i n g sexual behaviour. Thus, these data indicate that serotonergic drugs a l t e r sexual behaviour by acting d i r e c t l y on the brain. Although data suggest that the effects of 5-HT upon sexual behaviour are c e n t r a l l y mediated, questions remain as to exactly which areas of the brain are involved. However, much about the s p e c i f i c s i t e s of serotonergic a c t i v i t y can be deduced from exis t i n g data. For example, whereas the present study suggests a f a c i l i t a t o r y role for 5-HT in female sexual behaviour, such a conclusion appears to be incompatible with reports of sexual f a c i l i t a t i o n following substantial reductions in whole brain 5-HT. If serotonergic a c t i v i t y were indeed required for the lordosis behaviour, then drugs such as 5,7-DHT or PCPA that produce profound reductions in central 5-HT levels should eliminate, rather than f a c i l i t a t e lordosis behaviour, as has often been reported. However, though these data appear paradoxical, they may simply r e f l e c t regional brain differences in the extent of 5-HT depletion following treatment with 5,7-DHT or PCPA. If such were the case, then one could simply assume that the f a c i l i t a t o r y e f f e c t s of serotonin are manifest in those areas of the brain least affected by antiserotonergic treatments. Indeed, even large intraventricular doses of 5,7-DHT may have milder e f f e c t s in the mesencephalon than in the pe r i v e n t r i c u l a r areas such as the hypothalamus and septum (Baumgarten et a l . , 1973). S i m i l a r l y , although whole brain 5-HT levels may be depleted by more than 80% following PCPA treatment (Koe & Weissman, 1966), there i s evidence that t h i s depletion takes place primarily in forebrain structures. Mesencephalic 83 structures are less disturbed by PCPA, and at least one area, the nucleus l i n e a r i s , retains nearly normal levels of 5-HT in perikarya and synaptic terminals following a regimen of PCPA administration (Aghajanian , Kuhar, & Roth, 1973). Work in progress in our laboratory does in fact suggest that discreet lesions of this area i n h i b i t lordosis behaviour, a finding consistent with a mesencephalic s i t e of serotonergic f a c i l i t a t i o n of lordosis behaviour. Moreover, i t must be noted that while the cortex and caudate are the areas of the brain most densely populated by 5-HT2 receptors ,these receptors can also be found throughout the mesencephalon (Peroutka & Snyder, 1981). Thus a mesencephalic s i t e of f a c i l i t a t o r y serotonergic a c t i v i t y remains e n t i r e l y consistent with the present hypothesis. F i n a l l y , the p o s s i b i l i t y of a spinal s i t e of sexually f a c i l i t a t o r y serotonergic e f f e c t s must be considered. A spinal s i t e of action would be consistent with a report that quipazine produces a weak, lordosis-1ike effect in spinal females (Row, Zemlan, & Pfaff, 1979), that i s , in females that have had the neural connections between the brain and spinal cord severed. However, though such evidence