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

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DIFFERENTIAL ROLES OF SEROTONIN RECEPTOR SUBTYPES IN THE MODULATION OF LORDOSIS BEHAVIOUR IN THE FEMALE RAT.  By  SCOTT DOUGLAS MENDELSON M.A. The U n i v e r s i t y of B r i t i s h Columbia, 1985 B.A. Sonoma S t a t e U n i v e r s i t y , 1981  A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY in THE FACULTY OF GRADUATE STUDIES Department of Psychology  We accept t h i s t h e s i s as conforming t o the required  standard  THE UNIVERSITY OF BRITISH COLUMBIA April  1988  © Scott Douglas Mendelson, 1988  In  presenting  degree freely  at  this  the  available  copying  of  department publication  of  in  partial  fulfilment  University  of  British  Columbia,  for  this or  thesis  reference and  thesis by  this  for  his thesis  scholarly  or  her  for  of  Psychology  The University of British 1956 Main Mall Vancouver, Canada V6T 1Y3 D  a  t  e  DF-fifVfm  April  25,  Columbia  1988  I  I  purposes  gain  the  requirements  agree  that  further agree may  representatives.  financial  permission.  Department  study.  of  shall  be  It not  is  that  the  Library  permission  granted  by  understood be  for  allowed  an  advanced  shall for  the that  without  make  it  extensive  head  of  my  copying  or  my  written  i i  ABSTRACT In 1985, Mendelson and hypothesis  was  proposed  i t was proposed that s e r o t o n e r g i c  i n h i b i t or f a c i l i t a t e  suggested  l o r d o s i s behaviour.  facilitating 2  was  role  The  intraperitoneal  administration  mg/kg),  and k e t a n s e r i n  behavior  i n ovariectomized benzoate  ineffective  Specifically i t  whereas  lordosis-  the dual r o l e h y p o t h e s i s . of  (1 mg/kg), cyproheptadine  ineffective.  can  purpose of the f o l l o w i n g s e r i e s of s t u d i e s  both to confirm and t o extend  estradiol  activity  e f f e c t s of s e r o t o n i n are mediated by a c t i v i t y at 5-  receptors.  pizotefin  dual  that the l o r d o s i s - i n h i b i t i n g e f f e c t s of s e r o t o n i n  are mediated by a c t i v i t y at 5-HT, r e c e p t o r s ,  HT  the  of s e r o t o n e r g i c modulation of l o r d o s i s behaviour. In  t h i s hypothesis either  Gorzalka  The  the (1  (1 mg/kg) were found rats  that  5-HT  2  but  p i z o t e f i n , cyproheptadine,  agonist  antagonists  2  mg/kg),  metitepine  to i n h i b i t  had  (EB) and progesterone  alone,  5-HT  been  The  (1  lordosis  primed  with  ( P ) . Pipamperone was  guipazine  (3  mg/kg)  was  i t reversed the i n h i b i t o r y e f f e c t s of and k e t a n s e r i n . I t  d i d not  the e f f e c t s of m e t i t e p i n e . The h i g h l y s e l e c t i v e 5-HT  2  LY53857 (0.3 mg/kg) was a l s o found  to i n h i b i t  reverse  antagonist  lordosis  behaviour  in female r a t s that had been primed with EB and P. The l o r d o s i s i n h i b i t i n g e f f e c t of LY53857 (1 mg/kg) i n females primed with EB and P was reversed by q u i p a z i n e antagonist  (3 mg/kg). The n o n s e l e c t i v e 5-HT  methysergide (7 mg/kg) was found  to i n h i b i t  behavior  30 min a f t e r  i n t r a p e r i t o n e a l a d m i n i s t r a t i o n to  treated  chronically  with  methysergide was found  EB,  or  to f a c i l i t a t e  with  EB  and  P.  l o r d o s i s behavior  lordosis females However, 200 and  300 min a f t e r a d m i n i s t r a t i o n to female r a t s t r e a t e d a c u t e l y with  EB.  In  an  analysis  of  methysergide  (0.02 - 7  behavioural  testing  dose  mg/kg)  response  i t was  administered  produced  no  30  found  min  facilitation  that  prior  to  of l o r d o s i s i n  females primed with E B . However, when a d m i n i s t e r e d 200 min p r i o r to  testing,  methysergide  (1  mg/kg)  produced  a  significant  f a c i l i t a t i o n of l o r d o s i s . The a d m i n i s t r a t i o n of the 5 - H T , A a g o n i s t 8-hydroxy-2-(di-npropylamino)tetralin  (8-OH DPAT) i n h i b i t e d l o r d o s i s behavior i n  o v a r i e c t o m i z e d r a t s primed with E B . 8-OH DPAT was i n e f f e c t i v e at 0.01 mg/kg, whereas i n h i b i t i o n o c c u r r e d at the 0.03, 1.0,  0.1, 0.3,  and 3.0 mg/kg doses. In an e v a l u a t i o n of the e f f e c t s of 8-  OH DPAT on the e x p r e s s i o n of male sexual treated  chronically  i n c r e a s e d the increased  number  mount  with of  behaviour  testosterone, females  8-OH  mounting  with  females  DPAT ( 1 mg/kg)  and  significantly  frequency. The 5 - H T , A a g o n i s t s i p s a p i r o n e (0.1  mg/kg) and gepirone (0.3 mg/kg) f a c i l i t a t e d treated  by  lordosis in  E B . When a d m i n i s t e r e d at higher doses,  females  ipsapirone  (3.0 mg/kg) and buspirone (3.0 mg/kg) i n h i b i t e d l o r d o s i s i n r a t s t r e a t e d with E B . In females t r e a t e d with E B and P, i p s a p i r o n e (> 1.0 mg/kg), gepirone (> 0.3), and buspirone lordosis  behaviour.  7378 (0.2 mg/kg) treated  with  The  facilitated  E B . However,  lordosis this  to  i n females primed with  facilitate  females primed with  lordosis E B and  P,  behaviour  facilitation  EB  1 -(3-trifluoromethylphenyl)piperazine found  0.3)  inhibited  newly developed 5 - H T , A a n t a g o n i s t B M Y  apparent at the 5 mg/kg dose. B M Y 7378 ineffective  (>  in  in  was  (0.04 -  5  females  no longer mg/kg)  was  and P. The 5 - H T T B a g o n i s t (TFMPP, 0.2 -5 mg/kg)  was  females t r e a t e d with E B . In  TFMPP  (5  mg/kg)  produced  a  iv  significant  inhibition  of  chlorophenylpiperazine  lordosis.  The  5-HT,B  agonist  m-  (MCPP, 0.04 - 5 mg/kg) was i n e f f e c t i v e i n  f e m a l e s p r i m e d e i t h e r w i t h EB o r w i t h EB a n d P. The  Antagonist  5-HT3  facilitate  ICS 205-930 (5  l o r d o s i s behaviour,  mg/kg)  w h e r e a s t h e 5-HT  was  found  Antagonist  3  72222 ( 0 . 0 5 - 5 mg/kg ) was f o u n d t o be i n e f f e c t i v e  in  to MDL  females  p r i m e d w i t h EB. The  results  of  serotonergic a c t i v i t y behaviour. of  these  studies  can e i t h e r i n h i b i t  are  presynaptic  might  confirm  or f a c i l i t a t e  at  there  hold  mediated  by  activity  at  Finally,  that  lordosis  5-HT  2  i t is  and  effects  doses  low  of  5-HT,A  of  that  may m e d i a t e  agonists.  i s a d i s c u s s i o n of the i m p l i c a t i o n s these  behaviour.  and  possibly  suggested  5-HT,A autoreceptors  of  5-HTTA  effects  somato-dendritic  f o r the understanding  d r u g s on human  at postsynaptic  The l o r d o s i s - f a c i l i t a t i n g  5-HT,B receptors.  facilitatory closing,  Receptors.  5-HT3  serotonin  activity  to  I t i s suggested that the l o r d o s i s - i n h i b i t i n g e f f e c t s  s e r o t o n i n a r e m e d i a t e d by a c t i v i t y  possibly  tend  In  results  of the e f f e c t s of s e r o t o n e r g i c  TABLE OF CONTENTS ABSTRACT  i i  LIST OF TABLES  vi  LIST OF FIGURES  vii  ACKNOWLEDGMENTS  ix  INTRODUCTION  1  GENERAL METHODS  12  EXPERIMENTS Experiment  1  16  Experiment 2  28  Experiment 3  38  Experiment 4  62  Experiment 5  70  Experiment 6  83  Experiment 7  90  Experiment 8  96  Experiment 9  105  GENERAL DISCUSSION  112  E f f e c t s of 5-HT a n t a g o n i s t s on l o r d o s i s  115  E f f e c t s of 5-HT a g o n i s t s on l o r d o s i s  121  Conclusions  130  IMPLICATIONS FOR UNDERSTANDING  EFFECTS OF  SEROTONERGIC DRUGS ON HUMAN BEHAVIOUR  133  SUMMARY  141  REFERENCES  141  vi  LIST OF TABLES 1. The e f f e c t of 8 - h y d r o x y - 2 - ( d i - n - p r o p y l a m i n o ) t e t r a l i n expression male sexual behaviour in the female r a t  on  the 79  vii  LIST OF FIGURES 1. E f f e c t s of 5-HT a n t a g o n i s t s on l o r d o s i s behaviour that was induced by the a d m i n i s t r a t i o n of e s t r a d i o l benzoate and progesterone 20 2  2. E f f e c t s of 5-HT a n t a g o n i s t s and q u i p a z i n e on on l o r d o s i s behaviour that was induced by the a d m i n i s t r a t i o n of e s t r a d i o l benzoate and progesterone 23 2  3. E f f e c t s of LY 53857 on l o r d o s i s behaviour that was induced by the a d m i n i s t r a t i o n of e s t r a d i o l benzoate 32 4. E f f e c t s of LY 53857 on l o r d o s i s behaviour that was induced by the a d m i n i s t r a t i o n of e s t r a d i o l benzoate and progesterone 34 5. E f f e c t of LY 53857 and q u i p a z i n e on l o r d o s i s behaviour was induced by the a d m i n i s t r a t i o n - of e s t r a d i o l benzoate progesterone 6. Time-dependent e f f e c t s of methysergide that was induced by the a d m i n i s t r a t i o n benzoate and 150 jug progesterone  that and 36  on l o r d o s i s of 10 Mg  behaviour estradiol 45  7. Time-dependent e f f e c t s of methysergide on l o r d o s i s that was induced by c h r o n i c a d m i n i s t r a t i o n of 10 Mg benzoate  behaviour estradiol 48  8. Time dependent e f f e c t s of methysergide on l o r d o s i s that was induced by the a d m i n i s t r a t i o n of 5 Mg benzoate and 150 Mg progesterone  behaviour estradiol 51  9. Time-dependent e f f e c t s of methysergide on l o r d o s i s behaviour induced by c h r o n i c a d m i n i s t r a t i o n of 5 Mg e s t r a d i o l benzoate..54 10. Time-dependent e f f e c t s of methysergide on l o r d o s i s behaviour induced by the a d m i n i s t r a t i o n of 2 Mg e s t r a d i o l benzoate 57 11. Dose-dependent e f f e c t s of methysergide 30 min p r i o r t o testing on l o r d o s i s behaviour induced by the a d m i n i s t r a t i o n of e s t r a d i o l benzoate 66 12. Dose-dependent e f f e c t s of methysergide 200 min p r i o r to testing on l o r d o s i s behaviour induced by the a d m i n i s t r a t i o n of e s t r a d i o l benzoate ..68 13. Effects of lordosis behaviour benzoate  8 - h y d r o x y - 2 - ( d i - n - p r o p y l a m i n o ) t e t r a l i n on induced by the a d m i n i s t r a t i o n of e s t r a d i o l 75  14. E f f e c t s of buspirone, i p s a p i r o n e and gepirone on l o r d o s i s behaviour induced by the a d m i n i s t r a t i o n of e s t r a d i o l benzoate or e s t r a d i o l benzoate and progesterone 87  viii 15. E f f e c t s of BMY 7378 on l o r d o s i s behaviour induced by the a d m i n i s t r a t i o n of e s t r a d i o l benzoate or e s t r a d i o l benzoate and progesterone  94  16. E f f e c t s of 1 - ( 3 - t r i f l u o r o m e t h y l p h e n y l ) p i p e r a z i n e on l o r d o s i s behaviour induced by the a d m i n i s t r a t i o n of e s t r a d i o l benzoate or e s t r a d i o l benzoate and progesterone 100 17. E f f e c t s of m - c h l o r o p h e n l y p i p e r a z i n e on l o r d o s i s behaviour induced by the a d m i n i s t r a t i o n of e s t r a d i o l benzoate or e s t r a d i o l benzoate and progesterone 102 18. E f f e c t s of ICS 205-930 on l o r d o s i s behaviour a d m i n i s t r a t i o n of e s t r a d i o l benzoate 19. Effects of MDL 72222 on l o r d o s i s behaviour a d m i n i s t r a t i o n of e s t r a d i o l benzoate  induced by  the 108  induced by the 110  1  INTRODUCTION  Recent serotonin  evidence plays  indicates  a role  that  the  neurotransmitter  i n the modulation of a v a r i e t y of human  and animal behaviours. Among the behaviours that are thought be  at  least  partially  to  under s e r o t o n e r g i c c o n t r o l are f e e d i n g ,  s l e e p i n g , a g g r e s s i o n , a n x i e t y , depression and sexual behaviour. The  ways  behaviours  in  are  which  certain  serotonergically  expressed may d i f f e r c o n s i d e r a b l y i n humans and  animals. Nonetheless,  i t must be emphasized  molecule  identical  itself  is  in  by s e r o t o n e r g i c drugs a r e  quite  Indeed,  similar. animal  behaviour.  in  models  These  of  models  that  the s e r o t o n i n  humans and animals, and the  e f f e c t s produced  develop  modulated  often  found  to  some cases i t has been p o s s i b l e to serotonergic  control  of  human  have proved q u i t e u s e f u l i n s c r e e n i n g  substances f o r p s y c h o t h e r a p e u t i c v a l u e . In view of the f a c t very l i t t l e  i s known about  The  role  played  Meyerson i n the e a r l y study  sexual  prove to be extremely v a l u a b l e .  sexual behaviour of  the  that  the neuropharmacology of human sexual  behaviour, an animal model of s e r o t o n e r g i c modulation of behaviour might  be  of  by  the  serotonin female  in  r a t was  the modulation of the first  evaluated  by  1960's. As has f r e q u e n t l y been the case i n  female  sexual  behaviour,  Meyerson  primarily  i n v e s t i g a t e d the e f f e c t of s e r o t o n e r g i c drugs on the e x p r e s s i o n of  lordosis.  lifting rat  Lordosis  i s the downward f l e x i o n of the back and  of the rump and t a i l  that may be d i s p l a y e d by  i n response t o the mounting and p e l v i c  The d i s p l a y of l o r d o s i s behaviour  a  female  t h r u s t i n g of a male.  i s generally  regarded  as  an  2  indicator  of  sexual r e c e p t i v i t y  of a female r a t t o produce the estrogen  do  administration behaviour  not of  i s not  ovariectomized  l o r d o s i s behaviour Meyerson was  monoamine  oxidase and  the  inactive  estrogen  However,  chronic  restores  lordosis  the a d m i n i s t r a t i o n of  w i l l markedly  activity by  f o r m s . The  t h a t the  following  The  of  MAO  inhibition  rats. lordosis  administration  of  i n female r a t s primed  with  enzymes i n t h e b r a i n s e r v e  serotonin  altering  in  facilitate  i n c i d e n c e of  the  inhibitors  progesterone.  estrogen  to r e s t o r e the l o r d o s i s r e f l e x  observed  (MAO)  ability entirely  of  in estrogen-treated ovariectomized  decreased  neurotransmitters  of  such treatment  (1964a)  behaviour  is  females deprived  r a t s . Although  sufficient  females,  response  lordosis.  doses  in ovariectomized  progesterone  limit  display  low  f e m a l e r a t . The  lordosis  dependent. O v a r i e c t o m i z e d  replacement  estrogen  i n the  and  other  t h e i r molecular of t h e s e MAO  to  monoamine  structures into  enzymes  results  in  i n c r e a s e s i n t h e l e v e l s of a c t i v e n e u r o t r a n s m i t t e r s a v a i l a b l e i n the  brain.  the  metabolic  enhanced  Meyerson a l s o observed  the  precursor  to  t h a t t h e c o a d m i n i s t r a t i o n of  serotonin,  lordosis-inhibiting  5-hydroxytryptophan,  effects  of  MAO  inhibitors,  whereas the c o a d m i n i s t r a t i o n of the p r e c u r s o r s of t h e transmitters this  regard.  that  the  that  reduce  dopamine  and  In a f o l l o w i n g experiment,  administration levels  of  serotonin  in  in estrogen-primed  females.  effects  were l e s s e f f e c t i v e  Meyerson  o f r e s e r p i n e and  neurotransmitters  facilitatory  noradrenaline  and  were a t t e n u a t e d  it by  (1964b)  in  found  t e t r a b e n a z i n e , drugs  the  the b r a i n , f a c i l i t a t e d Moreover,  monoamine  other  monoamine  lordosis  appeared  behaviour  that  these  restoring serotonergic  3  activity  by  treatment with  Meyerson  to  propose  lordosis  behaviour.  a  In the y e a r s t h a t  5 - h y d r o x y t r y p t o p h a n . These theory  of  of  the  part,  most  manipulations with  serotonergic  of  these  data  For  in  drugs  example,  a  administration  serotonin,  females  variety of  the  Administration effects  of  behaviour. Kohl,  of  The  consisted  of  that  effects  of  that  &  Ward,  reported  synthesis reduces  Crowley  1976;  in estrogen-primed 1975;  &  Meyerson  Margules,  drugs  that  methysergide  block  (  &  1973).  to f a c i l i t a t e  al.,  p-  availability  the  lordosis Davis  Foremann & M o s s , 1978;  et  the  inhibitor  the  Jonsson,  antagonists  Zemlan  primed  &  Franck  (Ward, C r o w l e y ,  1973),  and,  in  low  (Fuxe, E v e r i t t , A g n a t i , Fredholm & Jonsson,  were r e p o r t e d  to  the  Zemlan e t a l . , 1 9 7 3 ) , c i n n a n s e r i n 1975;  rats  p r o g e s t e r o n e . Much of  l o r d o s i s behaviour  & Gerall,  metergoline  Treatments  female  researchers  serotonin antagonists,  Zemlan & M a r g u l e s ,  serotonin  and  pharmacological  hypothesis.  a treatment that  serotonin  of  in  serotonin  Zemlan,  Henrik  Ward, 1981;  reported  For  s e r o t o n i n , were a l s o r e p o r t e d  1978;  doses,  of l o r d o s i s b e h a v i o u r .  t o support Meyerson's  Fuxe, H o k f e l t  1966;  s t u d i e s , many his  evaluation  of  facilitated  (Everitt,  Lewander,  the  to  of  substantiate  activity  appeared  chlorophenylalanine,  1976)  studies  serotonergic  collected  serotonergic  &  inhibition  v a r i o u s c o m b i n a t i o n s of e s t r o g e n  the  of  effort  led  inhibition  f o l l o w e d Meyerson's i n i t i a l  e x p e r i m e n t s were p e r f o r m e d i n t h e hypothesis  serotonergic  data  to  produce  increase  inhibit  releasing  lordosis-facilitating  serotonergic  lordosis  activity  behaviour.  agents fenfluramine  For (Everitt  effects.  were g e n e r a l l y example, et a l . ,  the 1975)  4  and  p-chloroamphetamine  were  reported  estrogen  and  to  (Zemlna, T r u l s o n , Howell & Hoebel, 1977)  inhibit  lordosis  progesterone.  The  in  females  administration  primed of  a g o n i s t s , drugs that mimic the e f f e c t s of s e r o t o n i n , reported  to  inhibit  lordosis.  Moderately  s e r o t o n i n a g o n i s t s LSD ( E l i a s s o n , Meyerson,  Carrer  Sietnieks,  &  1980),  were r e p o r t e d Although  literature  &  were  also  doses of the  Meyerson,  1972;  n,n,dimethyltryptamine, and  psylocybin  (Everitt  t o produce l o r d o s i s - i n h i b i t i n g  there to  Michanek  serotonin  E l i a s s o n , 1974; E l i a s s o n & Meyerson, 1976;  methoxydimethyltryptamine, 1977)  high  with  was  a  support  good  Meyerson's  i n h i b i t i o n of l o r d o s i s , there (Mendelson & Gorzalka,  deal  were  of  of  many  1985b). In some cases,  and Fuxe,  effects.  evidence  theory  also  5-  in  the  serotonergic  inconsistencies  serotonergic  drugs  were found to have no e f f e c t on l o r d o s i s behaviour. For example, some  researchers  found  propyldopacetamide  the  serotonin  (Meyerson  chlorophenylalanine  &  (Ahlenius,  Lewander, Engel,  Sodersten, 1972; Wilson, Bonney Everard, be  ineffective  inhibitors a  1970)  Eriksson,  ( Segal  was  actually  & Whalen,  1970;  Org6582,  femoxitine  expected  to  increase  lordosis  and  found  to  Gorzalka  chloimipramine,  serotonergic behaviour  p-  Modigh  &  Parrot & Wise, 1982) t o  inhibit &  drugs  activity,  p-  lordosis  Whalen,  Moreover, i n at l e a s t one study the s e r o t o n i n re-uptake  facilitate  and  i n estrogen-primed females. In s e v e r a l cases,  chlorophenylalanine behaviour  synthesis  1977). blockers  that would be were  found  to  (Hamburger-Bar, R i g t e r & Dekker,  1978) . Because of  the  inconsistencies  in  the  literature,  the  5  precise nature of  lordosis  and  behaviour  Gorzalka  effects  of the r o l e played  by s e r o t o n i n  remained c o n t r o v e r s i a l .  o f s e r o t o n e r g i c d r u g s on l o r d o s i s roles  behaviour.  Neurotransmitters  as  such  messengers i n the b r a i n .  by  acting  at  and  translate Many  binds  sites  known  electrical species  discharge  movement  of  along  increased  messenger  the  r e c e p t o r s may r e s u l t  internal chemistry It of  in  or  enzyme  in  this  that  systems,  the  ions through the alters  the  the  neuron  will cases,  so-called  second  n e u r a l membrane. The a c t i v a t i o n o f  i n more  long-term  changes  i n the  of t h e neuron. to display  for a specific neurotransmitter.  of t h e shape of t h e n e u r o t r a n s m i t t e r role  channels i n  decreased. In other  i s c h a r a c t e r i s t i c of a receptor  selectivity  activity.  t h e n e u r a l membrane a n d , d e p e n d i n g on  to  systems,  the  actually  are activated,  particles  i o n , the probability  i s either  effects  When  that  to special  receptors  charged  onto  i t i s t h e changes i n t h e  are linked  of  r e c e p t o r s may be l i n k e d  these  receptors.  message i n t o c h a n g e s i n n e u r a l  example,  balance  chemical  produce t h e i r  open a n d a l l o w t h e p a s s a g e o f c e r t a i n This  i n the  a c t as  p r o p e r t i e s of t h e r e c e p t o r  t h e n e u r a l membrane. When t h e s e  the  as  to i t s receptor,  electrical  the chemical  membrane.  m i g h t be due  They a r e r e l e a s e d f r o m one n e u r o n  special  receptors,for  channels  serotonin  o f a s e c o n d n e u r o n where t h e y  neurotransmitter shape  behaviour  i n the  of subtypes of serotonin receptors  m o d u l a t i o n o f female s e x u a l  surface  I n 1985, M e n d e l s o n  suggested that.the apparent i n c o n s i s t e n c i e s  to d i f f e r e n t i a l  the  i n the modulation  selectivity.  The  a high  The r e c o g n i t i o n  appears t o p l a y a  process  by  degree  critical  which a receptor  6  recognizes and responds t o i t s n e u r o t r a n s m i t t e r l i k e n e d t o the mechanism of a lock possesses itself  the c o r r e c t  into  In reflect  structure,  the contours  a c t i v a t i o n . Molecules actuality  of  key. When  a  lock  the f u l l complexity  the  receptor,  and  key  model  and  produce  excluded.  i s too simple t o  of the i n t e r a c t i o n of a receptor and  For example, i n a simple  any molecule of proper  molecule  i t can b i n d , that i s , mold  of improper shape are simply  the  a neurotransmitter.  and  has i n f a c t been  lock and key model,  shape might be expected to  a c t i v a t e the  r e c e p t o r . Some drugs, c a l l e d receptor a g o n i s t s , do i n f a c t mimic the  effects  of  neurotransmitters  r e c e p t o r s and producing receptor  antagonists  antagonists)  binding  at  a c t i v a t i o n . However, some  agonists  (or, just  particular  drugs  bind t o r e c e p t o r s and prevent  Other drugs c a l l e d p a r t i a l partial  by  called  activation.  as  correctly,  bind to r e c e p t o r s and produce only  partial  activation. Receptors i n the b r a i n are, f o r the most p a r t , according  to  molecules.  their  However,  pharmacologists  have  within a population neurotransmitter. within  ability using found  of For  drugs that  example, of  that  receptors receptors.  to  as  receptors  a c e t y l c h o l i n e , there  transmitter  chemical  responds  i t has  responds t o the drug n i c o t i n e , and responds  specific  differences  receptors  the p o p u l a t i o n  neurotransmitter  t o recognize  categorized  long  that  may to  probes, e x i s t even the same  been known that to  the  i s one subpopulation  that  another  responds  subpopulation  that  the drug muscarine. These n i c o t i n i c and muscarinic  are In  referred  to  as  subtypes  of  acetylcholine  the "lock and key" analogy, a c e t y l c h o l i n e may be  7  t h o u g h t o f as a " m a s t e r k e y " . subtype  of  acetylcholine  a n o t h e r s u b t y p e of 'unlock'  both  serotonin  been  serotonin The  binding the  _in  "test  has  tube"  a  drug  r e c e p t o r . The  using  or basic  sufficient other  itself  readily  then r e l a t i v e l y  if  a  with  low  that  systems w i t h which concentrations  for receptor binding a  in  of a d r u g f a i l  in  any  substance, binds  to a  vitro  ligand specific  d r u g s or even the  natural  s i t e s on  that  receptor.  If a  h i g h degree of t e n a c i t y t o a i s , i f i t has of  a high  binding  the drug w i l l  f r o m t h e s e r e c e p t o r s . On binding  the drug w i l l sites.  technique  drug  but  to a  concentrations  of  of  analysis.  animals  i_n  a  subtypes  or s l i c e s of b r a i n t i s s u e  d r u g p o s s e s s e s a low  high concentrations  competitive  living  involved  to d i s p l a c e competitors  compete e f f e c t i v e l y this  and  technique  f a c t t h a t t h e a n a l y s i s of  that  for binding  as a s i n g l e  binding  that a drug that binds  c l a s s of r e c e p t o r s ,  hand,  only very  to  suggested  A  transmitter,  a l s o compete w i t h o t h e r  neurotransmitter  has  exist  ligand  the  principle  will  affinity,  is  subtypes.  b r a i n s of  natural  receptor  particular  able  term l i g a n d r e f e r s to  a n a l y s i s i s simply  binds  itself  identifying  homogenates  The a  to  i n the  binding  drug  'unlocks'  not  in  been i_n v i t r o  not  removed f r o m a n i m a l s . either  useful  refers  place  do  r a t h e r c o n s i s t of  vitro  takes  receptors  extremely  receptors  term  acetylcholine  one  muscarine  from a v a r i e t y of t e c h n i q u e s  homogenous g r o u p , but has  and  'unlocks'  subtypes.  central  that  nicotine  receptor,  receptor,  Evidence derived that  Whereas  The  affinity,  allow  i s to i d e n t i f y  interacts.  For  the then  the drug  most o b v i o u s use the  example,  be  to of  receptor if  high  to d i s p l a c e r a d i o a c t i v e l y l a b e l l e d  8  neurotransmitter considered  from  i t s receptor,  i n a c t i v e at that r e c e p t o r . I f ,  range of c o n c e n t r a t i o n s , labelled drug at  then  transmitter that  type  within  drug a  may  be  reasonable  the drug d i s p l a c e s v i r t u a l l y a l l of the  from of  the  i t s r e c e p t o r , then a c t i v i t y of the  receptor  can  be  strongly  suspected.  However, i f only a p o r t i o n of l a b e l l e d t r a n s m i t t e r i s d i s p l a c e d , and  f a r higher  concentrations  d i s p l a c e the remaining  of  the  drug  must be used t o  p o r t i o n , then i t i s p o s s i b l e  that  the  drug d i f f e r e n t i a t e s subtypes of r e c e p t o r s f o r that t r a n s m i t t e r . By  analysing  serotonin,  and  Peroutka  and  the  of  serotonergic  Snyder  e x i s t e n c e of two populations  and comparing the b i n d i n g c h a r a c t e r i s t i c s of  (1979)  drugs  were  pharmacologically central  LSD  able and  and  to  spiperone,  demonstrate  anatomically  distinct  s e r o t o n i n r e c e p t o r s . One p o p u l a t i o n of  s e r o t o n i n r e c e p t o r s d i s p l a y e d h i g h a f f i n i t y b i n d i n g of serotonin  and  was designated  of  as the 5-HT  2  subtype. LSD was a c t u a l l y  most  recent  evaluations  of  equal  the  chemical  population  spiperone  to both receptor subtypes with approximately The  the  s e r o t o n i n , 5-hydroxytryptamine.) The second  d i s p l a y e d high a f f i n i t y b i n d i n g of l a b e l l e d designated  labelled  as the 5-HT, subtype. (The common  a b b r e v i a t i o n f o r s e r o t o n i n , 5-HT, i s d e r i v e d from name  and  of  subtypes.  Two  distinct  affinity.  central  r e c e p t o r have been determined on  the  a f f i n i t y components i n the displacement serotonin  from  5-HT,  receptors  subtypes basis  of  serotonin  of  1981). These subtypes have been designated  the  high  by spiperone  (Pedigo,  was  found to bind  r e c e p t o r have i n d i c a t e d that the 5-HT, c l a s s of r e c e p t o r s consists  the  Yamamura  itself 5-HT,  and low  of l a b e l l e d & Nelson,  as 5-HT,A and 5-HT,B,  9 r e s p e c t i v e l y . Even more subtype  of  recently,  the 5-HT, receptor  the  existence  of  labelled  serotonin  the  finding  s i t e s by known receptors It  as 5-HT,C, i s  ligands  of  either  5-HT,A,  5-HT,B,  or  5-HT  2  (Pazos, Hoyer & P a l a c i o s , 1984). is  important to note that b r a i n t i s s u e c o n t a i n s a wide bind  b i n d i n g of the t r a n s m i t t e r to a p a r t i c u l a r  itself  suggested  that l a b e l l e d 5-HT i s not d i s p l a c e d from these  v a r i e t y of p r o t e i n s with the p o t e n t i a l to the  mesulergine  from s i t e s i n c h o r o i d plexus t i s s u e . The  uniqueness of t h i s r e c e p t o r , designated by  third  has been determined on the b a s i s  of a high a f f i n i t y component i n the displacement by of  a  prove that that s i t e  serotonin,  and  s i t e does not i n  i s a functional serotonin  receptor.  There i s , however, growing evidence that the subtypes of c e n t r a l b i n d i n g s i t e s as c h a r a c t e r i z e d by in v i t r o  serotonergic analyses  do represent  evidence  that  functional serotonin  5-HT,A  receptors  receptors.  a c t as  There  is  somato-dendritic  autoreceptors  on s e r o t o n e r g i c  &  Aghajanian,  1986),  i s , as r e c e p t o r s on s e r o t o n e r g i c c e l l  bodies that  that  mediate i n h i b i t o r y synaptic  5-HT,A  feedback  neurons  binding  of  (Sprouse  serotonergic  activity.  r e c e p t o r s , that i s , 5-HT,A r e c e p t o r s on t a r g e t  neurons, appear to mediate s t i m u l a t i o n of adenylate chemical 1986).  second 5-HT,B  autoreceptors,  messenger receptors  system appear  (Engel, Gothert,  (Markstein, to  activity.  that 5-HT,C  serotonergic  mediate  inhibitory  receptors  act  cyclase,  a  Hoyer & Engel,  as  prejunctional  Hoyer, S c h l i c k e r & H i l l e n b r a n d ,  1986), that i s , as r e c e p t o r s on the neurons  Post-  have  terminals  of  serotonergic  feedback  of  serotonergic  been  s t i m u l a t i o n of p h o s p h o i n o s i t i d e  found  to  mediate  h y d r o l y s i s , another  10  second  messenger mechanism, i n the c h o r o i d plexus  & Conn, 1986). Evidence i n d i c a t e s that 5-HT the  neural  (Peroutka  excitatory  of  receptors  2  serotonin  mediate  in brain tissue  & Snyder, 1979).  Finally, subtypes  effects  (Sanders-Bush  i t must  be  mentioned  that  the  discovery  of  of c e n t r a l s e r o t o n i n r e c e p t o r s complements the e a r l i e r  c h a r a c t e r i z a t i o n of the D and M subtypes of p e r i p h e r a l s e r o t o n i n receptors thought  (Gaddum & P i c a r e r l l i , to  (Bradley,  be  Engel,  Mylecharane, distinct  similar  receptor  i s now  i f not i d e n t i c a l to the 5-HT  receptor  Fenuik,  Richardson  1957). The  Fozard,  suggested that i t be designated the  Humphrey,  2  Middlemiss,  & Saxena, 1986). The M receptor  from the 5-HT, and 5-HT  With  D  discovery  of  2  subtypes,  as the 5-HT the  r e c e p t o r s , the p o s s i b i l i t y arose  and  appears  i t has  been  receptor.  3  subtypes  of  that the d i f f e r e n t  central  5-HT  subtypes  of  r e c e p t o r s might mediate d i f f e r e n t e f f e c t s of s e r o t o n i n on female sexual  behaviour.  As  was suggested by Mendelson and G o r z a l k a ,  much of the i n c o n s i s t e n c y i n the r e p o r t s concerning serotonin lack of  in  receptor-subtype  selectivity  serotonergic  classical  serotonin antagonists  bind  in  activity.  varying  effects  that  receptor  subtype  were  The  of - the  to  drugs  used  to  use of drugs such as the  or a g o n i s t s  degrees  subtypes, would not have allowed  The  of  female of sexual behaviour may have been due to a  evaluate  which  the r o l e  , f o r example,  LSD,  a l l of the 5-HT receptor  the p r e c i s e e v a l u a t i o n  of the  s e r o t o n i n might have produced i n a c t i n g upon each  5-HT  2  alone.  s e l e c t i v e a n t a g o n i s t s pirenperone  among the f i r s t  and  ketanserin  of the receptor subtype s e l e c t i v e drugs to  11  become a v a i l a b l e . U n l i k e  the  these  f o u n d t o be v i r t u a l l y  new  drugs  were  receptors  (Janssen,  reported  that  behaviour  in  1983).  In  pirenperone steroid  and  primed  1985b). Moreover, q u i p a z i n e , high  affinity  inhibitory proposal female  f o r 5-HT  e f f e c t of  of a dual sexual  classical  classical  1985, M e n d e l s o n ketanserin  females  role hypothesis  role hypothesis  Gorzalka,  with  relatively  results  l e d to the  Specifically,  modulation of  i t was p r o p o s e d t h a t t h e  effects  I will  by p e r f o r m i n g  formed  the basis  f o rthe o r i g i n a l  no a t t e m p t was made t o d i s t i n g u i s h  5-HT, r e c e p t o r . serve  I t i sconceivable  differential  There i s i n a d d i t i o n  receptors  play  a  receptor  has  peripheral  receptor,  recent  Tyers,  i n press,  exist  cited  2  In the  dual  between  role  effects  subtypes of  t h a t t h e s u b t y p e s o f 5-HT,  the  possibility  that  r o l e i n the modulation of l o r d o s i s .  3  does  more  r o l e s i n t h e modulation of l o r d o s i s  behaviour.  receptor  a  o f t h e e f f e c t s o f d r u g s t h a t a c t a t 5-HT  m i g h t be p r o d u c e d by a c t i v a t i o n o f t h e v a r i o u s  receptors  are  the dual  a l s o attempt t o extend the hypothesis.  that  hypothesis,  serotonin  attempt t o c o n f i r m  of Mendelson and G o r z a l k a  receptors. experiments  of  5-HT,  receptors.  2  evaluation  5-HT  Gorzalka  &  of serotonergic  facilitatory  extensive  of  (Mendelson  These  In t h e f o l l o w i n g s t u d i e s I w i l l  the  and  inhibited lordosis  a serotonin agonist  pirenperone.  whereas  m e d i a t e d by 5-HT  the  i n a c t i v e a t 5-HT,  i n h i b i t o r y e f f e c t s o f s e r o t o n i n a r e m e d i a t e d by  receptors,  that  antagonists,  r e c e p t o r s , was f o u n d t o a t t e n u a t e t h e  2  behaviour.  serotonin  generally evidence  been  i n Tyers,  indicates that t h i s  1988). T h e r e f o r e ,  in  3  Although  chraacterized  i n brain tissue (Kilpatrick,  5-HT  as  a  subtype  Jones and addition  12  to  e v a l u a t i n g the e f f e c t s of drugs a c t i v e a t  will  also  evaluate  determined  to  act  receptors. Together, understanding receptors  the  effects  selectively these  of at  5-HT  drugs S-HT^A,  studies w i l l  receptors, I  2  that  have  been  and  5-HTTB,  p r o v i d e a more  5-HT  3  complete  of t h e r o l e o f s e r o t o n i n and t h e v a r i o u s s e r o t o n i n  i n the modulation  of l o r d o s i s behaviour  i n t h e female  rat.  General  Animals  and  Methods  Surgery  F e m a l e S p r a g u e - D a w l e y a n d , i n some c a s e s , were  bred  i n our f a c i l i t i e s  Long-Evans  from s t o c k o r i g i n a l l y  obtained  C h a r l e s R i v e r Canada I n c . , M o n t r e a l . A t a p p r o x i m a t e l y age,  these  lumbar  incisions.  under  ether  females mesh  females  were Surgery  anesthesia.  i n a room m a i n t a i n e d  h r l i g h t c y c l e a t 21±1°C water.  through  was p e r f o r m e d w h i l e t h e a n i m a l s Immediately  following  . Animals  were  surgery, a l l laboratory wire  under a r e v e r s e d were a l l o w e d  from  70 d a y s o f  ovariectomized  were h o u s e d i n g r o u p s o f s i x i n s t a n d a r d  cages,  f o o d and  bilaterally  rats  12 h r d a r k / 1 2  free  access  to  13  Steroid  Treatments  In  a l l  (Steraloids)  cases,  have  estradiol  been  i n j e c t e d subcutaneously  dissolved  the  evaluated cases t h i s treatments this  in  peanut  warm  following  or  o i l , and  vehicle.  studies,  effects  of  d r u g s were  often  i n a n i m a l s t h a t h a d h a d p r i o r d r u g t r e a t m e n t s . I n some involved animals with  being  v a r y i n g doses  drug  treatments.  subjected  even  baseline  to  a  series  o f t h e same d r u g . I n o t h e r i n consecutive  In  of  cases  e v a l u a t i o n s of  s i t u a t i o n s s u c h a s t h e s e , some  c o n c e r n must be g i v e n t o t h e p o s s i b i l i t y drug,  progesterone  Effects  i n v o l v e d a n i m a l s b e i n g used  different  and  i n 0.1 m l o f t h i s  C o n t r o l of Drug C a r r y - o v e r  In  benzoate  behaviour  that  were  responses  influenced  to  a  by p r i o r  treatment(s). One way i n w h i c h subsequent  the a d m i n i s t r a t i o n of  evaluations  a  drug  i s f o r t h e drug t o remain  may  alter  or accumulate  i n t i s s u e s of t h e e x p e r i m e n t a l a n i m a l s . In r e g a r d t o t h e p r e s e n t s e r i e s of studies, there are at l e a s t that  t h i s was u n l i k e l y . F i r s t ,  in time, with intervals.  a l l of  the  studies are r e l a t i v e l y hydrophilic, in  water.  soluble  Drugs  i n water  (and  their  reasons  to  d r u g t r e a t m e n t s were w e l l  treatments, occurring  Secondly,  two  at  no  less  than  suggest spaced weekly  drugs a d m i n i s t e r e d i n these that  i s , relatively  soluble  metabolites) that are reasonably  are generally excreted  quite  readily  i n the  14  u r i n e and A  tend not to  second  way  accumulate. in  which  a l t e r subsequent drug t r i a l s process  the a d m i n i s t r a t i o n of a drug  is  by  initiating  a  physiolgical  that continues beyond the time the drug has  from the animal's  may  disappeared regard  is  the p o s s i b i l i t y of a drug producing an up- or down-regulation  of  receptors.  