suggests a weak f a c i l i t a t o r y effect of serotonin at the l e v e l of the spinal cord, i t i s unlikely that i t could be mediated by 5-HT2 receptors. At least two reports have indicated a lack of 5~HT2 receptors in the spinal cord (Leysen, Niemegeers, Van Nueten, & Laduron, 1982; Monroe & Smith, 1983). Whereas the conclusion can be made that the f a c i l i t a t o r y e f f e c t s of 5-HT are mediated by mesencephalic structures, the inh i b i t o r y effects of 5-HT appear to be mediated by forebrain 84 structures. Consistent with this conclusion are the f a c i l i t a t i o n s of lordosis that have been observed following the administration of methysergide or cinanserin d i r e c t l y into various hypothalamic nuclei . Moreover, the use of 5,7-DHT to produce lesions of serotonergic pathways has f a c i l i t a t e d lordosis behaviour when the effects of the neurotoxin have been limited primarily to forebrain areas. Indeed, the one author that reported 5,7-DHT to be i n e f f e c t i v e in female sexual behaviour had administered the drug into a midbrain s i t e . F i n a l l y , areas of the forebrain such as the hypothalamus, and esp e c i a l l y the hippocampus, are r i c h l y populated with 5-HT, receptors (Peroutka & Snyder, 1 9 8 1 ) , thus the suggestion that the inhibitory e f f e c t s of serotonin are manifest in the forebrain also remains e n t i r e l y consistent with the present hypothesis. Quest ions and caut ions In the present hypothesis the c l a s s i c a l inhibitory- e f f e c t s of serotonin are recognized, and i t i s proposed that these ef f e c t s are mediated by 5-HT, receptor a c t i v i t y . However,it must be noted that serious questions remain as to whether the inhib i t o r y e f fects of 5-HT are s p e c i f i c to sexual behaviour. Indeed, the evidence that the combined treatment of estrogen and progesterone does not reduce central serotonergic argues strongly against any important tonic sexually in h i b i t o r y e f f e c t s of serotonin. Furthermore, although 5-HT, antagonists may f a c i l i t a t e , and 5-HT, agonists i n h i b i t lordosis behaviour, there are reasons to question the assumption that such results r e f l e c t 85 a continuum of effects upon one or more sexually inhibitory serotonergic pathways. For instance, i f f a c i l i t a t i o n and i n h i b i t i o n did indeed represent a continuum of effects of 5-HT upon a system of inh i b i t o r y pathways, then one might expect gradual changes in the l e v e l of lordosis behaviour to follow gradual changes in the level of 5-HT a c t i v i t y . However, di s c o n t i n u i t i e s are apparent when lordosis behaviour i s viewed as a function of serotonergic a c t i v i t y . It appears that rather extreme increases or decreases in serotonergic a c t i v i t y are required to a l t e r lordosis behaviour. In the present hypothesis, d i f f e r e n t i a l roles of 5-HT2 and 5-HT, receptors have been proposed to explain a variety of inconsistencies in the l i t e r a t u r e . However, i t appears that the simple