When  body. Perhaps most notable i n t h i s  the r e c e p t o r s of a n e u r o t r a n s m i t t e r system are  under- or o v e r - s t i m u l a t e d , the system w i l l these  conditions  by  increasing  or  sometimes  decreasing  adapt  the number or  s e n s i t i v i t y of the t r a n s m i t t e r ' s r e c e p t o r s . These processes refered cannot  to  are  to as up- and down r e g u l a t i o n , r e s p e c t i v e l y . Although I with c e r t a i n t y  receptors  did  not  state occur,  that I  or  down-regulation  of  believe  i t u n l i k e l y to have  o c c u r r e d . G e n e r a l l y , up- and down-regulation  of r e c e p t o r s occurs  with r a t h e r extreme treatment, of  do  up-  t h a t i s , with the  administration  very l a r g e doses or with prolonged c h r o n i c a d m i n i s t r a t i o n of  moderate doses of drugs. To the best of my little  in  the  literature  to  suggest  knowledge, that  there  is  at the doses and  f r e q u e n c i e s at which they were administered, the drugs e v a l u a t e d in  the present  series  of  studies  would  have  produced  these  ef f e c t s . A  final  drug treatments is  mechanism  by which i t may  have been p o s s i b l e f o r  to have a l t e r e d the e f f e c t s of subsequent  by t o x i c i t y . However, to the best of my  knowledge,  the drugs e v a l u a t e d i n the f o l l o w i n g experiments to  be t o x i c w i t h i n the dose ranges Although  there  e f f e c t s of drugs,  was  little  trials  none  have been  of  found  that were a d m i n i s t e r e d . reason  s e v e r a l measures were  to suspect c a r r y - o v e r taken  to  insure  that  15  data  would  not  be  unduly  e x a m p l e , no a n i m a l s were u s e d experiments. Moreover, at of  effected  by p r i o r  in  than  more  baseline levels  t h e b e g i n n i n g of each experiment. behaviour  were n o t o b s e r v e d ,  treatments. For  three  consecutive  o f a n i m a l s were  monitored  I f expected b a s e l i n e l e v e l s  the experiment  was a b o r t e d and  new a n i m a l s were p r e p a r e d .  Behavioural Testing  Behavioural experimental testing In 60  testing  female  to  arena measuring  some c a s e s , a n a r r o w X  15  cm  was  involved  presentation  of  an  a s t u d male r a t i n a c y l i n d r i c a l  Pyrex  45 cm i n h e i g h t , a n d 29 cm i n  b i - l e v e l chamber w i t h d i m e n s i o n s  employed.  This  chamber  M e n d e l s o n & G o r z a l k a , 1987) a l l o w s t h e avenue of  of escape  receptive 500  state.  females  (fully described in  experimental  resembles  S t u d m a l e s were g i v e n b r i e f ( e a c h g i v e n 10 jug e s t r a d i o l  access  to  hr  after  thrusting  benzoate  48 h r and  commencement o f t h e d a r k c y c l e . male u n t i l  the  female  was  placed  c o n t a i n i n g another male. A female's considered  were  a  lordosis  response  in  conducted  10 mounts w i t h  a  response  prior  Each e x p e r i m e n t a l  h a d o c c u r r e d . On t h e r a r e o c c a s i o n t h a t a  mount,  an  fully  nq p r o g e s t e r o n e 4 h r b e f o r e p r e s e n t a t i o n ) i m m e d i a t e l y  f e m a l e was p l a c e d w i t h a s i n g l e  not  female  that observed i n  to s e s s i o n s w i t h experimental females. Sessions 4-6  o f 51 X  from t h e male, and t h u s a l l o w s t h e o b s e r v a t i o n  s e x u a l b e h a v i o u r t h a t more c l o s e l y  the n a t u r a l  diameter.  male  different to  i f some d e g r e e  pelvic  a  would chamber  mount  was  of c o n c a v i t y of  t h e b a c k was o b s e r v e d . L o r d o s i s q u o t i e n t s were c a l c u l a t e d  as t h e  16  p e r c e n t a g e of lordosis  mounts  with  pelvic  thrusting  resulting  in a  response.  EXPERIMENT 1  In  a  recent  series  of  a n t a g o n i s t s p i r e n p e r o n e and  experiments, the s e l e c t i v e  ketanserin  was  found  to  5-HT  2  inhibit  lordosis  behaviour i n female r a t s primed w i t h e s t r o g e n , or with  estrogen  and  Quipazine, receptors  an  progesterone agonist  (Mendelson  inhibitory  this  study  to  ketanserin with  Gorzalka,  1985b).  with relatively high a f f i n i t y  (Leysen & T o l l e n a e r e ,  the  &  effects  1 9 8 2 ) , was  found  f o r 5-HT  2  to attenuate  o f p i r e n p e r o n e . No a t t e m p t was made i n  attenuate  the  lordosis-inhibiting  effects  of  quipazine.  S e r o t o n i n h a s g e n e r a l l y been t h o u g h t t o s e r v e an i n h i b i t o r y role  in  the modulation  of female s e x u a l behaviour  (Meyerson,  1966); however, t h e above r e s u l t s l e d us t o h y p o t h e s i z e role  f o r 5-HT  (Mendelson  proposed that s e x u a l l y by 5-HT  2  inhibit  pirenperone  lordosis,  with  ketanserin unique  pharmacological inhibiting  e f f e c t s of s e r o t o n i n  are  activity. and  ketanserin  have  been f o u n d t o  t h e s e f i n d i n g s do n o t g u a r a n t e e t h a t a l l 5-HT  a n t a g o n i s t s would i n h i b i t and  we  e f f e c t s o f 5-HT a r e m e d i a t e d  r e c e p t o r s , whereas i n h i b i t o r y  Although  dual  & G o r z a l k a , 1985b). S p e c i f i c a l l y ,  facilitatory  m e d i a t e d by 5-HT, r e c e p t o r  a  represent molecular profiles.  this a  behaviour.  new c l a s s o f s e r o t n i n  structures It  Indeed,  and,  i s possible  2  pirenpirone antagonists  perhaps,  unique  that the lordosis-  e f f e c t s of these drugs a r e unique and a r e not t y p i c a l  17  o f 5-HT  antagonists. In order  2  blockade  of a c t i v i t y  lordosis, variety  i t was  o f 5-HT  evaluated the  necessary  would p r o v i d e an  to evaluate the  t h e e f f e c t s upon l o r d o s i s  5-HT a n t a g o n i s t s  pipamperone,  the effects  following  behaviour  evidence  of these  also evaluated  o f 5-HT  experiment,  metitepine,  e f f e c t s , the effects  of  after coadministration with  I  of k e t a n s e r i n and pizotefin,  a n t a g o n i s t s . To t e s t  2  of  of a wider  as t o whether t h e i n h i b i t i o n of  typical  that  inhibition  I t was hoped t h a t t h e e v a l u a t i o n o f t h e s e  effect  specificity  the conclusion  r e c e p t o r s produces  2  antagonists. In  2  cyproheptadine.  is  a t 5-HT  to strengthen  these  and drugs  lordosis f o r 5-HT  2  drugs  were  (ketanserin)  were  guipazine.  Methods  Drugs Pipamperone obtained from  and  as g i f t s  Sandoz,  metitepine  ketanserin  from Janssen cyproheptadine  from  Hoffmann-La  tartrate  Pharmaceutica, from Roche,  as  Mercke, and  was  Sharp  i n approximately  0.1  &  guipazine  ( g u i p a z i n e ) f r o m M i l e s L a b o r a t o r i e s . A l l d r u g s were intraperitoneally  pizotefin  maleate  administered  ml o f s a l i n e  r e g a r d l e s s o f d o s e . D r u g s were a d m i n i s t e r e d  Dohme,  vehicle,  blind.  Procedures In Experiment determine  the  1A, 5 g r o u p s  dose  response  of  12  females  were  t o e a c h o f t h e 5-HT  2  used  to  antagonists  18  pipamperone,  pizotefin,  ketanserin.  Within  cyproheptadine,  each group, animals  metitepine,  were a d m i n i s t e r e d  EB 48 h r , 500 P 4 h r , a n d e i t h e r 0, 0.1, 0.3, 1, o r 3 the  respective  5-HT  antagonist  1  hr  prior  experiment being conducted over  of treatment  f o r animals  simple L a t i n  square  In  to  administered  behavioural  1B,  t h e e f f e c t s of those  Mg  EB  5-HT  in a  were e v a l u a t e d  agonist  2  quipazine.  the  respective  quipazine,  o r t h e 5-HT  behavioural  t e s t i n g . The i n t e r v a l  week, a n d t r e a t m e n t s  5-HT  antagonist  2  2  antagonists  2  i n animals  Groups  received  the minimal  antagonist',  plus quipazine  co-  o f 12 new  animals  48 h r , 500 Mg P 4 h r , a n d e i t h e r s a l i n e ,  e f f e c t i v e dose of  of  arranged  5-HT  f e m a l e s e a c h were u s e d , a n d w i t h i n e a c h g r o u p 10  with  a 5 week p e r i o d . The o r d e r s  w i t h i n e a c h g r o u p were  l o r d o s i s behaviour the  of  design.  Experiment  found t o a l t e r  10 Mg  mg/kg  t e s t i n g . The i n t e r v a l b e t w e e n s u c c e s s i v e t e s t s was 1 week, the  and  3  mg/kg  1 hr prior to  b e t w e e n s u c c e s s i v e t e s t s was 1  were c o u n t e r b a l a n c e d  across  the four  weeks  testing.  Results  The the  form  (ANOVA) order effect  results of was  of  dose-response used  to  of treatment. of  (4,100)=35.94,  Experiment  1a a r e d i s p l a y e d i n F i g . 1a i n  curves.  evaluate  An  analysis  2 « <  0 0 0 1  dosage '  variance  t h e e f f e c t s o f dose, drug, and  The a n a l y s i s c o n f i r m e d  increased  of  of  Moreover,  the  a general 5-HT  the  2  inhibitory  antagonists,  ANOVA  F  indicated  s i g n i f i c a n t d i f f e r e n c e s i n e f f e c t i v e n e s s among t h e d r u g s ,  19  F i g . 1a Mean primed with  lordosis  q u o t i e n t s ± S.E.M. o f f i v e g r o u p s o f f e m a l e s  10 nq e s t r a d i o l  following  the  antagonist  1 hr p r i o r  benzoate and  administration  of  to behavioural  500  varying testing.  nq  doses For  progesterone, of each  a  5-HT  2  group,  LORDOSIS QUOTIENT % o I  M  yi  vi  i  I  1  ui  a  in  o o I  21  F(4,25)=6.18, comparison effective A  •  00 2  •  revealed  that  than e i t h e r  significant  Newman-Keuls  T n e  metitepine  pipamperone  interaction  was  between  Keuls  I n h i b i t i o n of l o r d o s i s  animals receiving  ketanserin,  metitepine,  the  with  (g<.05).  after  3 mg/kg was  drug  (p_<.05).  more e f f e c t i v e (2<.05). lordosis  that  drug  a l l o w e d the  was  also  effects  demonstrated  pizotefin,  of  In the case of m e t i t e p i n e , l o r d o s i s  3  mg/kg  any  of  the  pizotefin  b e h a v i o u r , 3 mg/kg o f  the  i n h i b i t i o n of l o r d o s i s pipamperone.  developed  and  four  was  observed  Finally,  neither  tolerance  the  significantly other  significantly  drug was  behaviour  1 mg/kg o f  mg/kg m e t i t e p i n e was  t h a n 3 mg/kg o f 1  i n those  cyproheptadine,  drugs  inhibited  ineffective.  No  i n those animals  the a n a l y s i s of v a r i a n c e  r e v e a l e d t h a t t h e r e were no s i g n i f i c a n t o r d e r e f f e c t s , animals  (p_<.05).  m i n i m a l e f f e c t i v e d o s e b e i n g 1 mg/kg f o r  Moreover,  received  was  s i g n i f i c a n t l y lower than a f t e r  Whereas  significant  and  more  of e a c h d r u g t o be c o m p a r e d by u s e o f t h e Newman-  method.  each drug  multiple  significantly  dose  1  doses  of  (2<.05), o r p i z o t e f i n  r e v e a l e d , F (1 6 ,1 00) =4. 42 , p_<'000 « This specific  method  nor  that  sensitivity  is,  to the  drugs.  The 1b,  r e s u l t s of E x p e r i m e n t  remained  consistent  although the e f f e c t s  with  1b, w h i c h a r e d i s p l a y e d those  of t h e f i r s t  were more p r o n o u n c e d .  was  ineffective  the  s e c o n d e x p e r i m e n t . A s e p a r a t e ANOVA was  effects  of e a c h  i n the f i r s t  5-HT  2  experiment,  Because i t was used  in  Fig.  experiment, pipamperone  not e v a l u a t e d i n to e v a l u a t e the  antagonist in combination with quipazine.  In t h e s e a n a l y s e s , t h e i n h i b i t o r y e f f e c t s  of t h e s e d r u g s  were  22  Fig.  1b  Mean l o r d o s i s q u o t i e n t s o f f o u r g r o u p s  of  females  with  10 Mg e s t r a d i o l  b e n z o a t e a n d 500 Mg p r o g e s t e r o n e ,  the  administration  of  q u i p a z i n e , a 5-HT vehicle included  2  1 hr prior  1  mg/kg o f a 5-HT  antagonist  plus  2  (KETA),  quipazine,  (CYPRO), a n d m e t i t e p i n e  pizotefin  following  a n t a g o n i s t , 3 mg/kg or  t o b e h a v i o u r a l t e s t i n g . The 5-HT  ketanserin  primed  (PIZO),  the 2  saline  antagonists  cyproheptadine  ( M E T I ) . F o r e a c h g r o u p , n=12.  24  again  confirmed,  demonstrated  with for  cyproheptadine,  main  pizotefin,  and  p_<.000l;  ketanserin,  Newman-Keuls method was s u b s e q u e n t l y  interactive  effects  of  each  drug  q u i p a z i n e alone d i d not a f f e c t four  drug  effects  groups,  of  ketanserin effect  lordosis  (p_<.05).  (p_<.05),  being  metitepine,  F (1 ,1 1 )=43.17,p<.0001 . used  with  i t significantly  pizotefin  effects  F ( 1 ,1 1 ) =49.75 ,p_<. 0001 ;  F(1 , 1 1 ) = 51 . 06 ,  F(1,11)=43.84,p<.0001; The  significant  to  evaluate  quipazine.  behaviour blocked  Although  i n any of t h e the  cyproheptadine  the  inhibitory  (p_<.05),  and  Quipazine d i dnot attenuate the i n h i b i t o r y  of m e t i t e p i n e .  Pi scussion  In Experiment pizotefin, lordosis  1,  behaviour  in  doses  differences  cyproheptadine 3  H-spiperone  also  evaluated.  i n potency  in  rats  to  primed  appeared  o f t h e d r u g was n o t  may be d i f f e r e n c e s example,  female  Pipamperone  however t h e e f f e c t of  and,  a  lesser  c y p r o h e p t a d i n e , a n d k e t a n s e r i n were f o u n d  progesterone.  range  metitepine  an  One  with  significant  i n t h e b i o a v a i l a b i l i t y of vitro  cortical  2  receptors  H o w e v e r , when a d m i n i s t e r e d i n t r a p e r i t o n e a l l y  lordosis,  within  2  these  preparation,  5-HT  and  the  f o rt h e apparent antagonists drugs.  For  pipamperone  and  were f o u n d t o be e q u a l l y e f f e c t i v e from  estrogen  i n t h e p r e s e n t g r o u p o f 5-HT  _in  to inhibit  to inhibit  explanation  degree,  in  displacing  (Leysen,  to live  rats,  1981). 1.5  jumol/kg o f p i p a m p e r o n e was n e e d e d t o b l o c k 5 0 % o f t h e b i n d i n g o f 3  H-spiperone  to  cortical  5-HT  2  receptors,  w h e r e a s o n l y 0.06  25  Mmol/kg  of  Radeke,  cyproheptadine  Buech  antagonists however  i n potency.  The  Bischoff,  present  f o r 5-HT,  5-HT  2  receptors,  that t h i s c o n t r i b u t e d t o the apparent For  example,  d e g r e e o f 5-HT, a c t i v i t y  ketanserin  (Ortman,  1982).  in their affinity  i t i s unlikely  significant  required  Delinistula,  also differ  differences  and  &  was  i svirtually  cyproheptadine  has  a  ( L e y s e n & T o l l e n a e r e , 1982)  i n a c t i v e a t 5-HT, r e c e p t o r s  (Leysen  & Tollenaere,  1 9 8 2 ) ; h o w e v e r , t h e s e d r u g s were e q u a l l y e f f e c t i v e  in  l o r d o s i s behaviour.  inhibiting  at  5-HT,  the  e f f e c t s of the present  with the  receptors  the e a r l i e r  was n o t a s i g n i f i c a n t  report  administration  antagonists  the  5-HT  2  is  antagonist  consistent  cyproheptadine,  metitepine,  l o r d o s i s at only  mg/kg  and  ketanserin  dose,  pizotefin  t h e 1 mg/kg d o s e . I t was i n e f f e c t i v e  dose. This dose-dependent e f f e c t of p i z o t e f i n  reflect  reported  (Colpaert dose,  & Janssen,  the  activity  5-HT  to a level  However, t h i s cyproheptadine activity  partial  agonist  activity  1 9 8 3 ) . Thus i t may be t h a t  agonist  of  at  component o f p i z o t e f i n  t h a t was s u f f i c i e n t  may  the drug  the  higher  restored  forlordosis  (Colpaert  In t h e present  metitepine  & Janssen, study,  may  also  5-HT  2  behaviour.  s p e c u l a t i v e a r g u m e n t i s c o u n t e r e d by e v i d e n c e and  is  1982).  at the higher the  by  pirenperone  pirenperone  (Leysen & T o l l e n a e r e ,  l o r d o s i s a t t h e 1 mg/kg a n d 3  inhibited  activity  factor i n determining  1985b). L i k e k e t a n s e r i n ,  i n a c t i v e a t 5-HT, r e c e p t o r s  inhibited  group of  that  that the l o r d o s i s response i s blocked of  (Mendelson & G o r z a l k a ,  Although  The s u g g e s t i o n  have p a r t i a l  that  agonist  1983).  quipazine  i n h i b i t o r y e f f e c t s of p i z o t e f i n ,  was f o u n d  cyproheptadine,  to  reverse  the  and k e t a n s e r i n .  26  These  findings  are consistent with the previous  a t t e n u a t i o n of the i n h i b i t o r y e f f e c t (Mendelson & G o r z a l k a , of  facilitatory  1985). I suggest t h a t the  inhibitory  of  the  drug  i n the present  effects  of  conclusion  i s consistent  Tollenaere,  1982), as w e l l as data  t o t h e 5-HT to  2  produce  Hammond,  Snyder,  did  not  metitepine.  Although  pizotefin,  cyproheptadine,  1982) vivo  affinities ,  5-HT  2  (Fig.  and  agonist.  This  (Leysen  &  studies. For  t o g e n e r a l i z e as a stimulus  response  (Green,  0'Shaughnessy,  1983), a behaviour  activity  believed  (Peroutka,  Lebovitz  in  reverse vitro  f o r 5-HT  2  the  inhibitory  effect  binding  data  ketanserin,  and  receptors  (Leysen  i t i s p o s s i b l e that metitepine  suggest  &  &  l o r d o s i s more e f f e c t i v e l y  attenuate  the e f f e c t  of metitepine.  Tollenaere,  mediated  by a n o n s e r o t o n e r g i c  r e s u l t s suggest that the observed t o t h e b l o c k a d e o f 5-HT  2  was f o u n d antagonists  may h a v e been  However,  remains that the i n h i b i t o r y e f f e c t of metitepine partially  have  may be more p o t e n t i n  than the other  1 ) . Thus a l a r g e r dose of q u i p a z i n e  of that  metitepine  . Indeed, i n t h e absence of q u i p a z i n e , m e t i t e p i n e  to i n h i b i t  to  cyproheptadine  1981).  Quipazine  similar  reversed  ( G l e n n o n , Young & R o s e n c r a n s , 1983) a n d  receptor  2  quipazine  from b e h a v i o u r a l  & Grahame-Smith,  t o be m e d i a t e d by 5-HT  a  report  Hole & Wilson,  w i t h _in v i t r o b i n d i n g d a t a  the head-twitch  Schachter  as  h a s been r e p o r t e d  a g o n i s t DOM  study  by q u i p a z i n e recent  (Hunter,  pizotefin,  k e t a n s e r i n upon l o r d o s i s by a c t i n g  example, q u i p a z i n e  of pirenperone  1985b), as w e l l as w i t h a  effects  f i n d i n g of the  required  the p o s s i b i l i t y was  at  least  m e c h a n i s m . The p r e s e n t  inhibition  r e c e p t o r s . However,  o f l o r d o s i s was due i_n v i t r o  binding  27  studies  have  d e m o n s t r a t e d t h a t t h e 5-HT  in the present (Leysen, The  activity  remains c o n t r o v e r s i a l , and thus of a , - a d r e n e r g i c  quipazine, these  inhibit  receptors  present  of  5-HT  (Rodriguez  data  5-HT  upon b e h a v i o u r upon  (Mendelson  &  administered  t o those  h a s been  of  by an a d r e n e r g i c is  inactive  i t may  1979).  antagonists  2  be  that  has a d e b i l i t a t i n g inhibitory  the  effect effect  reported  not  to  affect  i n male r a t s (Mendelson & G o r z a l k a ,  activity  Gorzalka,  inhibit  by  However, t h i s a p p e a r s u n l i k e l y , a s t h e  behaviour  1985a) o r w h e e l r u n n i n g  effects  1971; W i n t e r ,  i n g e n e r a l , but not a s p e c i f i c  open f i e l d  profoundly  & Pardo,  inhibitory  ketanserin  inhibitory  Nonetheless,  antagonist pirenperone  either  and  that quipazine  receptor a c t i v i t y  2  the  s t r o n g l y s u g g e s t t h a t 5-HT  l o r d o s i s behaviour. 2  that the  suggests  l o r d o s i s behaviour.  blockade  of  c o u l d h a v e been m e d i a t e d e n t i r e l y  mechanism. Indeed, e v i d e n c e  The  reversal  cyproheptadine,  i t appears u n l i k e l y  at adrenergic  behaviour  r e c e p t o r s was r e s p o n s i b l e f o r t h e i n h i b i t i o n o f  pizotefin,  drugs  i n female sexual  1981).  