categorization of serotonin receptors into 5-HT, and 5-HT2 subtypes may i t s e l f be inadequate. For example, there i s evidence the existence of at least two subtypes of the' 5-HT, receptor, that have been referred to as 5-HT, A and 5-HT, B (Pedigo, Yamamura, & Nelson, 1981). Moreover, although i t has been suggested that the receptor that mediates presynaptic i n h i b i t i o n of serotonergic neurons may be related to the 5-HT, B receptor (Middlemiss, 1984), the exact nature of the receptor remains to be determined. It is possible that the receptors mediating the _ presynaptic i n h i b i t i o n of serotonergic neurons represent a unique subtype of serotonin receptor. Recently, i t has been suggested that at least some types of 5-HT receptors are complex proteins containing binding s i t e s for one or more neuromodulators besides 5-HT (Gandolfi, Barbaccia, & Costa, 1985). Ostensibly, these neuromodulators could interact with 86 serotonin receptors to a l t e r the binding c h a r a c t e r i s t i c s of 5-HT upon target c e l l s . This type of complex, interactive binding at Serotonin receptors would be an example of a common mechanism in molecular biology known as allosterism. The authors that have proposed an a l l o s t e r i c serotonin receptor have gone even further in suggesting that the 5-HT2 receptor is merely one binding site on the serotonin receptor complex, and that the endogenous substance that binds at the so-called 5-HT2 receptor s i t e may be a peptide (Roth, Chuang, & Costa, 1984). If this were indeed the case, then some endogenous peptide with binding c h a r a c t e r i s t i c s similar to those of agents with 5-HT2 a f f i n i t y may interact with a hypothetical serotonin receptor complex to f a c i l i t a t e , or possibly i n h i b i t , female sexual behaviour. F i n a l l y , i t must be noted that caution i s necessary in the interpretation of pharmacological experiments. Because even the most selective drug w i l l have a c t i v i t y at a variety of receptors, a large number of drugs with d i f f e r i n g pharmacological p r o f i l e s must be evaluated before mechanisms of action can be deduced. Moreover, every drug w i l l produce unwanted and, unfortunately, unknown side-effects. Thus the p o s s i b i l i t y always remains that some nonspecific mechanism, such as sickness, sedation, motor impairment, or even general arousal may be responsible for the observed e f f e c t . However, perhaps the most serious problem that arises in using pharmacological methods to elucidate b i o l o g i c a l processes is the unavoidable fact that pharmacological manipulation can never duplicate physiological processes. Even the most precise delivery of a highly s p e c i f i c drug can imbalance and interfere with the 87 exquisitely complex web of natural processes. Thus whenever possible, pharmacological data must be corroborated with data derived from behavioural, anatomical, physiological, and biochemical studies. TABLE | TREATMENTS THAT DECREASE SEROTONERGIC ACTIVITY MONOAMINE STORAGE DEPLETORS S t e r o i d s C o n d i t i o n E f f e c t Reference R e s e r p i n e E E E E . P E E ovx ovx OV X ovx ovx-dexa ovx-adrx e e l 1ing ef f e c t s ? P a r i s , Resko, & Goy. 1971 Meyerson, 1964c Meyerson, 1964a Meyerson, 1964 P a r i s . Resko, & Goy 197 1 Meyerson, 1964c Tetrabenaz1ne ovx ovx ovx ovx ovx-adrx ce i I i ng ef f e c t s ? L a r sson. Feder, & Komisaruk, 1974 A h l e n i u s . Engel. E r i k s s o n . S So d e r s t e n . 1972 Meyerson, 1964b Meyerson. 1964c Larsson. Feder. & Komisaruk. 1974 SEROTONIN ANTAGONISTS S t e r o i d s C o n d i t i o n Reference Methyserg t de E ovx hypotha1 Ward. Crowley, Zemlan. fi Margules. 1975 E ovx + Henrik & G e r a l 1 . 1976 E ovx hypothal Foreman & Moss. 1978 E ovx R o d r i g u e z - S i e r r a & D a v i s . 1979 E ovx + h i pp.amygd Franck & Ward. 1981 E ovx 0 POA Clemens. 1978 E ovx 0 Mendel son 8 G o r z a l k a . p r e s e n t E chr ovx + Davis * Ko h l . 1978 E , P ovx - Meyerson.1978 E . , P ovx - POA Clemens. 1978 E , P ovx + 24 hr a f t e r P R o d r i g u e z - S i e r r a & D a v i s . 1979 E , P cone. ovx + 44 hr a f t e r E.P R o d r i g u e z - S i e r r a & D a v i s . 1979 E ovx-adrx Zemlan, Ward. Crowley, & Margules. 1973 E ovx-adrx hypothal Zemlan. Ward, Crowley, fi Margules. 1973 ) 1nanseri n E ovx + hypotha1 Ward. Crowley, Zemlan, S Margules, 1975 E chr ovx 0 E v e r i t t . Fuxe. H o k f e l t , S Jonsson. 1975 E ovx-adrx hypotha1 Zemaln. Ward. Crowley, fi Margules. 1973 Metergo11ne E E c h r E c h r ovx ovx ovx 50 „g/kg 500 „g-1 mg/kg Arendash & G o r s k i . 1983 Fuxe. E v e r i t t . A g n a t i , Fredholm, & Jonsson, 1976 Fuxe, E v e r i t t . A g n a t i . Fredholm, & Jonsson, 1975 A b b r e v i a t i o n s : E - e s t r o g e n , P = progesterone, ovx = o v a r i e c t o m i z e d . adrx - adrena1ectomized. dexa a dexamethasone. ch r - c h r o n i c , ac 1 acute. * * f a c i l i t a t i o n . - = i n h i b i t i o n , 0 * no e f f e c t 00 SEROTONIN ANTAGONISTS ( c o n t . ) S t e r o i d s C o n d i t i o n E f f e c t R eference P i renperone E ovx E.P ovx E , P ovx Ketanser i n E.P ovx Sp i perone E.P ovx C h l o r p r o m a z i n e E . P ovx SEROTONIN SYNTHESIS INHIBITORS Mendelson & G o r z a l k a . p r e s e n t Mendel son ft G o r z a l k a . p r e s e n t Mendelson & G o r z a l k a , p r e s e n t Mendelson S G o r z a l k a . p r e s e n t Mendelson & G o r z a l k a . p r e s e n t S t e r o i d s C o n d i t i o n a propyldopacetarnide E f f e c t Hours A f t e r Last I n j e c t i o n Meyerson, 1966 Reference E ovx 0 4-6 Meyerson ft Lewander, 1970 E chr ovx + 2-4 E v e r i t t . Fuxe. H o k f e l t , ft Jonsson, 1975 i - Ch1oropheny1 a 1 an ine E ovx + ac 2-4 E r i k s s o n ft S o d e r s t e n . 1973 E ovx + ac 4 Wilson,, Bonney, E v e r a r d . P a r r o t . & Wise. 1982 E ovx + ac 4(*5-HTP) Wilson, Bonney, E v e r a r d P a r r o t , ft Wise. 1982 E ovx ac 4-8 Meyerson ft Lewander, 1970 E ovx °) ac 28 Wi l s o n . Bonney. E v e r a r d . P a r r o t , ft Wise. 1982 E O V X chr 2-4 Hamburger-Bar. R i g t e r , & Dekker, 1978 E O V X + chr 24 Emery & L a r s s o n , 1979 E chr O V X + ac 2-8 A h l e n i u s . E n g e l . E r i k s s o n . Modigh, S Sodersten E chr ovx + ac 2-4 E v e r i t t , Fuxe. H o k f e l t , S Jonsson, 1975 E chr O V X + ac 2-4 E v e r i t t . Fuxe, H o k f e l t , & Jonsson, 1975 E chr O V X + ac 8-48 Davis & K o h l . 