i t i s p o s s i b l e that the blockade  l o r d o s i s . However, i n v i e w of t h e of  receptors  Laudron, Vandenberk & Janssen,  a -adrenergic  of  effects  evaluated  study a r e a l s o a c t i v e a t a,-adrenergic  Awouters, Kennis,  role  antagonists  2  i n steroid-primed  1985b),  animals  although  female t h e drug  i n d o s e s t h a t h a v e been  the lordosis  response  rats was  found  to  (Mendelson & G o r z a l k a ,  1985b). Serotonergic inhibit  lordosis  activity behaviour  However a v a r i e t y o f 5-HT inhibit  has  l o r d o s i s behaviour  2  generally  been  considered  i n t h e female r a t (Meyerson,  to  1966).  a n t a g o n i s t s have now been r e p o r t e d t o u n d e r some  conditions.  These  drugs  28  include  pizotefin,  cyproheptadine,  as w e l l as c h l o r p r o m a z i n e  (Meyerson,  Everitt,  Agnati,  (Clemens,  1978; M e y e r s o n  mianserin  (Hunter,  spiperone  (Mendelson  consistent in  with  Fredholm  Hole  &  &  the  &  &  1966),  methysergide  Eliasson,  1972),  cinanserin,  Wilson,  1985),  pirenperone,  1985b).  These  of a f a c i l i t a t o r y  Moreover,  role  (Fuxe,  1976),  our hypothesis  facilitatory  metergoline  Jonsson,  Gorzalka,  female sexual behaviour.  that  m e t i t e p i n e , and k e t a n s e r i n ,  of  these  5-HT  and  data role  are  f o r 5-HT  findings  indicate  i s mediated  by  5-HT  2  receptors.  EXPERIMENT 2  The  5-HT  ketanserin potent,  (Mendelson  though  (Experiment the  receptor  2  less  selective &  Gorzalka,  selective  classical  5-HT  and  of the  antagonists  l o r d o s i s behaviour i n  female r a t . These r e s u l t s a r e c o n s i s t e n t w i t h t h e h y p o t h e s i s a t 5-HT  2  receptors  However, w h e r e a s a l l t h e s e receptors,  2  adrenergic remains  they  sites  that  facilitates lordosis  partially The be  a  behaviour.  drugs bind w i t h high a f f i n i t y  also  (Janssen,  the inhibition  bind, 1983).  i n varying Therefore,  been due t o t h e b l o c k a d e  2  the  selective  t o a,  observed  a n t a g o n i s t s , has a t  o f a, a d r e n e r g i c  antagonist  of  5-  possibility  least  receptors.  e r g o l i n e d e r i v a t i v e L Y 5 3 8 5 7 h a s r e c e n t l y been highly  to  degrees,  o f l o r d o s i s t h a t h a s been  f o l l o w i n g t h e a d m i n i s t r a t i o n o f 5-HT  to  pirenperone  1985b) a n d a v a r i e t y  1) have been f o u n d t o i n h i b i t  that a c t i v i t y  HT  antagonists  activity  reported at  5-HT  2  29  receptors  (Cohen,  m a j o r i t y o f 5-HT inactive the  2  Fuller  &  1 9 8 3 ) . However, u n l i k e t h e  a n t a g o n i s t s , LY53857 a p p e a r s t o be  a t a, a d r e n e r g i c  lordosis  Kurz,  response,  sites. then  I f LY53857 i s f o u n d t o i n h i b i t  i t could  concluded  that  the  blockade  of a c t i v i t y  sufficient  to inhibit  lordosis  behaviour.  In  t h e f o l l o w i n g study  LY53857  on  strengthen its  lordosis  LY53857 w i l l agonist  more  a t 5-HT  of  evaluated.  w i t h a s u i t a b l e dose  2  If  2  receptors i s  doses  are  due  of  the  the e f f e c t s of the drug  r e v e r s e d by q u i p a z i n e . F i n a l l y ,  order  somewhat i n t h e p r e s e n c e o r a b s e n c e  the effects  i n females primed w i t h estrogen  of  2  been should  drugs  progesterone  t o d e t e r m i n e w h e t h e r t h e e f f e c t s o f a 5-HT  m i g h t be a l t e r e d by p r o g e s t e r o n e , evaluated  of  5-HT  i n several  i t h a s been f o u n d t h a t t h e e f f e c t s o f s e r o t o n e r g i c  may d i f f e r  to  a n t a g o n i s t , e f f e c t i v e doses of  t h e e f f e c t s o f L Y 5 3 8 5 7 have i n d e e d  r e c e p t o r s , then  of  Moreover, t o  t h a t e f f e c t s o f LY53857  coadministered  quipazine.  2  confidently  varying  5-HT  be a t l e a s t p a r t i a l l y  In  were  be  as a s e l e c t i v e  m e d i a t e d by 5-HT  studies  effects  behaviour  the p o s s i b i l i t y  action  the  relatively  2  antagonist  LY53857  were  and w i t h e s t r o g e n and  progesterone.  Methods  Drugs  LY 53857 a n d q u i p a z i n e m a l e a t e gifts  from L i l l y  respectively.  Pharmaceuticals  and  ( q u i p a z i n e ) were o b t a i n e d a s from  A l l d r u g s were a d m i n i s t e r e d  Miles  Laboratories,  intraperitoneally in  30  approximately  0.3 ml o f  saline  D r u g s were a d m i n i s t e r e d  vehicle,  regardless  of  dose.  blind.  Procedures In  Experiment  determined were  0.3, In  the  i n estrogen-primed,  placed  received  2a,  randomly  into  dose  response  ovariectomized  females.  Experiment  2b,  this  1 hr prior  procedure  A l l females  to behavioural  was r e p e a t e d ;  48 h r a n d 500 Mg p r o g e s t e r o n e In Experiment animals  that  2c,  received  LY53857  F e m a l e s were d i v i d e d r a n d o m l y each  group, animals  6 h r , and e i t h e r  saline,  o r LY53857 p l u s q u i p a z i n e  behaviour  4  0.1,  testing.  however, the  to testing. was  concurrently  into  0,  t h a t r e c e i v e d 10 Mg EB  4 t o 6 hr p r i o r  lordosis  was  Females  10 jug EB 48 h r , a n d e a c h g r o u p r e c e i v e d e i t h e r  e x p e r i m e n t was p e r f o r m e d w i t h new a n i m a l s  to  LY53857  5 g r o u p s o f 11 a n i m a l s .  1, o r 3 mg/kg o f LY35758  Within  to  evaluated  with  groups  of  in  quipazine. 16  animals.  r e c e i v e d 10 Mg EB 48 h r , 500 Mg P 4 1 mg/kg L Y 5 3 8 5 7 , 3 mg/kg q u i p a z i n e ,  1 hr p r i o r  to behavioural  testing.  Results  I n F i g . 2a i t c a n be s e e n t h a t dependent  inhibition  with estrogen. inhibitory  of  lordosis  LY53857 behaviour  produced  of  LY53857  in  F ( 4 , 50) = 1 0.11 , p_<.000l. By u s e o f t h e  dose-  i n females primed  An a n a l y s i s o f v a r i a n c e c o n f i r m e d  effect  a  a  estrogen-primed Newman-Keuls  was d e t e r m i n e d t h a t t h e 0.1 mg/kg d o s e o f LY53857 was  significant females, method,  i t  31  Fig.  2 a . Mean l o r d o s i s  10 jug e s t r a d i o l  q u o t i e n t s ± S.E.M. o f f e m a l e s p r i m e d  benzoate  f o l l o w i n g the a d m i n i s t r a t i o n of  d o s e s o f LY 53857 1 h r p r i o r  to behavioural  testing.  with  varying  32  % 1N3I10H0 SISOQeJOl NV3H  33  Fig. 10  2b. Mean l o r d o s i s uq  estradiol  q u o t i e n t s ± S.E.M. o f f e m a l e s p r i m e d  b e n z o a t e and 500  a d m i n i s t r a t i o n of v a r y i n g doses behavioural  testing.  of  jug p r o g e s t e r o n e f o l l o w i n g LY  53857  1  hr  prior  with the to  34  % INGIlOnO SISOQclOl  35  Fig. 10  2 c . Mean l o r d o s i s q u o t i e n t s ± S.E.M. o f f e m a l e s p r i m e d vq e s t r a d i o l b e n z o a t e  f o l l o w i n g t h e a d m i n i s t r a t i o n of e i t h e r  1 mg/kg LY 53857, 3 mg/kg q u i p a z i n e , LY 53857 a n d q u i p a z i n e , the  with  s a l i n e v e h i c l e 1 hr p r i o r  to behavioural  testing.  or  LORDOSIS QUOTIENT % o  _l  o  I  o  I  o  I  o  I  o  o  I  I  ID '•<  cn  c CD  £ co m ^4  z 13  o  o  o I  I  37  ineffective,  whereas  the  significantly  inhibited  0.3, 1, a n d 3 mg/kg d o s e s o f LY53857  lordosis  behaviour  (p<.05).  In F i g . 2b, i t c a n be s e e n t h a t LY53857 p r o d u c e d a inhibition  of lordosis  progesterone. confirmed of  i n females  The s i g n i f i c a n t  p r i m e d w i t h both e s t r o g e n and  inhibitory  effect  d o s e o f LY53857 was i n e f f e c t i v e . doses  lordosis  of  t h e drug  However,  produced  of  estrogen  a  1  5-HT  effect  a  dose  t h a t t h e 0.1 mg/kg  the  0.3,  significant  2c  again  1,  and  3  i n h i b i t i o n of  show  an  o f LY53857 i n f e m a l e s  However,  quipazine.  significant  F(1,60)=10.126,  and  was  inhibitory primed  with  that  the  i t i s apparent  o f LY53857 was r e v e r s e d by c o a d m i n i s t r a t i o n o f  agonist  2  confirmed  effect  mg/kg  and p r o g e s t e r o n e .  inhibitory the  LY53857  behaviour.  The d a t a d i s p l a y e d i n F i g . effect  of  by a n a l y s i s o f v a r i a n c e , F ( 4 , 5 0 ) = 5 . 3 2 , 2<.0013. By u s e  t h e Newman-Keuls method i t was d e t e r m i n e d  mg/kg  similar  A  2  X  inhibitory  2<.0024. A l t h o u g h  of q u i p a z i n e , a s i g n i f i c a n t  2 a n a l y s i s of v a r i a n c e effect  of  LY53857,  t h e r e was no s i g n i f i c a n t m a i n interaction  between  LY53857  q u i p a z i n e was r e v e a l e d , F ( 1 , 60) = 25. 3 ,p_<. 0001 . By u s e o f t h e  Newman-Keuls method i t was d e t e r m i n e d  that the i n h i b i t o r y  o f LY53857 was s i g n i f i c a n t l y a t t e n u a t e d  by q u i p a z i n e  effect  (p_<.05).  Discussion  In E x p e r i m e n t to  inhibit  drugs  bind  receptors,  1, a v a r i e t y  lordosis with  o f 5-HT  behaviour.  relatively  high  2  a n t a g o n i s t s were  found  However, b e c a u s e a l l o f t h e s e affinity  to  t h e r e was some d o u b t a s t o what r o l e  a-adrenergic  the blockade of  38  a-adrenergic effects.  r e c e p t o r s might  In  have  the present  played  i n producing  experiment,  the  selective  a n t a g o n i s t LY53857 was a l s o f o u n d t o i n h i b i t l o r d o s i s . as was o b s e r v e d Experiment reversed  lordosis-inhibiting  coadministration  of  effect  t h e 5-HT  B e c a u s e LY53857 h a s a v e r y h i g h a f f i n i t y but  a  very  low a f f i n i t y  suggest that the blockade sufficient  5-HT  activity  LY53857  agonist  f o r 5-HT  f o r a-adrenergic of  2  of  2  5-HT  quipazine. receptors, data  receptors  2  in was  r e c e p t o r s , these  at  2  Moreover,  w i t h p i z o t e f i n , k e t a n s e r i n and cyproheptadine  1, t h e by  these  is  to inhibit lordosis.  EXPERIMENT 3 Introduction In  Experiments  cyproheptadine, to  inhibit  1  metitepine,  lordosis  metitepine,  a n d 2, t h e 5-HT  the  coadministration  of  of  in  1985  these  activity  at  5-HT  lordosis  behaviour.  a p p e a r somewhat effects  of  l o r d o s i s . Although inhibition  observed  2  reversed  agonist  quipazine.  that  facilitates  the  expression  the r e s u l t s of these of  of  experiments  reports  on t h e  5-HT a n t a g o n i s t m e t h y s e r g i d e on  t h e r e h a v e been a t behaviour and  by  by  are consistent with the hypothesis  However,  (Meyerson  found  and  non-selective  of l o r d o s i s  methysergide  were  i n c o n s i s t e n t w i t h a number  the  were  Mendelson  receptors  2  drugs  t h e n o n - s e l e c t i v e 5-HT  and  pizotefin,  Moreover, w i t h t h e exception of  These e f f e c t s a r e s i m i l a r t o those Gorzalka  antagonists  k e t a n s e r i n a n d LY 53857  behaviour.  effects  2  least  following  Eliasson,  three  reports  of  the a d m i n i s t r a t i o n of 1977; C l e m e n s ,  1978;  39  Sietnieks,  1985),  facilitate  this  facilitate  lordosis  Zemlan Kohl,  and  i n most c a s e s behaviour. in  Margules,  the  drug  Methysergide  both  been  found  to  h a s been r e p o r t e d t o  ovariectomized  (Ward,  1975; H e n r i k a n d G e r a l l ,  Crowley,  1976; D a v i s a n d  1978; Foreman a n d M o s s , 1978; R o d r i g u e z - S i e r r a a n d  1979;  Davis,  F r a n c k a n d Ward, 1 9 8 1 ; H u n t e r , H o l e a n d W i l s o n , 1985) a n d  ovariectomized-adrenalectomized females and  has  Margules,  1973)  (Zemlan,  , and a f t e r e i t h e r  central  Ward,  Crowley  (Zemlan e t a l .  1973; Ward e t a l . 1975; Foreman a n d M o s s , 1978; F r a n c k a n d Ward, 1981) and  or peripheral administration Gerall,  Davis,  1976; D a v i s  1979; H u n t e r  ( Zemlan e t a l . 1 9 7 3 ; H e n r i k  a n d K o h l , 1978; R o d r i g u e z - S i e r r a a n d  e t a l . , 1985).  Because methysergide  b i n d s a t t h e 5-HT, r e c e p t o r ( P e r o u t k a ,  L e b o v i t z and Snyder,  1981), t h e l o r d o s i s - f a c i l i t a t i n g  methysergide  be  receptors. dual  could  Indeed,  role  receptors of  i s known  of  blockade of c e r t a i n  of  facilitating  effects  this  determine facilitatory  Mendelson  and  Gorzalka.  receptors  2  behaviour,  under  of methysergide  effects  that  5-HT  inconsistency,  conditions  effects  at  However,  reports  of  had  i t was  which  the  the  lordosis-  In order t o  necessary  to  inhibitory  and  occur.  o f m e t h y s e r g i d e have been o b s e r v e d been  treated  p r o g e s t e r o n e . Thus i t seemed p o s s i b l e  2  blockade  inhibits  of methysergide a r e s u r p r i s i n g .  apparent  Inhibitory females  lordosis  the  5-HT,  t o be a v e r y p o t e n t a n t a g o n i s t a t 5-HT  activity  expression  in  the  ( J a n s s e n , 1983). I n view o f t h e e v i d e n c e t h a t  serotonergic  resolve  to  of  s u c h a m e c h a n i s m w o u l d be c o n s i s t e n t w i t h t h e  hypothesis  methysergide  due  effect  with  both  only  estrogen  that the i n h i b i t o r y  and  effect  40  of  methysergide  another  is  possibility  entirely was  progesterone-dependent.  that  the  l e n g t h o f t i m e between t h e  a d m i n i s t r a t i o n o f t h e d r u g a n d t h e commencement testing  is  the  methysergide reported  critical  on l o r d o s i s  that  the  et  serotonin  i n d e t e r m i n i n g t h e e f f e c t of  maximal f a c i l i t a t o r y  effect  antagonist  as  rapidly  administration  as  20  administration  a  30  min  methysergide.  r e p o r t s p u b l i s h e d on t h e e f f e c t s peripheral administration, simple  facilitatory  inhibition  of  administration Eliasson, 1  1977);  of  was  methysergide  in a third  hr (Mendelson  of methysergide then  some  1 hr a f t e r  the  A l t h o u g h t h e r e h a v e been  four  of  methysergide  of  the  et  facilitatory  1  hr  after  1  (Sietnieks,  with  I n two c a s e s an hr  after  the  1985; M e y e r s o n a n d  case, methysergide  was  ineffective  and G o r z a l k a , 1 9 8 5 b ) ; w h e r e a s i n t h e f o u r t h  al.,1985). effect  drug.  observed  i n s t a n c e , the e f f e c t s of methysergide (Hunter  after  r e s u l t s h a v e n o t been c o n s i s t e n t  effect  lordosis  central  Normansell  s i m p l y due t o a r e d u c t i o n o f s e r o t o n e r g i c a c t i v i t y ,  of  there i s  as  to  effect  been  peripherally  (Browne a n d Ho, 1975;  Panksepp, 1985). I f t h e f a c i l i t a t o r y  administration  at  of  i s active  d e g r e e o f f a c i l i t a t i o n s h o u l d be e x p e c t e d w i t h i n  a  i t has  occurs 2 t o 6 hr a f t e r  i n the r a t , methysergide  intraperitoneal  is  behavioural  a l . 1973; D a v i s a n d K o h l , 1 9 7 8 ) . However,  evidence that  and  of  behaviour. I n t e r e s t i n g l y ,  administered methysergide (Zemlan  factor  However,  of  In  the  at  1  latter  methysergide  hr  were  equivocal  experiment,  was  observed  a in  exhibiting  l o w l e v e l s o f r e c e p t i v i t y ; however l o r d o s i s  was r e d u c e d  i n females d i s p l a y i n g  though t h i s  r e d u c t i o n d i d not reach s t a t i s t i c a l  high  levels  of  modest females activity  receptivity,  significance.  41  The  results  of  h a v e been o b s e r v e d the  possibility  peripherally lordosis within  s t u d i e s where t h e e f f e c t s  1 hr a f t e r p e r i p h e r a l a d m i n i s t r a t i o n  of a b i p h a s i c e f f e c t  administered  reflex  , and  may  i n h i b i t s the be  followed  facilitation.  series  possibility  of  time-dependent  methysergide  by  a  initially  inhibition  current  after  the  this  suggest  o f t h e d r u g . I t may be t h a t  methysergide  that  s e v e r a l h o u r s by a  In  of methysergide  observing  of  experiments,  I evaluated the  inhibitory  lordosis  effect  b e h a v i o u r a t vari.ous times  the a d m i n i s t r a t i o n of the drug. Moreover, t o t e s t  possibility  that  the  inhibitory  effects  f o r the  of methysergide are  p r o g e s t e r o n e d e p e n d e n t , t h e d r u g was a d m i n i s t e r e d primed  of  to  estrogen-  females both i n t h e presence and absence of p r o g e s t e r o n e .  Methods  Drugs  M e t h y s e r g i d e b i m a l e a t e ( m e t h y s e r g i d e ) was d i s s o l v e d saline in  and  a d m i n i s t e r e d i n t r a p e r i t o n e a l l y a t a d o s e o f 7 mg/kg  approximately  administered  i n warm  0.3  ml  of  the  vehicle.  Methysergide  was  blind.  Procedures In evaluated  Experiment  3a,  the  effects  i n females primed w i t h w i t h both  progesterone  ( P ) . In t h i s experiment,  of  methysergide  estradiol  were  (EB) a n d  10 nq EB was a d m i n i s t e r e d  42  48 h r , and this  150  steroid  Mg P 3.5 regimen  behaviour,  generally  inhibitory  or  hr p r i o r t o t e s t i n g .  allowing  Behavioural  and  the  effects  the  other group  t e s t i n g was  steroid  treatment. In Experiment  regimen  was  differed  from  because  lordosis  were  similar  t r e a t m e n t s . The  tested  group  received  r e c e i v e d the s a l i n e  vehicle.  t e s t , one  and  the f i r s t  200  min.  observed  experiments  10  quotients  to  those  in  the  Mg  EB  absence  of  s i m i l a r to those produced experiment.  I f the  of the f i r s t  of m e t h y s e r g i d e  by  results  experiment, observed  two e x p e r i m e n t s a f a c i l i t a t i o n  in  one the  of l o r d o s i s  a f t e r t h e a d m i n i s t r a t i o n of m e t h y s e r g i d e ,  the  facilitatory  l i t e r a t u r e . However, effect  were  facilitatory  observed effects  lower doses  similar animals  t e s t i n g , and  control  a n i m a l s . I t was  of m e t h y s e r g i d e might  have  of EB been e m p l o y e d . E x p e r i m e n t s  to the f i r s t received  in  in  these  i n Experiment  150  Mg  P 3.5  possible been  3d a n i m a l s r e c e i v e d  5 Mg EB  that  observed  3c and  hr p r i o r t o  have  behaviour  3d were  two e x p e r i m e n t s . However, i n E x p e r i m e n t  5 Mg EB and  was  results  of m e t h y s e r g i d e may  been masked by t h e m o d e r a t e l y h i g h l e v e l s o f l o r d o s i s  had  The  only i n regards to  females r e c e i v e d  produced,  c o n t r a r y t o much o f t h e r e l e v a n t  that  either  two e x p e r i m e n t s were n o t p r o g e s t e r o n e d e p e n d e n t . In the f i r s t  not  of  lordosis  3b,  it  c o u l d conclude that the e f f e c t s first  lordosis  for  t r e a t m e n t w i t h EB and P i n t h e f i r s t obtained  experience  24 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 i s hormone  chosen  progesterone,  and  drug  t h e n r e p e a t e d a t 30  experiment  and  of  of the i n i t i a l  second  96,72,48,  evaluation  i n t o two g r o u p s  b e h a v i o u r . W i t h i n 10 min methysergide  our  i n d u c e s m o d e r a t e l y h i g h l e v e l s of  facilitatory  a n i m a l s were d i v i d e d  In  3c  lordosis 96,72,48,  43  and  24 h r  prior  observed  in  to  the  testing.  