1978 E c h r ovx 0 ac 26-50 Ah I e n i u s . Enge1. E r i k s s o n , Mod i gh, S Sodersten E chr O V X + ac 26-52 E v e r i t t . Fuxe. H o k f e l t . ft Jonsson, 1975 E chr O V X 0 ac 48 Segal ft Whalen, 1970 E chr O V X + ac 48-50 E v e r i t t . Fuxe. H o k f e l t . ft Jonsson, 1975 E chr O V X 0 chr 24 Sodersten, L a r s s o n . A h l e n i us, ft Enge1. 1976 E chr ovx 0 chr 48 Segal ft Whalen. 1970 E . P ovx 0 chr 5 S i n g e r . 1972 E ,P ovx 4- 5 E l i a s s o n ft Meyerson, 1977 E . P ovx - 0 chr 28 Emery ft Larss o n , 1979 E ,P ovx 0 chr 24-72 E l i a s s o n ft Meyerson. 1977. E chr , P ovx - ac 48 Segal ft Whalen. 1970 E chr . P ovx 0 chr 48 Segal & Whalen, 1970 1972 1972 A b b r e v i a t i o n s : E = e s t r o g e n . P = progesterone, ovx = ovar1ectomized. adrx • adrena1ectornized. dexa = dexamethasone. chr « c h r o n i c , ac • acute. + » f a c i l i t a t i o n . - - i n h i b i t i o n . 0 - no e f f e c t SEROTONIN SYNTHESIS INHIBITORS (cont ) Hours Af ter S t e r o i ds Cond i t i on E f f e c t Last I n j e c t ion Reference E ovx-dexa 0 chr 24 Emery 8 Larsson , 1979 E ovx *adrx 0 ac 2-4 E r i k s s o n & Sodersten, 1973 E ovx-adrx + ac 66-74 Zemlan, Ward. Crowley, ft Margules. 1973 E ovx-adrx 0 ac 66-72 Gorzalka ft Whaler i. 1975 E ovx-adr x - chr 2-4 Hamburger-Bar. Ri g t e r . ft Dekker. 1978 E c hr ovx-adr x • ac 2-4 E v e r i t t , Fuxe. H o k f e l t . & Jonsson. 1975 E c h r ovx-adr x ac 2-4 E v e r i t t . Fuxe. H o k f e l t , ft Jonsson. 1975 E c hr ovx -adrx ac 26-28 E v e r i t t , Fuxe. H o k f e l t . Jonsson. 1975 E c h r ovx-adr x + ac 48-50 E v e r i t t , Fuxe. H o k f e l t . ft Jonsson. 1975 £ .P ovx-adrx - ac 74 Gor z a l k a ft Whalen i . 1975 none ovx 0 chr 5 Sing e r . 1972 none i n t a c t - ac 24 A 1 Sat 11 ft Aron. 198 1 none intact*5-HTP 0 ac 24 A 1 Sa11i ft Aron. 198 1 E i n t a c t 0 ac 24 A1 Sat 1i ft Aron. 198 1 SEROTONERGIC NEUROTOXINS Days A f t e r S t e r o i d s Condot ion E f f e c t L a s t I n j e c t ion Reference 5.7-dihydroxytryptamine E c hr OVX + 1-7 E v e r i t t . Fuxe, ft Jonsson. 1975 E c h r OVX 0 7- 13 E v e r i t t , Fuxe. 8 Jonsson. 1975 E chr OVX + 9- 14(hypoth1 Luine. F r a n k f u r t . Ra i nbow Biegon. ft Azn E c hr OVX 0 13- 16 Sodersten, Berge. & Hole. 1978 E c hr OVX * 14- 160 Ever i 11, Fuxe, ft Jonsson. 1975 E chr.P ovx 0 17 Sodersten. Berge, ft Hole 1978 P on! y ovx 0 10 Sodersten. Berge, ft Hole. 1978 none ovx 0 7-9 Sodersten, Berge, ft Hole. 1978 p-chloroamphetarn i ne E chr ovx 0 3 Zemlan. T r u l s o n . Howel1. ft Hoebel. 1977 E chr ovx 0 13- 16 Sodersten. Berge, . & Hole. 1978 E . P ovx - 60-150 (mini Michanek ft Meyerson. 1977. E chr . P ovx - 15 Imin) Zemlan, Tru1 son, Howel1. ft Hoebel. 1977 E chr . P Ovx + 3-5 Zemlan, T r u l s o n , Howe 11, & Hoebel. 