first  q u o t i e n t s were r i s i n g is possible that behavioural  repeated and  3d  was  not  lordosis  i n d r u g - t r e a t e d a n i m a l s a t 200 m i n , and i t  testing  30 and  facilitation  two e x p e r i m e n t s , i n b o t h c a s e s  facilitation been  whereas i n the f i r s t  Although  two  might  have  been  observed  had  c o n t i n u e d b e y o n d 200 m i n . T h e r e f o r e , experiments  behavioural  testing  was  200 min a f t e r d r u g t r e a t m e n t , i n E x p e r i m e n t s  testing  was  repeated  30,  200,  and  300  min  3c  after  treatment. In Experiment  3e,  females r e c e i v e d a s i n g l e  d o s e o f 2 nq  48 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 , a s t h i s d o s e o f e s t r o g e n expected  to  in control were  a n i m a l s . As  tested  initial group  produce o n l y a m i n i m a l l e v e l of l o r d o s i s  for  i n the f i r s t  lordosis  t e s t , one g r o u p  four  received  methysergide  r e c e i v e d the s a l i n e v e h i c l e .  b e h a v i o u r a l t e s t i n g was  r e p e a t e d 30,  these t r e a t m e n t s . In Experiments  As  i n Experiments 200,  and  animals  10 min o f  and  300  was  behaviour  experiments,  b e h a v i o u r , and w i t h i n  EB  the  other  3c and min  the  3d,  after  3a t h r o u g h 3e, m e t h y s e r g i d e  and  s a l i n e were a d m i n i s t e r e d b l i n d .  R e s u l t s : Experiment  3a  L o r d o s i s b e h a v i o u r and  the time-response to methysergide  f e m a l e s a c u t e l y a d m i n i s t e r e d 10 txq EB and It lordosis  is  apparent  in  b e h a v i o u r 30 min  Fig.  3a  150 uq  that methysergide  in  P. inhibited  a f t e r a d m i n i s t r a t i o n ; however, t h i s  44  Fig.  3a. L o r d o s i s q u o t i e n t s  minutes  after  10 m i n u t e s p r i o r  t o , a n d 30 and  treatment w i t h methysergide or the s a l i n e  in ovar iectomized r a t s a d m i n i s t e r e d 150 Mg p r o g e s t e r o n e . F o r e a c h g r o u p ,  10 jug e s t r a d i o l n=l2.  200  vehicle  benzoate  and  100  o  0  SALINE  J  -50  0  50  100  150  MINUTES AFTER TREATMENT  200  250  46  inhibitory slight  e f f e c t was  increase  animals  at  200  significant the  no l o n g e r p r e s e n t a t 200  min.  An  analysis  interval,  interaction  The  There  Newman-Keuls  were  tested  200  significantly  min  after  However, a t no t i m e d i d t h e treated animals d i f f e r  R e s u l t s : Experiment  indicated  was  and  of  no  main  animals  treatment  treatment mean  of  comparisons with  t h a n t h o s e of (p_<.05),  quotients  from those of c o n t r o l  a  effect  w i t h the drug  lordosis  and  treated  l o w e r a t 30 min to  a  the time of  method o f m u l t i p l e  t h e same a n i m a l s when t e s t e d p r i o r when  a  i . e . , t h e l e n g t h of  methysergide  r e v e a l e d t h a t the l o r d o s i s q u o t i e n t s methysergide  variance  F ( 2 , 4 4 ) = 6 . 6 2 , p_< .003,  between  F ( 2 , 4 4 ) = 4.97, p_< .011.  methysergide.  of  of t h e time of t e s t i n g ,  post-methysergide  testing,  Indeed,  of l o r d o s i s b e h a v i o u r o c c u r r e d i n d r u g - t r e a t e d  effect  significant  min.  and  (p_<.05). of  drug  animals.  3b  L o r d o s i s b e h a v i o u r and  the time-response  to methysergide  in  f e m a l e s c h r o n i c a l l y a d m i n i s t e r e d 10 jug EB. An inhibited  examination  of  l o r d o s i s 30 m i n ,  .At 200 m i n ,  Fig.3b  b u t n o t 200 min  testing,  that  after  methysergide  administration.  t h e l o r d o s i s q u o t i e n t s of b o t h groups appear t o have  i n c r e a s e d above t h o s e o b s e r v e d of v a r i a n c e  suggests  revealed  a  i n the i n i t i a l  significant  F ( 2 , 4 4 ) = 1 2.34 ,p_<. 0001 ,  i n t e r a c t i o n between m e t h y s e r g i d e  and  as  t e s t s . An  effect  of  the  well  as  a  the time of  analysis time  of  significant  testing,  47  Fig.  3b. L o r d o s i s q u o t i e n t s  minutes  after  10 m i n u t e s p r i o r t o , and 30 and  t r e a t m e n t w i t h m e t h y s e r g i d e or the s a l i n e  in ovariectomized  rats chronically  benzoate. For each group,  n=12.  administered  10 uq  200  vehicle  estradiol  100  o SALINE ® METHYSERGIDE  Ld  O ZD  O  50-  CO CO  o on  O 25-  0  J  -50  0  50  100  150  MINUTES AFTER TREATMENT  200  250  oo  49  F ( 2 , 4 4 ) = 12.52,p_<.000l . T h e r e Use  of  treated  a t 30 m i n ,  animals  (p_<.05),  treatment min  of  methysergide.  and  lower  (p_<.05).  to  as t h e l o r d o s i s  quotients  than  The  treatment  those  of  R e s u l t s : Experiment  both  h i g h e r t h a n t h o s e of (g<.05),  drug-  groups  prior  the  to  at  control  30  200  group  however they d i d not d i f f e r  from  to treatment.  3c  L o r d o s i s b e h a v i o u r and  the time-response  to methysergide  f e m a l e s a c u t e l y a d m i n i s t e r e d 5 nq EB and examination  inhibited  of  l o r d o s i s q u o t i e n t s of b o t h groups  those of the e x p e r i m e n t a l group p r i o r  An  effect  were l o w e r , t h a n t h o s e of c o n t r o l a n i m a l s a t  were s i g n i f i c a n t l y  prior  no main e f f e c t  t h e Newman-Keuls method c o n f i r m e d t h e i n h i b i t o r y  of m e t h y s e r g i d e  min  was  of  suggests  30  min  that  methysergide In  c o n t r a s t t o the d r u g - t r e a t e d a n i m a l s , the l o r d o s i s q u o t i e n t s  of  animals  behaviour  3c  jug P.  after administration.  control  lordosis  Fig.  150  in  increased  e f f e c t s of m e t h y s e r g i d e increase this with  methysergide  identical. effect  of  significant testing  were no  i n r e c e p t i v i t y was  t i m e . A t 300 min  An the  at  30  m i n . A t 200  min,  inhibitory  longer present, rather a  apparent  slight  i n drug-treated animals at  the l o r d o s i s q u o t i e n t s of a n i m a l s  and  t h o s e o f c o n t r o l a n i m a l s were  analysis time  interaction  of of  variance testing,  indicated  a  treated virtually  significant  F ( 2 , 54) =2 . 95 ,p_<. 04 ,  between m e t h y s e r g i d e  and  , F ( 2 , 5 4 ) = 4 . 4 0 , p < . 0 0 8 . H o w e v e r , t h e r e was  the  and  time  no main  a of  effect  50  Fig. and  3C.  Lordosis  300 m i n u t e s a f t e r  vehicle  in  b e n z o a t e and  q u o t i e n t s 10 m i n u t e s p r i o r  t o , and  30,  treatment w i t h methysergide or the  ovariectomized  rats  administered  150 Mg p r o g e s t e r o n e . F o r e a c h g r o u p ,  5  Mg n=l0.  200,  saline  estradiol  51  % INBIlOnO SISOQdOl  52  of m e t h y s e r g i d e .  The Newman-Keuls  method r e v e a l e d t h a t a t 30 min  the l o r d o s i s q u o t i e n t s of animals a d m i n i s t e r e d methysergide  were  significantly  time  (p_<.05).  The  significantly at  30  min  lower than those of c o n t r o l lordosis  quotients  animals at  o f d r u g - t r e a t e d a n i m a l s were  h i g h e r a t 200 m i n t h a n t h o s e o f t h e (p_<.05);  however,  that  same  a t 200 and 300 min t h e l o r d o s i s  q u o t i e n t s of d r u g - t r e a t e d a n i m a l s d i d not d i f f e r from control  females c h r o n i c a l l y An  examination  of  of methysergide  P  to methysergide i n  a d m i n i s t e r e d 5 nq EB.  F i g . 3d  observed  suggests that the i n h i b i t o r y  i n females a d m i n i s t e r e d both  EB  was a l s o p r e s e n t i n f e m a l e s a d m i n i s t e r e d e s t r o g e n a l o n e .  As i n E x p e r i m e n t apparent increase at  of  3d  L o r d o s i s b e h a v i o u r and t h e t i m e - r e s p o n s e  and  those  animals.  R e s u l t s ; Experiment  effect  animals  in  3 a , an i n h i b i t i o n  drug  treated  in lordosis  of  lordosis  behaviour  was  a n i m a l s a t 30 m i n , w h e r e a s a s l i g h t  b e h a v i o u r was o b s e r v e d  in  control  animals  t h i s t i m e . A t 200 min t h e l o r d o s i s q u o t i e n t s o f d r u g - t r e a t e d  a n i m a l s were h i g h e r t h a n t h o s e o f c o n t r o l  animals;  however,  at  300 min t h e two g r o u p s d i d n o t a p p e a r t o d i f f e r . An  analysis  of v a r i a n c e i n d i c a t e d  the time of  testing,  interaction  between  F ( 2 , 5 4 ) = 3 .07 ,p_<. 035, methysergide  F (2 , 54) = 5. 077 ,p_<. 0037 . methysergide. effect  The  Again,  Newman-Keuls  of methysergide  a s i g n i f i c a n t e f f e c t of  and  there  the was  and  a  time no  significant of t e s t i n g  main  effect  , of  method c o n f i r m e d t h e i n h i b i t o r y  a t 30 m i n , a s t h e l o r d o s i s q u o t i e n t s o f  53  Fig.  3d. L o r d o s i s q u o t i e n t s  and  300 m i n u t e s a f t e r  vehicle  to,  and  30,  t r e a t m e n t w i t h m e t h y s e r g i d e or t h e  i n ovariectomized  estradiol  10 m i n u t e s p r i o r  rats  chronically  b e n z o a t e . For each group,  n=l0.  administered  200, saline 5  ug  100  o  -50  0  50  SALINE  100  150  200  250  MINUTES AFTER TREATMENT  300  350  55  animals  receiving  methysergide  t h o s e o f c o n t r o l a n i m a l s a t 30 lordosis  quotients  of  higher than those  of  however,  and  at  200  min  significantly  (p<„05).  At  the  same  300  animals  min  at  lower  than  min  the  200  d r u g - t r e a t e d a n i m a l s were  t r e a t e d a n i m a l s d i d not d i f f e r R e s u l t s ; Experiment  were  30  significantly min  (p_<.05);  t h e l o r d o s i s q u o t i e n t s of  from those  of  control  drug-  animals.  3e  L o r d o s i s b e h a v i o u r and  the time-response  to methysergide  in  f e m a l e s a c u t e l y a d m i n i s t e r e d 2 jug EB. I t c a n be seen lordosis EB. in  behaviour  Indeed,  receptivity  A  d i d not  is  apparent  at  of l o r d o s i s b e h a v i o u r  subsequent  analysis  30  1-4,  a slight  min.  A  i s apparent  of  more  at  200  t e s t i n g , F ( 3 , 9 0 ) = 7 . 1 5 , p < . 0 0 0 3 . The  significant testing,  interaction  F ( 3 , 9 0 ) = 3 . 21 ,  K e u l s method lordosis  failed  behaviour  to  of  with  control  min  methysergide animals  l o r d o s i s a t 300 min  Subsequent  reveal  dramatic and  300  a  and use  significant  the  time  indicated a  the  time  of  o f t h e Newmandifference  in  b e t w e e n d r u g - t r e a t e d and c o n t r o l a n i m a l s a t  30 m i n . H o w e v e r , a t 200 treated  analysis also  between m e t h y s e r g i d e £<.021.  increase  variance revealed significant  e f f e c t s o f b o t h m e t h y s e r g i d e , F ( 1 , 3 0 ) = 4 . 4 1 , p < . 0 4 2 , and of  inhibit  i n f e m a l e s p r i m e d w i t h a s i n g l e low d o s e o f  i n contrast w i t h Experiments  facilitation min.  i n F i g . 3e t h a t m e t h y s e r g i d e  the l o r d o s i s  were s i g n i f i c a n t l y  (p_<.05). was  quotients  A  significant  also confirmed  (p_<.05).  of  animals  h i g h e r than  those  facilitation  of  56  Fig.  3e.  Lordosis  and 300 m i n u t e s a f t e r vehicle  in  quotients  10 m i n u t e s p r i o r  t o , a n d 30,  treatment w i t h methysergide or the  ovariectomized  rats  e s t r a d i o l benzoate. For each group,  acutely n=16.  administered  200,  saline 2  nq  100  n  o  SALINE  MINUTES AFTER TREATMENT  58  Discussion  The  serotonin antagonist methysergide  reported There  to  have,  following of  facilitate however,  dependent on  to  of  was  the  peripheral  and  3d, i n h i b i t i o n was  was  300 min  the  d r u g was It  after  is  facilitate experiments  In  o b s e r v e d 30  was  that  at  merely  masked  Nonetheless, observed  the  it  is  200  or  clear  methysergide inhibition  is  3a  and  following  after  observed  200  however,  treatment.  300  that  a  min  i n the  of  methysergide  in  the  first  control of  of  No  the a d m i n i s t r a t i o n  inhibitory least of  three  this  may  methysergide.  f o u r e x p e r i m e n t s was  at  four  groups  inhibition  sexually  to  That i s , m o d e r a t e l y  effects the  with  3c min  lordosis not  simply  inhibition  b e h a v i o u r were s i m i l a r t o t h o s e a t 30  consistent  3b,  o r 300  o r 300 m i n , a l t h o u g h i n e v e r y c a s e  p r e s e n t f i n d i n g of  time-  facilitatory  was  of t h e b a s e l i n e l e v e l of r e c e p t i v i t y .  l e v e l s of l o r d o s i s  series  a  methysergide;  a c e i l i n g problem.  i n the f i r s t  o b s e r v e d a t 200  The  of  failure  facilitatory  a t 30 min  a function was  any  in  , b u t n o t 200  3e, f a c i l i t a t i o n  h i g h l e v e l s of r e c e p t i v i t y observed have  act  Experiments  i n e f f e c t i v e 30 min a f t e r  lordosis  to  b o t h i n h i b i t o r y and  the a d m i n i s t r a t i o n  possible  inhibition  of m e t h y s e r g i d e . In E x p e r i m e n t s  t r e a t m e n t . In Experiment  and  of  o b s e r v e d 30, b u t n o t 200 min  administration also  reports  found  behaviour.  lordosis  been  of the d r u g . In the p r e s e n t  produce  lordosis  generally  behaviour i n the female r a t .  several  methysergide  manner  inhibition  after  been  the a d m i n i s t r a t i o n  experiments,  effects  lordosis  has  baseline min.  effect  of  r e p o r t s of  drug.  In  one  59  case,  inhibition  was  o b s e r v e d a s e a r l y a s 30 min  a d m i n i s t r a t i o n of m e t h y s e r g i d e d i r e c t l y of  the  cases,  hypothalamus inhibition  administration Seitneiks, animals  (Clemens,  was  of  1978).  observed  1  In  hr  pre-treated  preoptic  t h e two  after  methysergide,(Meyerson  1985). C o i n c i d e n t a l l y ,  were  i n t o the  following  area  additional  the  and  peripheral  Eliasson,  i n the three  latter  1977;  studies,  w i t h b o t h e s t r o g e n and p r o g e s t e r o n e ,  w h e r e a s i n t h e m a j o r i t y o f s t u d i e s , t h e y were a d m i n i s t e r e d estrogen.  On  t h e b a s i s o f t h e p u b l i s h e d d a t a one m i g h t  that methysergide and  facilitatory  provide  great  is inhibitory  i n i t ' s absence.  However,  the  progesterone The  (Figs.  (Figs.  3b and  inhibition  3 d ) , as i n  been r e p o r t e d t o f a c i l i t a t e of  the  (Zemlan  et a l . ,  drug  occurring  at least presence  as of  o f m e t h y s e r g i d e has  generally  2 t o 6 hr a f t e r  administration  1973; D a v i s and K o h l , 1 9 7 8 ) . H o w e v e r , i n v i e w data  magnitude  unexpected.  methysergide  observed  l o r d o s i s b e h a v i o u r , w i t h the maximal  pharmacokinetic are  the  data  3a and 3 c ) .  peripheral administration  effect  conclude  present  f o l l o w i n g m e t h y s e r g i d e a d m i n i s t r a t i o n was  i n the absence  only  i n the presence of p r o g e s t e r o n e ,  no s u p p o r t f o r t h i s c o n c l u s i o n . The  30 m i n u t e s  the  on  methysergide, The  following peripheral  suggests  that  rapid  (Doepfner,  1962; M e i r and S c h r e i e r ,  latencies  uptake  and  this  distribution  administration  pharmacological  of  of  effects  1976). Indeed  the are  , the  of  of drug  likely maximal  concentration  of m e t h y s e r g i d e  i n t h e b r a i n and o t h e r t i s s u e s i n  the  been  to  rat  has  intravenous  reported  administration  occur  (Doepfner,  i n t r a p e r i t o n e a l l y , the maximal e f f e c t  10  to  15  min  after  1 9 6 2 ) . When a d m i n i s t e r e d  of m e t h y s e r g i d e  on  whole  60  brain  s e r o t o n i n l e v e l s was r e p o r t e d t o o c c u r a s e a r l y a s 30 m i n  after  treatment  behavioural  (Sofia  studies  relatively  and  has  Vassar,  confirmed  fast-acting  intraperitoneally,  1975). that  drug.  methysergide  e a r l y a s 20 t o 30 m i n a f t e r  A  variety  methysergide  When  min  after  the  h a s been e f f e c t i v e c e n t r a l l y a s  administration  of l o r d o s i s observed  administration  of  direct action  o f t h e d r u g on c e n t r a l  in  recent  view  of  l o r d o s i s behaviour that to  evidence  (Mendelson  the i n h i b i t o r y  effect  t h e b l o c k a d e o f 5-HT  (Browne a n d Ho, 1975;  at  least  treatment one  report  that  the  antagonist  diminishes Ferrini  5-HT  that  within  receptors.  5-HT  effect  on  the  and  of  time-response  effectiveness rapidly  of  suggest  peripherally  during  and G l a s s e r ,  has  been  Schreier,  e f f e c t of methysergide  1976).  to  this  levels  has  often reported  been  a  time  the e f f e c t of reported  to  1975),  suggest t h a t a t to  5-HT  of  ( S o f i a and V a s s a r ,  reported  I t may  as  period  1965). S i m i l a r l y ,  1978),  methysergide  the drug  behaviour, t i s s u e l e v e l s of the drug a r e (Meir  I  h a s been r e p o r t e d t o o c c u r f r o m 2 t o 6  1 hr of a d m i n i s t r a t i o n  methysergide  1985b),  o f m e t h y s e r g i d e was due s p e c i f i c a l l y  and d a t a on t h e h a l f - l i f e o f m e t h y s e r g i d e when  Moreover,  antagonists inhibit  2  and G o r z a l k a ,  m e t h y s e r g i d e on b r a i n s e r o t o n i n decline  i n t h e p r e s e n t s t u d y 30  ( Z e m l a n e t a l . , 1973; D a v i s a n d K o h l ,  indicates  (Beretta,  conclude  receptors.  2  administered methysergide after  to  m e t h y s e r g i d e was due t o t h e  A l t h o u g h t h e maximal f a c i l i t a t o r y  hr  is a  administered  N o r m a n s e l l a n d P a n k s e p p , 1 9 8 5 ) . T h e s e d a t a l e a d me that the i n h i b i t i o n  of  times  facilitate  lordosis  substantially  reduced  be t h a t t h e f a c i l i t a t o r y in  the  literature,  and  61  observed  in  the  administration,  present  i s due  study  to  the  200  effect  and of  300  a  min  after  metabolite  of  methysergide. A l t e r n a t i v e l y , the f a c i l i t a t o r y lordosis  2  to  6  hr  enhancement o f 5-HT  2  after  effect  of methysergide  adminstration  a c t i v i t y by l o w ,  may  residual  be  upon  due t o an  levels  of the  d r u g . I t h a s been r e p o r t e d t h a t l o w , b u t n o t h i g h c o n c e n t r a t i o n s of  methysergide  enhance  the excitatory  spontaneously active, neurons  effect  of t h e somatosensory  Bradshaw and S z a b a d i , 1974). M e s c a l i n e , a selectively  to  5-HT  2  receptors,  activity also  (Leysen a t 5-HT  explain  observed  2  and  Tollenaere,  estrogen-primed  (Mendelson  Although  the present  hypothesis that methysergide of  5-HT  receptors,  2  n e u r o t r a n s m i t t e r systems  to  receptors  suggest  that  lordosis  behaviour  exists  (Foreman  controversial  role  receptor  2  of l o r d o s i s 1  hr  after  the  agonist  2  1985b).  