1977 E chr , P OVX 0 17 Sodersterv. Berge, , ft Hole 1978 E chr . P ovx-dexa 0 3 Zemlan, T r u l s o n , HowelI. 8 Hoebel. 1977 E chr , P ovx-dexa + 5-7(low pCA) Zemlan, T r u l s o n , Howel1. ft Hoebel. 1977 E chr . P ovx-dexa •4- 3 ( h i g h pCAI Zemlan, T r u l s o n , Howel1, S Hoebe1. 1977 E chr , P ovx-dexa 0 5-7(high pCAI Zemlan, T r u l s o n , Howe 11. 8 Hoebe1. 1977 P on 1 y ovx 0 10 Sodersten. Berge, , ft Hole. 1978 none ovx 0 7-9 Sodersten. Berg. & Hole. 1978 A b b r e v i a t i o n s : E a e s t r o g e n , P = p r o g e s t e r o n e , ovx * ov a r i e c t o r n i z e d , adrx » adrena1ectornized. dexa = dexamethasone. chr = chron i c, ac * acu te. + = f a c i l i t a t i o n , - = i n h i b i t i o n . 0 • no e f fec t TREATMENTS THAT INCREASE SEROTONERGIC ACTIVITY SEROTONIN AGONISTS S t e r o i d s C o n d i t i o n S e r o t o n i n E f f ec t Dose Reference E 1 ow ovx 0 hypoth Foreman 8 Moss. 1978 E h i g h ovx - hypoth Foreman 8 Moss. 1977 E . P OVX - hypoth Clemens. 1978 y s e r g i c a c i d d i e t h y l a m i d e E chr OVX 0 1 „g/kg S e i t n i e k s & Meyerson 1983a E c h r OVX + 10 „g/kg S e i t n i e k s 8 Meyerson 1983a E chr ovx + 5-20 i,g/kg E v e r i t t . Fuxe. H o k f e l t . & Jonsson. 1975 E c h r ovx - 40 „g/kg E v e r i t t . Fuxe, H o k f e l t , 8 Jonsson 1975 E chr OVX 0 100 j,g/kg S e i t n i e k s 8 Meyerson. 1980 E . P OVX + 1 „g/kg S e i t n i e k s & Meyerson 1983a E , P OVX - 50-250 „g/kg Meyerson, 1974 E . P OVX - 100-500 „g/kg E l i a s s o n 8 Meyerson 1977 E , P OVX - 100 „g/kg S e i t n i e k s 8 Meyerson. 1980 E .P OVX 0 chr o n i c Meyerson et a l . 1974 i i - h y d roxytryptophan E c h r OVX 0 .10 mg/kg S e i t n i e k s 8 Meyerson 1983 E c h r OVX + .25 mg/kg S e i t n i e k s 8 Meyerson 1983 E chr OVX 0 .50 mg/kg. S e i t n i e k s 8 Meyerson 1983 E . P OVX + .05 mg/kg S e i t n i e k s & Meyerson 1983 E .P ovx 0 .10-.25 mg/kg S e i t n i e k s 8 Meyerson 1983 E.P(low) OVX 0 2.5 mg/kg S e i t n i e k s 8 Meyerson 1982 E . P ( h i g h ) OVX - 2.5 mg/kg S e i t n i e k s 8 Meyerson 1982 's i 1 ocyb i ne E chr ovx .05 -1.0 mg/kg Fuxe. E v e r i t t . Agnati . Fredholm. 8 Jonsson. E chr OVX - >1.0 mg/kg Fuxe, E v e r i t t , Agnati . Fredholm. 6 Jonsson. 1,N-d i methy1t ryptam i ne E chr ovx + .10 mg/kg Fuxe. E v e r i t t . Agnati . Fredholm. 8 Jonsson. E chr ovx - 1.0 mg/kg Fuxe, E v e r i t t . Agnati , Fredholm. 8 Jonsson, i-methoxy-N, , N-d imethyltryptam i ne E chr ovx + .10 mg/kg Fuxe, E v e r i t t , Agnati , Fredholm. 8 Jonsson, E chr ovx - 1.0 mg/kg Fuxe, E v e r i t t , Agnati . Fredholm. 8 Jonsson. E , P Ovx - .30 mg/kg R o d r i g u e z - S i e r r a & Da v i s . 1979 E . P ovx 0 .20 mg/kg Mendelson 8 G o r z a l k a . present 1975 1975" A b b r e v i a t i o n s : E = e s t r o g e n , P = progesterone, ovx = o v a r i e c t o r n i z e d . adrx « adrena1ectornized. dexa = dexamethasone. chr = c h r o n i c , ac = ac u t e . + * f a c i l i t a t i o n . - = i n h i b i t i o n , 0 = no e f f e c t SEROTONIN AGONISTS ( c o n t . ) S t e r o i d s C o n d i t i o n Mesca1i ne E f f e c t E c h r E chr ovx ovx .50-5 mg/kg 25 mg/kg Reference Fuxe. E v e r i t t . A g n a t i . Fredholm. 8 Jonsson. Fuxe. E v e r i t t . A g n a t i , Fredholm. 8 Jonsson. 1975 1975 2 . 4 . 5-tr1methoxy-amphetamine E chr ovx * .50-5 mg/kg Fuxe, E v e r i t t . A g n a t i . Fredholm. 8 Jonsson. 1975 2,5-methoxy-4-methy1-amphetamine (DOM) E c hr ovx • .10-50 mg/kg Fuxe. E v e r i t t . A g n a t i , Fredholm. & Jonsson. 1975 2.5-methoxy-4-methyl-phenylethylam1ne E chr ovx • .10-50 mg/kg Fuxe, E v e r i t t , A g n a t i , .Fredholm. 8 Jonsson, 1975 Ou i paz1ne E ovx 0 Mendelson 8 G o r z a l k a . p r e s e n t E ovx + +methysergide Mendelson 8 G o r z a l k a . p r e s e n t E.P ovx - R o d r i g u e z - S i e r r a 8 D a v i s , 1979 E.P ovx 0 Arendash 8 G o r s k i , 1983 E.P ovx 0 Mendelson 8 G o r z a l k a , p r e s e n t Fenf1uramIne E .P E.P ovx ovx E v e r i t t . Fuxe, H o k f e l t . 8 Jonsson, Mlchanek 8 Meyerson, 1977. 1975 a -methyltryptamine E c hr E . P ovx ovx Espino.,Sano. 8 Wade. 1975 Esplno. Sano. 8 Wade. 1975 A b b r e v i a t i o n s : E - e s t r o g e n . P = p r o g e s t e r o n e , ovx = o v a r i e c t o r n i z e d . adrx * adrena1ectomized. dexa » dexamethasone, chr = c h r o n i c , ac = acute. * = f a c i l i t a t i o n , - = i n h i b i t i o n , 0 » no e f f e c t VO MAO INHIBITORS S t e r o i d s C o n d i t i o n E f f e c t Reference N i a t am i de E . P E . P dB 5 16 E.P E.P Pargy1 i ne E.P E . P E.P E.P ovx ovx ovx ovx ovx ovx ovx ovx var1ed 0 +5-HTP +5-HTP .PCPA hypothaa Meyerson. 1964a Meyerson, 1964a Meyerson, 1964a Meyerson, 1964a Meyerson. 1964a Meyerson, 1964a Meyerson 8 Lewander, 1970 Luine 8 F i s c h e t t e , 1982 REUPTAKE BLOCKERS S t e r o i d s C ondotion Im ipram ine E.P ovx E f f e c t Remarks Reference Meyerson. 1966 Clomipramine E . P E v e r i t t . 1977 H102/09 E . P E v e r i t t . 1977 GEA654 E.P 0rg6582 E.P E.P E E ovx ovx ovx ovx-adrx E v e r i t t . 1977 E v e r i t t , 1977 Hamburger-Bar. R i g t e r . S Dekker, Hamburger-Bar. R i g t e r , 8 Dekker, 1978 1978 Hamburger-Bar. R i g t e r , & Dekker. 1978 Femox1t1ne E.P ovx E . P ovx E.P ovx-adrx Ch1 o r i m i p r a m i n e E.P ovx 10 mg/kg 22 mg/kg Hamburger-Bar. R i g t e r . 8 Dekker. 1978 Hamburger-Bar, R i g t e r . S Dekker. 1978 Hamburger-Bar. R i g t e r . 8 Dekker. 1978 Hamburger-Bar. R i g t e r , 8 Dekker. 1978 A b b r e v i a t i o n s : E = e s t r o g e n , P = progesterone, ovx = o v a r i e c t o r n i z e d . adrx = adrena1ectornized, dexa = dexamethasone. chr = c h r o n i c , ac = a c u t e . + = f a c i l i t a t i o n , - * i n h i b i t i o n , 0 * no e f f e c t I I VO 94 REFERENCES Aghajanian, G.K., M.J. Kuhar, & R.H. Roth.(1973). Serotonin-containing neuronal perikarya and terminals, D i f f e r e n t i a l effects of p-CPA. Brain Res. , 54,85-101. Aghajanian, G.K., W.E. Foote,, & M.H. Sheard. (1968). Lysergic acid diethylamide: Sensitive neuronal units in the midbrain raphe. Science ,161,706-708. Aghajanian, G.K. & H.J. Haigler. (1975). 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