results  are consistent  inhibits lordosis  the p o s s i b i l i t y might  might  t h a t h a s been  (3 mg/kg) a n d t h e 5-HT  mediate  has been r e p o r t e d t o h a v e a l o w , b u t dopamine  by 5-HT  ) . The enhancement o f  females  and G o r z a l k a ,  binds  the head-twitch  r e c e p t o r s by l o w l e v e l s o f m e t h y s e r g i d e  c o a d m i n i s t r a t i o n of methysergide quipazine  1982  (Bevan,  agonist,  and produces  t h e marked f a c i l i t a t i o n  in  cortex  5-HT  r e s p o n s e , a b e h a v i o u r b e l i e v e d t o be m e d i a t e d activity  o f m e s c a l i n e on  by  the  remains  the  blockade  that  this effect. significant  with  other  Methysergide affinity  for  ( J a n s s e n , 1983). A l t h o u g h t h e r e i s e v i d e n c e  blockade  of  dopamine  activity  facilitates  ( E v e r i t t e t a l . 1974), c o n t r a r y e v i d e n c e and of  Moss, dopamine  1979). in  Notwithstanding  female  sexual  also the  behaviour,  62  dopaminergic  m e d i a t i o n of the i n h i b i t o r y e f f e c t  c a n n o t be c o m p l e t e l y r u l e d adrenergic  receptors  methysergide.  In  o u t . However,  mediate  contrast  to  the many  methysergide has r e l a t i v e l y l i t t l e 1983).  Finally,  I  1983).  reflect  a  suggest  that  agonist  increase  including  Janssen,  effects  quipazine  receptors  in  explanation  activity,  inhibitory  of  antagonists,  2  (Colpaert  and  Thus t h e i n h i b i t o r y e f f e c t o f m e t h y s e r g i d e  this  and  5-HT  effect  adrenergic a c t i v i t y (Janssen,  (Mendelson  inhibit  reversed  by  and G o r z a l k a ,  and  may  activity.  Research  antagonists  pizotefin  1983),  are  serotonergic  i s unlikely.  i n d i c a t e s t h a t o t h e r 5-HT  (Colpaert  inhibitory  that  n o t e t h a t m e t h y s e r g i d e h a s been r e p o r t e d t o  transitory  laboratory  i t i s unlikely  other  h a v e p a r t i a l a g o n i s t a c t i v i t y a t 5-HT Janssen,  of methysergide  with  I  i n our partial  cyproheptadine  lordosis,  and  these  the coadministration of  1985b).  EXPERIMENT 4  In Experiment dependent  effects  3, I of  observed  methysergide  t e s t i n g o c c u r r e d 30 m i n a f t e r produced 200  appeared  on l o r d o s i s  to  be  facilitation of  t r e a t m e n t , 7 mg/kg o f m e t h y s e r g i d e occurred  t r e a t m e n t , t h e same d o s e o f m e t h y s e r g i d e  of t h i s behaviour. I suggested that methysergide  was  time-  b e h a v i o u r . When  i n h i b i t i o n o f l o r d o s i s . H o w e v e r , when t e s t i n g  min a f t e r  effect  what  due  a n t a g o n i s t , whereas t h e f a c i l i t a t o r y  to  the  i t s action  effect  produced  inhibitory as  a 5-HT  of methysergide  2  may  h a v e been due t o t h e a c t i o n o f a m e t a b o l i t e o f m e t h y s e r g i d e . The  above e x p l a n a t i o n o f t h e t i m e r e s p o n s e  is consistent with the hypothesized f a c i l i t a t o r y  t o methysergide role  of  5-HT  2  63  receptors  in  the  modulation  of l o r d o s i s  however, a n o t h e r e q u a l l y p l a u s i b l e t h a t 30 min tissue found  after  would 200  possibility  considerably after  that  facilitatory  the  apparent of  concentration-dependent  suitably inhibition  dose  that  the  lordosis  the  of  peripheral  of  argue  activity  the  effects  lordosis  behaviour  of a v a r i e t y  both  at  30  and  actually  be  If this  were  administration  of  rather  a  than  30 min  after  treatment.  against  the  hypothesis  out  receptors inhibits  2  that  of doses  min  be  inhibitory  may  a t 5-HT  behaviour. In order to r u l e  examined  in brain  the  facilitation  be o b s e r v e d  be u s e d t o  noted  suggests  methysergide.  of m e t h y s e r g i d e ,  antagonism  fact  methysergide  of l o r d o s i s might  Such a r e s u l t s might  This  time-dependent  effects  following  small  be  h i g h e r than those t h a t would  treatment.  effects  the case, then  e x p l a n a t i o n . I t may  t r e a t m e n t , t h e l e v e l s of m e t h y s e r g i d e  be  min  b e h a v i o u r . There i s ,  and  possibility,  I  of m e t h y s e r g i d e  on  at  200  min  after  treatment.  Method  Drugs Methysergide saline  and  b i m a l e a t e ( m e t h y s e r g i d e ) was  administered intraperitoneally  ml o f t h e v e h i c l e .  M e t h y s e r g i d e was  dissolved  i n warm  in approximately  0.3  administered blind.  Procedures In E x p e r i m e n t  4 a , 80 o v a r i e c t o m i z e d r a t s  received  48 h r p r i o r t o t e s t i n g . T h e s e f e m a l e s were d i v i d e d  lOjug  into 5  EB  groups  64  each of which r e c e i v e d 0.15,  or  prior  0.02  peripheral administration  mg/kg m e t h y s e r g i d e  o r t h e s a l i n e v e h i c l e 30 m i n  t o t e s t i n g . The p r o c e d u r e s f o l l o w e d  identical  to  ovariectomized administered  those  of  o f e i t h e r 7, 1,  i n Experiment  Experiment  4a,  a n i m a l s were u s e d , a n d d o s e s 200 min p r i o r t o b e h a v i o u r a l  4b  except  were  that  35  of methysergide  were  testing.  Results  In e x a m i n i n g F i g . 4a, i t i s apparent high  doses  of methysergide produced  min a f t e r a d m i n i s t r a t i o n levels doses  of of  lordosis  following with  appear  Although treatment  the r e s u l t s of  this  no  methysergide  were f o u n d . B e c a u s e s e v e r a l  highest  dose  of  non-receptive,  that  failure  observe  to  i s , had a  Indeed,  increasing  in  lordosis  methysergide  lordosis  methysergide  females.  3,  nor  o f l o r d o s i s 30  decline  with  experiment  the  low  to decline with  Experiment  significant  neither  facilitation  estrogen-primed  activity  methysergide.  behaviour consistent  to  that  in  the  inhibiting females  appears present  effects treated  of with  were f o u n d t o be c o m p l e t e l y  lordosis  quotients  significant  m e t h y s e r g i d e may have been due a t l e a s t  of  inhibitory partially  0%,  this  effect to  a  of  floor  effect. In  F i g 4b  methysergide 200  min  i t can  produced  after  seen  that  a marked i n c r e a s e  administration  a l o n e . The o t h e r d o s e s ineffective.  be  of  the in  1  mg/kg d o s e o f  lordosis  behaviour  t o females t r e a t e d w i t h  methysergide  An a n a l y s i s o f v a r i a n c e  appear  to  confirmed that  estrogen  have  been  methysergide  65  Fig.  4 a . Mean l o r d o s i s q u o t i e n t s ± S.E.M. o f f e m a l e s p r i m e d  10  Mg  estradiol  benzoate  following  the  intraperitoneal  a d m i n i s t r a t i o n o f v a r y i n g d o s e s o f m e t h y s e r g i d e 30 min p r i o r behavioural  testing.  with  to  METHYSERGIDE: DOSE RESPONSE 30 MINUTES/ ESTROGEN ALONE 100^ 9080f—  LxJ  70-  r—  O  LxJ 20-  10-  i  0  :  1  1  1  2  1  1  1  1  1  3  4  5  6  7  METHYSERGIDE mg/kg  67  Fig.  4b. 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 s p r i m e d  10  Mg  following  estradiol  benzoate  the  with  intraperitoneal  a d m i n i s t r a t i o n o f v a r y i n g d o s e s o f m e t h y s e r g i d e 200 min p r i o r behavioural  testing.  to  68  % lN3llOflO SlSOdcJOl NV3kN  69  produced  a significant effect  after administration the  behaviour  200  F ( 4 , 30) =6.554 ,p_<. 0007. By s u b s e q u e n t  Newman-Keuls  facilitation  upon l o r d o s i s  method  of l o r d o s i s  it  was  was  found  produced  that  by  the  a  min  use o f  significant  1  mg/kg  dose,  (p_<.05). O t h e r d o s e s o f m e t h y s e r g i d e were i n e f f e c t i v e .  Discussion  In  Experiments  inhibitory occur  effects  in  behaviour occurs  of  a "time-  Inhibition,  or  at  occurs  at  200  3  and  min  rather  brain  as  administration the  effect  inhibit  of  of  dose in  after  treatment.  however,  manner.  of  lordosis of  lordosis  peripherally  within it  an  was  a s a 5-HT  hour  in  after  suggested  that  a n t a g o n i s t was  that  in  some  cases  been a d m i n i s t e r e d d i r e c t l y i n t o b r a i n h a s been o b s e r v e d as e a r l y  has  effect  been  and these  found  within  h y p o t h a l a m i c a r e a s (Zemlan  Interestingly,  levels  Because  antagonist  t r e a t m e n t . Areas of the b r a i n  hippocampus  dependent  has been r e p o r t e d t o be most a c t i v e  5-HT  of l o r d o s i s  methysergide  the  methysergide  min, whereas f a c i l i t a t i o n  noted,  has  facilitating  the  a  that  to  behaviour.  be  methysergide facilitation  than  methysergide acting  lordosis  determined  administered  ( S o f i a and V a s s a r , 1 9 7 5 ) ,  I t must  after  a  was  reduction  30  administered methysergide the  i t  peripherally  least at  4  30  i n which the  where tissue,  as  30  administration  to  produce  a  min  are  preoptic  the  lordosisand  e t a l . , 1973; Ward e t a l . , 1 9 7 5 ) ,  amygdala  (Franck  and  areas  the b r a i n  are a l l found  of  min  Ward,  and  1981). i n the  70  f o r e b r a i n . When a d m i n i s t e r e d have  reached  areas  i n both  peripherally,  administered  of  receptors of 5-HT  2  course  peripherally  i n t o t h e b r a i n may s i m p l y r e f l e c t effects  methysergide.  of  regional  Although  the  differences  the blockade  i n the hindbrain  effects  of  as opposed t o d i r e c t l y  i n t h e f o r e b r a i n may f a c i l i t a t e receptors  would  t h e f o r e b r a i n a n d t h e h i n d b r a i n . The  apparent i n c o n s i s t e n c y i n t h e time methysergide  methysergide  i n the  of c e r t a i n  lordosis,  may  inhibit  I  provided  5-HT  the blockade the  lordosis  response.  EXPERIMENT 5  In  Experiments  facilitatory lordosis  1  r o l e f o r 5-HT  behaviour.  hypothesis  through  of  Mendelson  receptors  2  These  4,  data  and  tend  (Middlemiss receptor  and  with  & Fozard,  subtypes  high  and  effects  on  evaluated  thought  Gorzalka,  DPAT  i n the present  Although been  8-OH  to  1 9 8 3 ) . I t may be t h a t  been p r o p o s e d f o r 5-HT, of  The  5-HT  the  lordosis  of role 8-  5-HT,A r e c e p t o r  receptors. in  and  5-HT,B  f u n c t i o n s , as has  the  Therefore, female  the  r a t were  study.  increases i n serotonergic a c t i v i t y to inhibit  agonist  5-HT,A  behavioural 2  5-HT  of a  (8-OH DPAT) a p p e a r s t o b i n d  affinity  serve d i s t i n c t  the modulation  to confirm the dual  Gorzalka.  hydroxy-2-(di-n-propylamino)tetralin selectively  in  evidence  male s e x u a l behaviour  have  generally  (see Mendelson &  1985a f o r r e v i e w ) , t h e a d m i n i s t r a t i o n o f 8-OH DPAT h a s  been r e p o r t e d t o  produce  dramatic  facilitation  of  homotypic  71  sexual  behaviour  Hjorth,  i n t h e male r a t ( A h l e n i u s , L a r s s o n ,  Carlsson,  Hacksell  Lindberg,  & N i l s s o n , 1981;  Wikstrom,  Ahlenius & Larsson,  Larsson,  1984b). I n t e r e s t i n g l y , male  observed  i n female  with  rats, especially  testosterone (Sodersten,  of 8-OH  DPAT upon t h e  behaviour specific the  in  sexual those  of  of  it  seem  lordosis  h a v e be due specific OH  DPAT  unlikely  male  and  can  behaviour,  t h a t the  in  mechanism. T h e r e f o r e ,  & be  DPAT  but  sexual  or  f o r noninhibited  facilitated  female  inhibition  effects  female  8-OH  t o s e d a t i o n , motor impairment,  on  behaviour  i t seemed p o s s i b l e t o c o n t r o l  e x p r e s s i o n of male s e x u a l b e h a v i o u r would  1984a; A h l e n i u s  t h a t h a v e been t r e a t e d  e f f e c t s of t h e d r u g . T h a t i s , i f  expression  Arvidsson,  1 9 7 2 ) . By c o n t r a s t i n g t h e  expression  the female  Sanchez,  Svensson,  rats,  then  of l o r d o s i s some  the it  would  other  non-  i n Experiment 5 the e f f e c t s of  t h e e x p r e s s i o n of m a l e s e x u a l b e h a v i o u r  in  8-  females  were a l s o e x a m i n e d .  METHODS  Drugs  Testosterone and  ( S t e r a l o i d s ) , was  administered subcutaneously  d i s s o l v e d i n warm p e a n u t o i l ml  of t h e  8-hydroxy-2-(di-n-propylamino)tetralin  HBr  (8-OH  Biochemicals  in  concentrations  Inc.)  was  were  dissolved  adjusted  were d e l i v e r e d i n t r a p e r i t o n e a l l y solvent.  Because  i n 0.05  such  warm  vehicle. DPAT,  Research  saline  and  t h a t a l l d o s e s of t h e  in approximately  0.3  ml o f  b r o m i d e s a l t s h a v e l o n g been known t o  The  drug the  depress  72  central  nervous system a c t i v i t y  employed  that  controlled  i o n s upon s e x u a l  dose  of  0.7  dose  of  8-OH  approximated  NaBr was  solution  DPAT  design  was  of bromide  proportionately  to  such that every animal r e c e i v e d a  received.  This  t h e amount d e l i v e r e d  regardless  amount  of  of the  bromide  with the highest  ion  d o s e o f 8-OH  E x p e r i m e n t 5a  I t h a s been h y p o t h e s i z e d inhibitory effect  the  added  a  effects  mg / k g B r " w i t h e a c h t r e a t m e n t ,  DPAT.  an  1975),  f o r any p o t e n t i a l  behaviour.  each drug and c o n t r o l  (Harvey,  5-HT  Gorzalka, receptor  receptor  2  of s e r o t o n i n  on l o r d o s i s  mediates a f a c i l i t a t o r y  1985b). However, t h e e x i s t e n c e  of  s u b t y p e s may n e c e s s i t a t e r e v i s i o n  examine t h i s p o s s i b i l i t y , 5-HT,A  t h a t t h e 5-HT,  the e f f e c t  a g o n i s t , was a s s e s s e d  receptor  mediates  behaviour, effect  whereas  (Mendelson &  5-HT,A  and  5-HT,B  of the hypothesis.  on l o r d o s i s  To  o f 8-OH DPAT, a  i n estrogen-primed,  ovariectomized  rats.  Method  F e m a l e s were d i v i d e d hr  prior  benzoate  to  testing  (EB).  i n t o 7 g r o u p s o f 10 a n i m a l s  each  animal received  or  would  allow  inhibitory  testing,  and  48  10 Mg o f e s t r a d i o l  I n o u r l a b o r a t o r y , t h i s EB d o s e h a s been shown t o  produce moderately low l e v e l s of l o r d o s i s which  ,  each  i n control  t h e e v a l u a t i o n o f any p o t e n t i a l  effects group  of  8-OH  of  DPAT.  animals  Thirty received  animals,  facilitatory  minutes  before  intraperitoneal  73  a d m i n i s t r a t i o n o f e i t h e r 0.01, 0.03, 0.1, 0.3, 1, o r 3 mg/kg OH  DPAT, o r t h e N a B r - s a l i n e  8-  v e h i c l e . 8-OH DPAT was a d m i n i s t e r e d  blind.  Results  A t t h e 0.01 mg / k g d o s e , 8-OH DPAT a p p e a r e d slight  facilitation  higher  doses,  inhibitory significant subsequent  of l o r d o s i s behaviour  8-OH  An  analysis  effect  of  8-OH  comparisons,  of  produce  the  of  variance  lordosis-  confirmed  a  DPAT , F ( 6 , 63) = 1 9.31 , 2<-00°1«  Newman-Keuls  a  ( F i g . 5 a ) . However, a t  DPATappeared t o produce a s t r o n g  effect.  use  to  method  of  B v  multiple  i t was d e t e r m i n e d t h a t t h e 0.01 mg/kg d o s e o f 8-OH  DPAT was i n e f f e c t i v e . However, e a c h d o s e g r e a t e r t h a n produced a s i g n i f i c a n t  inhibition  0.01 mg/kg  of l o r d o s i s behaviour  (2<«05).  E x p e r i m e n t 5b  I n E x p e r i m e n t 5 a , 8-OH DPAT was f o u n d t o behaviour  in  the  role hypothesis finding  of Mendelson and G o r z a l k a .  of t h e s e  Interestingly,  t h a t h a s been r e p o r t e d t o o c c u r  f o l l o w i n g treatment & Larsson,  lordosis  female r a t , r e s u l t s c o n s i s t e n t w i t h t h e dual  i s i n marked c o n t r a s t w i t h t h e d r a m a t i c  sexual behaviour  Ahlenius  inhibit  with  8-OH  DPAT  1984a; A h l e n i u s  (Ahlenius & Larsson,  this  f a c i l i t a t i o n of i n t h e male r a t et  a l . , 1981;  I984ba).  I n view  d i f f e r e n c e s , i t may be u s e f u l t o d e t e r m i n e what e f f e c t s  74  Fig.  5. Mean l o r d o s i s q u o t i e n t s ±S.E.M. o f  primed  with  administration  10 of  propylamino)tetralin testing.  jug  estradiol  varying (8-OH  benzoate,  doses DPAT)  ovariectomized  30  of  following  rats the  8-hydroxy-2-(di-n-  min p r i o r t o b e h a v i o u r a l  MEAN LORDOSIS QUOTIENT %  76  8-OH  DPAT  would  behaviour  in  have  upon  females.  Mounting  s t e r e o t y p i c a l l y male s e x u a l have r e c e i v e d c h r o n i c will  occasionally  (Sodersten, resembling  expression with  behaviour.  of  pelvic However,  treatment with  estrogen  in  some  displayed  f e m a l e s t h a t h a v e been p l a c e d  i sa  female r a t s  that  cases  by  male  with  rats in  behaviour  facilitate  male s e x u a l  found  do i n m a l e s ( A h l e n i u s  to  concluded that  behaviour  the drug a c t s  gender-  dependent  manner.  unlikely  that the i n h i b i t i o n  in  behaviour i n  drug  has  a  i n h i b i t o r y e f f e c t on  females,  as  i t has  been  e t a l . , 1 9 8 1 ) , t h e n i t m i g h t be  in Such  a  behavioura  result  rather  than  i m p a i r m e n t , o r some o t h e r  Therefore,  i n E x p e r i m e n t 5b I e v a l u a t e d  upon  display  of male s e x u a l  a  w o u l d make i t seem  o f l o r d o s i s by 8-OH DPAT i s due  motor  been c h r o n i c a l l y t r e a t e d w i t h  females.  i f 8-OH DPAT were f o u n d t o  toxicity,  the  penile  l o r d o s i s i n females i n  and p o s s i b l y n o n - s p e c i f i c i n f e m a l e s . However,  closely  steroid-primed  E x p e r i m e n t 5 a , t h e n i t c o u l d be c o n c l u d e d t h a t t h e  sexual  female  during  receptive stimulus  a s i t h a d been f o u n d t o i n h i b i t  gender-dependent  testosterone  behaviours  8-OH DPAT were f o u n d t o i n h i b i t male s e x u a l  females,  sexual  thrusting  or  i n t r o m i s s i o n a n d e j a c u l a t i o n c a n be o b s e r v e d  If  male  a t t e m p t t o mount a s e x u a l l y r e c e p t i v e  1972). Indeed, those  the  non-specific  effect.  t h e e f f e c t o f 8-OH  behaviour  to  DPAT  i n females t h a t had  testosterone.  Method  F e m a l e s were d i v i d e d i n t o 3 g r o u p s o f 9 animals  received  daily  injections  of  animals,  100  Mg  and  a l l  testosterone  77  propionate received  ( T P ) . On day 21 o f 1  mg/kg 8-OH vehicle  mg/kg  of  8-OH  Behavioural  treatment,  group  to behavioural  testing  received  receptivity  was  female  in  induced  saline-NaBr  a  Pyrex  a r e n a s and a l l o w e d presentation  of  10 min  to  receptive  parameters analyzed of animals  latency  , i . e . , time  arena.  progesterone  habituate  stimulus  to  the  females. of  4  arena  before  The b e h a v i o u r a l  animals  mounting,  the mount  from p r e s e n t a t i o n of the s t i m u l u s female t o  from  thrusting;  presentation  i n t r o m i s s i o n - l i k e behaviour;  ,  intromission  to  mount  the  first  frequency,  latency display  a n d c o p u l a t o r y e f f i c i e n c y . The d i s p l a y o f m a l e  behaviour  by  f e m a l e was o b s e r v e d  f e m a l e s were s h i f t e d a t 10 min  , of  intromission  frequency,  each  hr  in testing  d i s p l a y i n g i n t r o m i s s i o n - l i k e behaviour,  mount w i t h p e l v i c  time  testing  f e m a l e s were p l a c e d  were t h e number  number  of a s t i m u l u s  i n s t i m u l u s f e m a l e r a t s by t h e  t o t e s t i n g . The T P - t r e a t e d  i.e.,  the  presentation  a d m i n i s t r a t i o n o f 10 /jg EB 48 h r a n d 500 uq  first  group  testing.  involved  f e m a l e t o an e x p e r i m e n t a l  the  first  Testing  Behavioural  prior  the  DPAT, t h e s e c o n d g r o u p r e c e i v e d 0.1  DPAT, a n d t h e t h i r d  30 m i n p r i o r  Sexual  TP  sexual  f o r 30 m i n a n d s t i m u l u s  intervals.  R e s u l t s and D i s c u s s i o n The  data  d i s p l a y e d i n Table  1 show t h a t t h e  of 8-OH DPAT e n h a n c e d t h e e x p r e s s i o n females  treated  with  administration  o f male s e x u a l b e h a v i o u r  testosterone. This f a c i l i t a t i o n  a p p a r e n t i n t h e i n c r e a s e d mount f r e q u e n c y ,  in  was most  a n d i n t h e number o f  78  TABLE 1. The (8-OH  effects  DPAT)  on  ovar i e c t o m i z e d testosterone  the  of  8-hydroxy-2-(di-n-propylamino)tetralin  expression  females  propionate.  of  chronically  male  sexual behaviour  administered  100  by jug  T H E E F F E C T S O F 8-OH DPAT ON T H E EXPRESSION O F M A L E S E X U A L BEHAVIOR BY O V A R I E C T O M I Z E D F E M A L E S C H R O N I C A L L Y ADMINISTERED T E S T O S T E R O N E PROPIONATE  Behavioral Parameter Number of animals mounting Number of animals intromitting Mount  0.1 mg/kg 8-OH DPAT  Control  1.0 mg/kg 8-OH DPAT  3  5  8  0  2  3  1312.89 ± 206.0  978.44 ± 285.6  579.11 ± 236  latency Intromission  latency Mount frequency Intromission frequency Copulatory efficiency  1800.00 ±  0.00  1575.33 ±  1.91  1287.22 ± 256  0.08 ±  0.04  0.53 ±  0.2  0.56 ±  0.15  0.00 ±  0.00  0.01 ±  0.01  0.03 ±  0.02  0.00 ±  0.00  0.01 ±  0.01  0.04 ±  0.02  Values are means ± S.F..M. All latencies are in seconds; frequency scores are per minute; and copulatory efficiency scores are calculated from the formula 1/1 +M, where I = number of intromissions and M = number of mounts in 30 min.  80  animals  showing  a l s o produced animals  mounting  in  the  number  of  i n t r o m i s s i o n b e h a v i o u r , a n d t h i s was r e f l e c t e d  to a s m a l l degree i n the  The  T r e a t m e n t w i t h 8-OH DPAT  a small, but notable increase  showing  efficiency  behaviour.  intromission  latency  and  copulatory  scores. s i g n i f i c a n c e o f t h e e f f e c t s o f 8-OH DPAT on t h e number  of a n i m a l s d i s p l a y i n g mounting and e v a l u a t e d by a C h i s q u a r e mounting  animals  intromitting  t e s t . The d i f f e r e n c e s  approached  behaviour  i n t h e number o f  significance,  x (2)=5.83, 2  p<.0542.The o t h e r p a r a m e t e r s  were e v a l u a t e d i n s e p a r a t e  of v a r i a n c e f o r i n d e p e n d e n t  groups.  significantly However,  8-OH  was  DPAT  was  analyses found  to  i n c r e a s e t h e mount f r e q u e n c y , F ( 2 , 24) =3.39, p_<.05.  subsequent  use  of  the  Newman-Keuls  method d i d not  r e v e a l a d o s e d e p e n d e n t e f f e c t o f 8-OH DPAT.  General Discussion In Experiment DPAT was f o u n d females.  5a, t h e h i g h l y s e l e c t i v e  t o suppress  l o r d o s i s behaviour  than  those s u f f i c i e n t  in  females  to toxicity  suggest  that  serotonin  the  o r motor impairment. classical  a r e mediated  f a c i l i t a t e the at  doses  even  t o e l i m i n a t e l o r d o s i s . The l a t t e r  d a t a w o u l d i n d i c a t e t h a t t h e e f f e c t o f 8-OH simply  8-OH  i n estrogen-primed  H o w e v e r , t h e d r u g was f o u n d t o s l i g h t l y  e x p r e s s i o n of male s e x u a l b e h a v i o u r higher  5-HT,A a g o n i s t  DPAT  Together,  lordosis-inhibiting  at least partially  was  not  these  results  effects  by a c t i v i t y  due  of  a t 5-HT,A  receptors. A v a r i e t y o f 5-HT a g o n i s t s , i n c l u d i n g LSD ( E v e r i t t 1975),  N,N-dimethyltryptamine,  and  et  a l . ,  5-methoxy-N,N-  81  dimethyltryptamine  (Fuxe e t a l . , 1 9 7 6 ) , have  been  inhibit  behaviour. A recent  i n d i c a t e s t h a t LSD  lordosis  binds t o both Frazer,  5-HT,A  and  1 9 8 4 ) . The a g o n i s t s  N,N-dimethyltryptamine  5-HT,B  report  receptors  et  also  a l , 1984).  possibility  of  an  (Sills,  to  Wolfe  &  5-methoxy-N,N-dimethyltryptamine and bind  to  s u b t y p e s ; a l t h o u g h , w i t h some s e l e c t i v i t y (Sills  reported  These  data  inhibitory  both  5-HT,  receptor  f o r t h e 5-HT,A s u b t y p e  are consistent  effect  of  with  activity  the  a t 5~HT,A  r e c e p t o r s on l o r d o s i s b e h a v i o u r . It  i s of i n t e r e s t t o  note  that  a g o n i s t s t h a t h a v e been r e p o r t e d LSD  (Everitt  et  a  number  to inhibit  of  the  lordosis , including  a l , 1975), N , N - d i m e t h y l t r y p t a m i n e ,  N , N - d i m e t h y l t r y p t a m i n e , a n d p s i l o c y b i n (Fuxe e t a l , also  been  reported  to  r a t s when a d m i n i s t e r e d effects result  of of  (Everitt  the  the  low  agonists  inhibition  and some  doses.  These  facilitatory  of  t o be t h e  serotonergic  activity  e t a l , 1 9 7 6 ) . The s y n a p s e i s t h e releases  i t s neurotransmitter  neuron  located  on  (postsynaptic), the  serotonergic  some  serotonin  neuron and  itself releases  s e r o t o n i n , most o f t h a t s e r o t o n i n r e a c h e s t h e t a r g e t activates the of t h i s  neruon and  have  l o r d o s i s i n estrogen-primed  ( p r e s y n a p t i c ) . When t h e s e r o t o n e r g i c n e u r o n f i r e s its  1976)  n e r u o n . A l t h o u g h most s e r o t o n i n r e c e p t o r s a r e  target  are  5-methoxy-  h a v e been c o n s i d e r e d  where a n e u r o n  target  l o c a t e d on t h e receptors  5-HT  a l , 1975; F u x e  point of contact onto  i n very  presynaptic  et  facilitate  5-HT,  postsynaptic  serotonin  receptors.  neuron  However,  s e r o t o n i n may d i f f u s e b a c k t o w a r d t h e s e r o t o n e r g i c  bind  to  serotonin receptors  presynaptic  (autoreceptors)  receptors.  When  presynaptic  are activated, the result i s  82  a  decrease  i n the f i r i n g  r a t e of t h e s e r o t o n e r g i c neuron and a  d e c r e a s e i n t h e amount o f s e r o t o n i n This process, one  means  firing  by  which  authors  has  reported  depolarization-induced  only  that  can r e g u l a t e  DPAT  8-OH  of  DPAT  inhibits  Pichat,  Glowinski  1984). I n t h e p r e s e n t  8-OH  I f presynaptic  with  autoreceptors.  DPAT  the tissue  &  Hamon,  to  (Rogawski  &  the  inhibition  conclusion  of  personal  presynaptically  inhibit  1979).  reported e f f e c t s of l i s u r i d e inhibitory  serotonergic  (Sietnieks,  As  highly  at  serotonergic with  prazosin  5-  activity  8-OH DPAT, t h e o n l y  drugs are  have  been  simply  dominant  effects.  5-HT,A  haloperidol  lordosis  behaviour  r e c e p t o r s . H o w e v e r , i t h a s been  t h a t some e f f e c t s o f 8-OH DPAT a r e a t t e n u a t e d antagonist  selective  c o m m u n i c a t i o n ) , h a s been  I h a v e s u g g e s t e d t h a t 8-OH DPAT i n h i b i t s acting  data a r e  I t may be t h a t t h e p o s t s y n a p t i c  l o r d o s i s - i n h i b i t i n g e f f e c t s of these over any p r e s y n a p t i c  activity  then the present  upon l o r d o s i s b e h a v i o u r  1985).  were  t h a t 8-OH DPAT i s i n a c t i v e a t  ( S.J. Peroutka,  Aghajanian,  experiment,  upon l o r d o s i s b e h a v i o u r  However, l i s u r i d e , a n o t h e r  agonist  reported  by  their  presynaptically  3  se f a c i l i t a t e s l o r d o s i s b e h a v i o u r ,  consistent  HT,A  i s b e l i e v e d t o be  r e l e a s e of [ H]5-HT from c o r t i c a l  (Middlemiss,  effects  inhibitory. per  synapse.  h o w e v e r , a n o t h e r g r o u p h a s f o u n d t h e d r u g t o be i n a c t i v e  at autoreceptors the  8-OH  the  r e m a i n s c o n t r o v e r s i a l . One g r o u p  (Gozlan, Mestikawy, Bougoin, H a l l , 1983);  neurons  that  serotonergic a c t i v i t y  at  inhibition,  serotonergic  r a t e s . The p o s s i b i l i t y  inhibits of  known a s p r e s y n a p t i c  released  and  the  a,  (Tricklebank, F o r l e r & Fozard,  by  the  adrenoceptor  reported dopamine  antagonist  1 9 8 5 ) . T h u s , i t c o u l d be  83  that  the i n h i b i t o r y  are  mediated  by  e f f e c t s o f 8-OH DPAT on  remains  controversial.  lordosis  facilitation  dopamine  antagonist  For  pimozide  controversy,  female  example,  following  dopamine a g o n i s t apomorphine  the i n h i b i t o r y  (Everitt  et  central  the  a l . , 1975) o r t h e of  of dopaminergic m e d i a t i o n of  the r o l e of a c t i v i t y  phenoxybenzamine  in  However,  i n another  estrogen-primed  phenoxybenzamine  or  case  was  estrogen 1985).  and  females the  a  -adrenergic  ill-defined.  I n one  to  facilitate  (Foreman & M o s s ,  peripheral  1978b).  administration  of  p r a z o s i n was r e p o r t e d t o be i n e f f e c t i v e i n  progesterone  Notwithstanding the  at  reported  e s t r o g e n - p r i m e d females, and i n h i b i t o r y  literature,  either  of  a d m i n i s t r a t i o n of t h e a - a d r e n e r g i c b l o c k e r s  lordosis  Beyer,  with  reports  e f f e c t s o f 8-OH DPAT on l o r d o s i s b e h a v i o u r c a n n o t  phentolamine or  both  are  behaviour  (Foreman & M o s s , 1 9 7 9 ) . I n v i e w  r e c e p t o r s i n female s e x u a l behaviour remains the  sexual  there  treatment  the p o s s i b i l i t y  be r u l e d o u t . S i m i l a r l y ,  case  behaviour  d o p a m i n e r g i c o r a, a d r e n e r g i c m e c h a n i s m s . The  r o l e of dopamine i n t h e m o d u l a t i o n of  this  lordosis  possibility  i n females t r e a t e d  (Fernandez-Guasti,  the  contradictions  remains  with  Larsson &  within  the  t h a t t h e e f f e c t s o f 8-OH  DPAT on l o r d o s i s were m e d i a t e d by an a d r e n e r g i c s y s t e m .  EXPERIMENT 6  In Experiment found t o i n h i b i t the  5, t h e s e l e c t i v e  lordosis behaviour. I t  lordosis-inhibiting  least partially  5-HT,A a g o n i s t 8-OH DPAT was  effects  by a c t i v i t y  of  a t 5-HT,A  was  hypothesized  that  serotonin a r e mediated a t receptors.  The  putative  84  anxiolytic  drugs  buspirone,  1985)  and g e p i r o n e  have  a l s o been f o u n d t o b i n d  t o 5-HT,A r e c e p t o r partial Eison was  TVX Q 7821 ( i p s a p i r o n e )  (personal communication, Dr.  sites.  (Peroutka,  S.J.  s e l e c t i v e l y and w i t h h i g h  T h e s e d r u g s may  a g o n i s t s a t 5-HT,A r e c e p t o r s  a c t as  (Smith  agonists  i n t e r e s t t o d e t e r m i n e what e f f e c t t h e a d m i n i s t r a t i o n o f  DPAT  i n females t h a t had r e c e i v e d estrogen  alone. I n t e r e s t i n g l y ,  i s evidence  in  the l i t e r a t u r e  For  example,  lordosis  behaviour  and t h e i n h i b i t o r y  (Sietnieks  e f f e c t s of  Meyerson,  i n t e r a c t i o n s between t h e s e the  effects  of  serotonergic  these  a n i m a l s t h a t h a d been a d m i n i s t e r e d  drugs  LSD  1980, 1 9 8 3 ) .  Experiment 6 t h e e f f e c t s of buspirone,  progesterone,  and  and  with  h a s been r e p o r t e d t o  ipsapirone,  g e p i r o n e upon l o r d o s i s b e h a v i o u r were e v a l u a t e d .  possible  evaluated  t h a t t h e e f f e c t s o f some  progesterone  enhance b o t h t h e f a c i l i t a t o r y  Therefore,in  were  d r u g s on l o r d o s i s may be a l t e r e d by t r e a t m e n t  progesterone.  and  behaviour.  I n E x p e r i m e n t 5, t h e e f f e c t s o f 8-OH  serotonergic  on  or  a n d P e r o u t k a , 1986;  t h e s e 5 - H T 1 A - s e l e c t i v e d r u g s w o u l d h a v e on l o r d o s i s  there  affinity  e t a l . , 1 9 8 6 ) . I n v i e w o f t h e r e s u l t s o f E x p e r i m e n t 5, i t of  only  Peroutka)  Because of  agonists  and  were e v a l u a t e d i n  e i t h e r estrogen,  or  estrogen  progesterone.  Methods  Drugs Buspirone obtained  as  ipsapirone  HC1 ( b u s p i r o n e )  gifts  from  the  and g e p i r o n e H C l (gepirone) Bristol-Meyers  Company,  f r o m M i l e s L a b o r a t o r i e s . A l l d r u g s were  as  were was  administered  85  intraperitoneally  i n a p p r o x i m a t e l y 0.3  ml  of  saline  vehicle.  D r u g s were a d m i n i s t e r e d b l i n d .  Procedures In  Experiment  6a,  g e p i r o n e , and i p s a p i r o n e females.  A l l females  Experiment animals  drug  were  dose  0,  45  0.1,  min  10  behavioural  received  prior  500  uq  0.3,  6b, i d e n t i c a l p r o c e d u r e s  also  responses  determined  received  groups r e c e i v e d e i t h e r experimental  the  EB 48 h , a n d e a c h or  3  mg/kg  behavioural  were  buspirone,  i n estrogen-treated  1,  to  to  followed  jug p r o g e s t e r o n e  of 5  of  the  t e s t i n g . In except  4-6  h  that  prior to  testing.  Results In Experiment  6a, i n which  females  r e c e i v e d EB a l o n e ,  lower  doses of b u s p i r o n e , i p s a p i r o n e , and gepirone produced  increases  in  (Fig.  lordotic activity.  At t h e h i g h e s t dose of each drug  lordosis  behaviour  was  variance  confirmed  significant  F ( 4 , 7 0 ) = 6.06,2<.0003;  virtually  ipsapirone,  eliminated. effects  of  gepirone  t h a t 0.1  ipsapirone  (p_<.05)  facilitated  lordosis  i n h i b i t e d by 3 mg/kg o f e i t h e r  buspirone  (p_<.05). and  (p_<.05)  mg/kg  However, t h e apparent  inhibitory  effect  of  method i t was  and  0.3  mg/kg  (p_<.05)  were  or  effect not  ipsapirone  of buspirone statistically  signi f icant. In  females  and  b e h a v i o u r . L o r d o s i s was  facilitatory  gepirone  of  buspirone,  F(4,70)=9.53,p_<.000l ;  g e p i r o n e , F ( 4 , 5 5 ) = 5 . 7 6 , p < . 0 0 0 7 . By t h e Newman-Keuls determined  Analyses  6),  t r e a t e d w i t h EB a n d p r o g e s t e r o n e ,  increasing  86  Fig. with  6. 10 uq  benzoate  Mean l o r d o s i s q u o t i e n t s e s t r a d i o l benzoate and  500  uq  (EB),  or  progesterone  a d m i n i s t r a t i o n of v a r y i n g doses gepirone.  ± S.E.M. o f f e m a l e r a t s p r i m e d  of  with  10  (EB+P),  buspirone,  uq  estradiol  following  the  ipsapirone,  or  MEAN LORDOSIS QUOTIENT % o « 8 8 S S 8 3 S 8 §  1  1  1  1  1  1  '  1  1  1  1  1  1  1  1  1  1  1  1  MEAN LORDOSIS QUOTIENT %  O S 8 8 S 8 8 3 8 8 8  1  o 8 8 8 S 8 8 3 § 8 § I  MEAN LORDOSIS QUOTCNT %  I  1  -1——1  I  I  U  t  I  I  o 6 8 8 £ 8 8 3 8 8 §  I  I  I  I  o S 8 8 S 8 8 3 8 8 S !  '  1  1  1  1  1  I  I  I  I  I  I  i'  o s 8 8 S 8 8 3 8 8 § I  I  f  88  animals  showing  gepirone, display  and of  mounting  ipsapirone  lordosis  behaviour, resulted  behaviour  confirmed the i n h i b i t o r y e f f e c t s P<.0001;  ipsapirone  F(4,50)=22.55, determined  0.3  l o r d o s i s behaviour were s t i l l 1.0 still  the  mg/kg  of  buspirone  p_<.000l;  buspirone  and  method  was p r o d u c e d  1.0 a n d 3.0 mg/kg  buspirone  determined  by  3.0  that  (p_<.05), a n d  mg/kg  (p_<.05), a n d f u r t h e r i n h i b i t i o n  by t h e 3.0 mg/kg d o s e  i t was inhibited  ipsapirone  The 0.3 a n d 1.0 mg/kg d o s e s o f g e p i r o n e a l s o  l o r d o s i s behaviour  gepirone,  significantly  i n h i b i t e d l o r d o s i s behaviour  further inhibition  reduced  ,F(4 ,55) = 19.86,  Newman-Keuls  (p_<.05), a n d t h a t  ipsapirone  buspirone,  ( F i g . 6 ) . Analyses of variance  more e f f e c t i v e ( p < . 0 5 ) . I t was a l s o  mg/kg  (p_<.05).  By  of  progressively  F ( 4 , 50) =20 . 62 ,  £<.0001.  that  in  doses  inhibited  was  produced  (p_<.05).  Discussion In  Experiment  6,  the  highest  i p s a p i r o n e , and g e p i r o n e v i r t u a l l y lordosis  behaviour  in  females  doses  eliminated treated  receptors  inhibits  lordosis.  i p s a p i r o n e a n d g e p i r o n e were f o u n d these  animals.  Facilitatory  been a t t r i b u t e d t o a r e d u c t i o n presynaptic present  results  ipsapirone 1986)  inhibition are  (Dourish  consistent  5-  doses  of  lordosis  in  and with  activity  Meyerson, this  reduce  activity  have  through  1983).  The  explanation,  as  a l . , 1986) a n d g e p i r o n e  h a v e b o t h been f o u n d t o  at  lower  facilitate  i n serotonergic  of  e s t r o g e n . These  e f f e c t s o f some 5-HT a g o n i s t s  (Sietnieks  et  display  that a c t i v i t y  However, to  buspirone,  the  with  r e s u l t s are consistent with the p o s s i b i l i t y HT,A  of  (Eison et a l . , in  the  dorsal  89  raphe. Although et  buspirone  a l . , 1986),  possible profile  reduces  the drug  that  some  serotonergic a c t i v i t y  d i d not  component  facilitate  peculiar  lordosis.  to  the pharmacogical  unlike  f o r dopamine r e c e p t o r s ( P e r o u t k a , 1986;  al.,  8-OH  1986).  lordosis  activity  DPAT  also  inhibited,  i n e s t r o g e n - t r e a t e d females  buspirone  in  the  present  was o b s e r v e d  Eison  et  but d i d not f a c i l i t a t e  (see Experiment  5) As  with  study, a small increase i n l o r d o t i c  a t t h e l o w e s t d o s e o f 8-OH  DPAT,  however  i n c r e a s e was n o t s i g n i f i c a n t . Of  particular  differences  interest  in  administered as  to  females  opposed  been  ineffective  found  to inhibit  lordosis  in  treated  either  animals  l o r d o s i s behaviour  are the  I t h a s been h y p o t h e s i z e d behaviour  in  to  5-HT,A simply  those observed  primed  with  serotonergic activity these  and  data  alone. or  females  & Pfaff, agonist  reduced  by  1974). may  levels  enhances reducing Thus,  the  have  restored  of  lordosis  i n females w i t h estrogen alone. In  estrogen  alone,  may be o f l i t t l e  suggest  and  lordosis  progesterone  estrogen-primed  the  serotonergic activity  estrogen  facilitated  that  administration  of  with  i n animals t r e a t e d with both  (Kow, M a l s b u r y  animals  study  t r e a t e d w i t h e s t r o g e n a l o n e were  serotonergic a c t i v i t y  behaviour  present  t o those t r e a t e d w i t h estrogen  Doses of t h e s e drugs t h a t had  steroids.  the  i n the e f f e c t s of b u s p i r o n e , i p s a p i r o n e and gepirone  progesterone  hand,  For  i p s a p i r o n e and g e p i r o n e , b u s p i r o n e p o s s e s s e s a  high a f f i n i t y  when  It is  o f b u s p i r o n e masked t h e a p p e a r a n c e o f f a c i l i t a t i o n .  example,  this  (Dourish  that  small  increases  in  c o n s e q u e n c e . On t h e o t h e r  progesterone  may e n h a n c e t h e  90  e f f e c t s of a c t i v i t y consistent  with  a t 5-HT,A  the  receptors.  report  This  possibility  that both the l o r d o s i s - i n h i b i t i n g  e f f e c t s of l a r g e doses and t h e l o r d o s i s - f a c i i i t a t i n g small  doses  LSD  are  enhanced  ( S i e t n i e k s and Meyerson, its  by t r e a t m e n t w i t h  (Engel  t o enhance t h e l o r d o s i s - f a c i l i t a t i n g  HT,A a g o n i s t s  was n o t a p p a r e n t  min  i n the present  been  of  study,  although i t of  administered.  The e f f e c t i v e n e s s o f b u s p i r o n e ,  i p s a p i r o n e , a n d g e p i r o n e 45  after  present  induce  administration  symptoms  Peroutka,  of  the  and  substrate  serotonin  serotonergic  appears  syndrome a t t h i s  be n o t e d ,  however,  time that  fail  to to  (Smith and 8-OH  DPAT  l o r d o s i s b e h a v i o u r a t t i m e s and doses a t which i t  Peroutka, of  study  t h a t b u s p i r o n e and i p s a p i r o n e  1986). I t s h o u l d  effects  in  d o e s n o t i n d u c e symptoms o f s e r o t o n i n Smith  in  e f f e c t s o f 5-  i t may have been o b s e r v e d h a d s m a l l e r d o s e s  contrast with the report  also  progesterone  e t a l . , 1986). E v i d e n c e of t h e a b i l i t y  p r o g e s t e r o n e o r t h e 5-HT,A a g o n i s t s  of  h i g h a f f i n i t y t o 5-  progesterone  is possible that  effects  1980, 1 9 8 3 ) . A l t h o u g h n o n - s e l e c t i v e  b i n d i n g , LSD i s known t o b i n d w i t h v e r y  HT!A r e c e p t o r s  is  syndrome  1986). These d a t a  lordosis  behaviour  stimulation  than  may  the  (Experiment  5;  suggest that t h e n e u r a l be  more  substrate(s)  sensitive  to  of s e r o t o n i n  syndrome.  EXPERIMENT 7  The ipsapirone behaviour  selective and in  5-HT,A  gepirone  females  agonists have  primed  been either  8-OH  DPAT,  buspirone,  found t o i n h i b i t  lordosis  with  or  estrogen,  with  91  estrogen 5-HTTA  and progesterone.  receptors mediate  l o r d o s i s behaviour. found data  to  mediate  that  lordosis-facilitating  lordosis  activity  serotonin  at  S-H^A  lordosis.  Until  available  that  These may  the  activity  of  certain  drugs  5-HT,A that  receptors  block  the  inhibits  effects  of  r e c e p t o r s w o u l d be e x p e c t e d t o f a c i l i t a t e  very  recently,  there  have  a c t s e l e c t i v e l y a s 5-H^A  5-HT,A  were  autoreceptors  been  receptor  no  antagonist  (Yocca,  drugs  antagonists.  R e c e n t e v i d e n c e i n d i c a t e s t h a t t h e new d r u g BMY 7378 a c t s selective  on  pathways.  postsynaptic then  serotonin  primed females.  5-HT,A  in  serotonergic  behaviour,  of  postsynaptic  e f f e c t s of s e r o t o n i n . O s t e n s i b l y ,  reductions  at  effects  i n estrogen  somato-dendritic  lordosis-inhibiting  suggest that  doses, i p s a p i r o n e and gepirone  lordosis  t h i s w o u l d be due t o  If  inhibitory  At lower  facilitate  suggest  These d a t a  Hyslop,  as  Smith  a &  Maayani,1987). In t h e f o l l o w i n g e x p e r i m e n t s I w i l l BMY 7378 on l o r d o s i s b e h a v i o u r or w i t h estrogen  and  evaluate  the e f f e c t s of  i n females primed with  estrogen,  progesterone.  Methods  Drugs BMY  7378  was  obtained  Company. The d r u g was d i s s o l v e d intraperitoneally  as a g i f t  i n warm s a l i n e a n d  i n approximately  d r u g was a d m i n i s t e r e d  blind.  from t h e B r i s t o l - M e y e r s administered  0.3 ml o f t h e v e h i c l e . The  92  Procedures In Experiment  7,  o v e r a p e r i o d of f i v e w e e k l y mg/kg  of  testing  the  r e c e i v e d 10 uq  10 f e m a l e s  tests,  experimental  drug  either 30  0,  min  EB  0.04,  prior  i d e n t i c a l procedures  4-6  h  prior  and,  1, or  5  to behavioural  were f o l l o w e d e x c e p t  uq p r o g e s t e r o n e  a l s o r e c e i v e d 500  h  0.2,  i n a repeated measures d e s i g n . For a second  females,  48  group of that  to  10  animals  behavioural  testing.  R e s u l t s and D i s c u s s i o n  Females  administered  estrogen  somewhat more r e s p o n s i v e t h a n alone.  and  females  t o BMY  7378 a p p e a r e d whereas the lordosis animals  7378 was  similar  to produce s l i g h t highest  dose  behaviour. treated  responsive  received  An  with  than  of  i n each group.  BMY  analysis estrogen  those  7378 of  and  that  effect  d o s e s o f BMY  increasing  found of  significant  BMY  appeared  variance  estrogen  confirmed  o f BMY  7378 were f o u n d n o t t o be s i g n i f i c a n t  with  estrogen  e f f e c t s were f o u n d  i n females  inhibit  were  that more  alone,  significant  treatment  t o examine the  s t e r o i d treatment  progesterone.  to  7378, F (4 , 72) = 4. 57 ,p_ <.003.  7378, d a t a were p a r t i t i o n e d  and  a  BMY  behaviour,  estrogen  e f f e c t s of both s t e r o i d  e f f e c t s of dose w i t h i n each  d o s e s of  confirmed  progesterone  received  analysis also  of  Low  increases in lordosis  F(1 , 18)=4.76,p_<.04. The  dose  that  appeared  H o w e v e r , t h e d a t a d i s p l a y e d i n F i g . 7 show t h a t t h e d o s e  response  Having  progesterone  However,  group.  The  i n females  simple effects treated  significant  treated with estrogen  alone  and  dose  93  Fig. 10  7. Mean l o r d o s i s  jug e s t r a d i o l b e n z o a t e o r 10 Mg e s t r a d i o l  progesterone following BMY  q u o t i e n t s ± S.E.M. o f f e m a l e s p r i m e d  7378 30 min p r i o r  the a d m i n i s t r a t i o n of to behavioural  testing.  b e n z o a t e and varying  with 500  doses  Mg of  % JLNBIiOnt) SISOQcJOl  NV3h  95  F(4,36)=5.11,2<.002.  B  Y  t  n  Newman-Keuls  e  method  d e t e r m i n e d t h a t t h e 0.2 mg/kg d o s e o f BMY 7378 of  lordosis  after  behaviour s i g n i f i c a n t l y higher  treatment  quotients  with  saline,  (p_<.05).  were s i g n i f i c a n t l y l o w e r a f t e r  o f BMY 7378 t h a n a f t e r  produced  than those  observed  However,  lordosis  t r e a t m e n t w i t h 5 mg/kg  Under b o t h s t e r o i d  to  treatments,  BMY  7378  lordosis  the  drug.  If  higher  BMY 7378 a c t s a s 5-HT,A r e c e p t o r  t h e n t h e a p p a r e n t weak  f a c i l i t a t o r y effect  appeared  b e h a v i o u r was  i n c r e a s e d a t t h e lower doses and d e c r e a s e d a t t h e of  levels  t r e a t m e n t w i t h 0.2 mg/kg (p_<.05).  I n E x p e r i m e n t 7, t h e d o s e - r e s p o n s e biphasic.  i t was  doses  antagonist,  of the drug c o u l d  be  due t o b l o c k a d e o f l o r d o s i s - i n h i b i t i n g a c t i v i t y a t p o s t - s y n a p t i c 5-HT,A  receptors.  activity it  seems  unlikely  hypothesis  i n i n h i b i t i o n of  that  lordosis,  a d r u g t h a t b l o c k s a c t i v i t y a t 5-HT,A  i s necessary  f o r the  expression  However, i t w o u l d seem more l i k e l y  a c t as a pure a n t a g o n i s t ,  agonist  course,  of  5-  lordosis  t h a t BMY 7378 d o e s  b u t r a t h e r a c t s a s a weak, p a r t i a l  ( p a r t i a l a n t a g o n i s t ) . Indeed, i n the i n i t i a l  the e f f e c t s  very  the  cannot r u l e out the p o s s i b i l i t y that a c t i v i t y a t c e r t a i n  behaviour.  in  that  results  of  w o u l d p r o d u c e l o r d o s i s - i n h i b i t i n g e f f e c t s . Of  HT,A r e c e p t o r s  not  i n view  a t 5-HT,A r e c e p t o r s  receptors one  However,  report  o f BMY 7378 on s e r o t o n i n - s e n s i t i v e a d e n y l a t e  t h e r a t h i p p o c a m p u s i t was r e p o r t e d s m a l l d e g r e e , mimic t h e e f f e c t s  on  cyclase  t h a t BMY 7378 d o e s , t o a  of s e r o t o n i n  (Yocca e t a l . ,  1 9 8 7 ) . I f BMY 7378 a c t s a s a weak p a r t i a l a g o n i s t ,  then  dose  of serotonin  of  without  the itself  receptors.  drug would tend producing  However  at  a  higher  to block strong doses,  the effects stimulation  of  enough 5-HT,A  a  low  5-HT,A receptors  96  might  be a c t i v a t e d  this  regard  t o produce  i t should  be  a lordosis-inhibiting noted  that  i n d i c a t e s t h a t BMY 7378 a l s o p r o d u c e s in  male  rats  Moreover,  (Mendelson  as would  and  very  be e x p e c t e d f r o m  a  dose  response  unpublished  drug  In  recent evidence  a biphasic  Gorzalka,  effect.  active  data).  at  5-HT,A  r e c e p t o r s , t h e e f f e c t o f t h e d r u g upon s e x u a l b e h a v i o u r i n m a l e s appears rats,  t o be t h e o p p o s i t e o f t h a t o b s e r v e d  low doses  prior  to  o f BMY 7378 i n c r e a s e t h e number o f i n t r o m i s s i o n s  ejaculation,  an  effect  i n h i b i t o r y e f f e c t . High doses intromissions  prior  intromissions prior effect  commonly  regarded  t o e j a c u l a t i o n . A decrease  7378  notion that  an  to ejaculation,  i n t h e number o f  considered  a  on m a l e s e x u a l b e h a v i o u r , i s a l s o p r o d u c e d  BMY  as  o f BMY 7378 d e c r e a s e t h e number o f  a g o n i s t 8-OH DPAT ( A h l e n i u s e t a l . , that  i n f e m a l e s . I n male  1981).  These  facilitatory by t h e 5-HT,A data  suggest  a c t s as p a r t i a l a g o n i s t and tend t o c o n f i r m t h e  5-HT,A  receptors  mediate  inhibitory  effects  of  s e r o t o n i n on l o r d o s i s b e h a v i o u r .  EXPERIMENT 8  Experiments  5,  6  and  7  have p r o v i d e d e v i d e n c e t h a t t h e  l o r d o s i s - i n h i b i t i n g e f f e c t s of serotonin are at least mediated doses primed  by a c t i v i t y  a t 5-HT,A r e c e p t o r s . M o r e o v e r ,  o f some 5-HT,A a g o n i s t s f a c i l i t a t e females,  somatodendritic facilitation  I  have  suggested  lordosis that  5-HT,A a u t o r e c e p t o r s f a c i l i t a t e s  would  likely  partially because low  i n estrogenactivity lordosis.  at This  be due t o d e c r e a s e s i n t h e a c t i v i t i e s  97  of  lordosis-inhibiting 5-HT,A  Although behaviour,  the  become a v a i l a b l e brain.  receptors  pathways.  appear  that bind  selectively  Spampinato  behaviour.  appeared  E x p e r i m e n t 6;  receptors  1986).  the e f f e c t s of t h e s e In  order  to  occur  between 5 - H T ^  these  drugs  e i t h e r with estrogen  were  In  or w i t h e s t r o g e n  following  the  and  in  on  possible  progesterone,  evaluated  been  agonists  5-HTTB  a g o n i s t s and  m-  (Hamon,  the  evaluate  in  and  to 5-HT,B receptors  Gozlan,  in  drugs have  t h a t have r e c e n t l y  b e t w e e n 5 - H T , B a g o n i s t s and  to  S-HT^B receptors  5-HT,B  to  5-HT agonists  are  and  experiment I evaluated  interaction  lordosis  1 -(3-Trifluoromethylphenyl)piperazine  f o u n d t o b i n d w i t h some s e l e c t i v i t y  lordosis  by  inhibit  l o r d o s i s r e m a i n s unknown. R e c e n t l y ,  chlorophenylpiperazine  Cossery,  to  r o l e t h a t m i g h t be p l a y e d  t h e m o d u l a t i o n of  rat  serotonergic  such  as  progesterone  in  animals  primed  progesterone.  Method  Drugs 1-(3-trifluoromethylphenyl)piperazine chlorophenylpiperazine Biochemicals. administered  Both  (MCPP)  drugs  were  were  intraperitoneally  (TFMPP)  purchased  dissolved  in  in approximately  v e h i c l e . D r u g s were a d m i n i s t e r e d  and  from  m-  Research  warm s a l i n e 0.3  ml  and  of  the  blind.  Procedures In  E x p e r i m e n t 8,  determined d r u g , 40  t h e d o s e r e s p o n s e s t o TFMPP and  in estrogen-treated  females r e c e i v e d  10 Mg  females. EB  48  In the  h, and  testing  each of  MCPP were of  each  5 groups  of  98  8  animals  received  experimental drug second  series  except  that  prior  either  0, 0.04, 0.2, 1, o r 5 mg/kg o f t h e  30 m i n p r i o r  of experiments, animals  also  to behavioural  to behavioural identical  received  testing.  procedures  In the  were f o l l o w e d  500 jug p r o g e s t e r o n e  4-6 h  testing.  R e s u l t s and D i s c u s s i o n  As may be s e e n of  TFMPP a p p e a r e d  mg/kg o f  the  behaviour effect  i n the t o p panel of F i g . 8a, t h e lowest  t o be i n e f f e c t i v e ,  drug  produced  o f TFMPP  was  determined  that  By  the  by  the  0.04  increases  in  lordosis  f e m a l e s . The l o r d o s i s - f a c i l i t a t i n g  confirmed  F(4,35)=8.53,p_<.000l .  w h e r e a s d o s e s f r o m 0.2 t o 5  dramatic  i n estrogen-primed  dose  an  analysis  Newman-Keuls  mg/kg  dose  of  of  variance,  method  TFMPP  i t was  was  indeed  ineffective.  However, t h e 0.2, 1, a n d 5 mg/kg d o s e s o f t h e d r u g  each produced  significant  In TFMPP  increases i n lordosis  (p_<.05).  t h e b o t t o m p a n e l o f F i g . 8a i t i s e v i d e n t t h a t d o s e s up  to  1  mg/kg  were i n e f f e c t i v e  i n females primed  of with  e s t r o g e n a n d p r o g e s t e r o n e . H o w e v e r , t h e 5 mg/kg d o s e o f t h e d r u g appeared  to  responding. did in  produce  a  reduction  females primed By  significant effect In  the  level  of  lordosis  By a n a l y s i s o f v a r i a n c e i t was c o n f i r m e d t h a t TFMPP  indeed produce a s i g n i f i c a n t  p_<.004.  in  the effect  effect  upon l o r d o s i s  w i t h e s t r o g e n and p r o g e s t e r o n e , Newman-Keuls o f TFMPP was  o f t h e 5 mg/kg  method due  i t was solely  to  behaviour  F(4,35)=4.695, found an  that the inhibitory  dose.  t h e t o p p a n e l o f F i g . 8b i t a p p e a r s  t h a t MCPP  produced  99  Fig.  8 a . Mean l o r d o s i s  10 jug e s t r a d i o l and  500  Mg  benzoate  varying  testing.  ± S.E.M. o f f e m a l e s p r i m e d  (Top p a n e l ) o r 10 jug e s t r a d i o l  progesterone  a d m i n i s t r a t i o n of behavioural  quotients  (Bottom  doses  of  panel) TFMPP  30  benzoate  following min  with  prior  the to  MEAN LORDOSIS QUOTIENT % M O  _J  CM O  I  *. O  L_  O _L_  O  _ l _  o _L_  00  o —1  M E A N LORDOSIS QUOTIENT % <£> o 1  o o  o  I  o-.  TJ "0  m  CO  +  3  (O  O I  o • I  o i _.  00  o  101  Fig.  8b. Mean l o r d o s i s  10 /ig e s t r a d i o l and  500  Mg  administration behavioural  q u o t i e n t s ± S.E.M. o f f e m a l e s p r i m e d  benzoate  ( T o p p a n e l ) o r 10 Mg e s t r a d i o l  progesterone of  testing.  varying  (Bottom doses  of  panel) MCPP  30  benzoate  following min  with  prior  the to  103  an  e f f e c t on l o r d o s i s s i m i l a r  t o , t h o u g h l e s s m a r k e d t h a n TFMPP  i n females primed with estrogen l o r d o s i s behaviour  alone.  estrogen. estrogen  effects  MCPP was  of  also  Experiment  produce a strong primed  upon  8  receptors  believed  to  lordosis  act  in  females  primed  with  in  females  primed  with  the  agonist  5-HTTB  alone.  a  These d a t a  facilitates  decrease  in  the  lordosis.  serotonergic  facilitating  effect  of  release  neurons. TFMPP  decrease i n serotonergic a c t i v i t y . recent  evidence  neurons  (Kennett,  that  Dourish  Curzon,  d o s e o f TFMPP showed s i g n i f i c a n t  to  be  the  syndrome,  time  surface  1987).  indicative  Together, these  data  of  however,  of  target  Indeed,  i n the (5  low  symptoms  posture  of  the  and  abducted  symptoms i s g e n e r a l l y  regarded  postsynaptic  open t h e  the  enhancement o f l o r d o s i s  exhibiting  particularly  The d i s p l a y o f t h e s e  to  lordosis-  estrogen-primed females r e c e i v i n g the highest  w h i l e a t t h e same  facilitating  from  be n o t e d ,  the  mg/kg)  hindlimbs.  serotonin  I t should  study,  serotonin  w o u l d be e x p e c t e d  a c t u a l l y be due t o a n e t  present  behaviour  (Engel et a l . ,  Therefore,  i s , on &  are  t h a t 5 - H ^ B r e c e p t o r s may a l s o  suggests  exist postsynaptically,  females  receptors  5-HTTB  of  could  in  suggest that s t i m u l a t i o n  as p r e j u n c t i o n a l a u t o r e c e p t o r s  t e r m i n a l s of  that  TFMPP was f o u n d t o  of l o r d o s i s behaviour  1986). S t i m u l a t i o n of S - H ^ B a u t o r e c e p t o r s produce  in  ( F i g 8b, bottom p a n e l ) .  facilitation  with estrogen  S-HTTB  increase  i n d i c a t e d t h a t MCPP p r o d u c e d no  ineffective  and p r o g e s t e r o n e  In  slight  c a n be n o t e d a t t h e 1 mg/kg d o s e o f t h e d r u g .  H o w e v e r , an a n a l y s i s o f v a r i a n c e significant  A  serotonergic  possibility  that  stimulation. the  lordosis-  e f f e c t o f TFMPP i s due t o a mechanism o t h e r  than a  1 04  net r e d u c t i o n of s e r o t o n e r g i c a c t i v i t y . Interestingly, significant  inhibition  e s t r o g e n and inhibiting receptors should 5-HT,B  5  the  of  progesterone.  effect  mg/kg  dose  lordosis It  in  could  females  be  that  of a c t i v i t y a t a c e r t a i n  i s e n h a n c e d by e x p o s u r e  receptors, whereas  receptor appears  Cossery, the  the  ability  a  with  lordosis5-HT,B  p o p u l a t i o n of  However,  o f TFMPP t o s t i m u l a t e  t o be l o w ( S p r o u s e & A g h a j a n i a n ,  ability  of  progesterone  i t  primed  with  estrogen  and  completely  ineffective  affinity  for  the 5-HT,B  r e c e p t o r appears  MCPP (Hamon e t a l . , could  bioavailability.  also  partially  site.  1 9 8 6 ) .  3  Differences  partially  be  was 5-HTTB  was n o t  of  to  to  agonist  i n females  significant.  i n the e f f e c t s  due  due  females primed  with  o f MCPP  differences  in  o f TFMPP f o r t h e 5 -  times h i g h e r than that  of  i n the responses t o these due  to  I t s h o u l d be n o t e d , h o w e v e r ,  e v a l u a t i o n s of the e f f e c t s  effects  behaviour  The a f f i n i t y  t o be r o u g h l y  the  the  8,  in  e s t r o g e n a n d p r o g e s t e r o n e . The d i f f e r e n c e a n d TFMPP c o u l d be a t l e a s t  (Hamon,  progesterone  a slight increase in lordosis  was  receptors  o f t h e h i g h d o s e o f TFMPP i n  primed w i t h e s t r o g e n ; however, t h i s e f f e c t drug  i t does  6 ) , i t i s tempting t o  o f 5-HT,A s i t e s . I n E x p e r i m e n t  MCPP p r o d u c e d  t h e 5-HT,A  1 9 8 7 ) ,  enhance  o f 5-HT,A r e c e p t o r s ( E x p e r i m e n t  females  sites  I n v i e w o f what a p p e a r s t o  to  that the i n h i b i t o r y effect  activation  f o r these  1 9 8 6 ) .  suggest  drugs  the  i t does n o t b i n d s e l e c t i v e l y t o t h e s e  Spampinato & G o z l a n ,  activation  HTTB  produced primed  to progesterone.  have a s i g n i f i c a n t l y h i g h a f f i n i t y  The  TFMPP  be n o t e d t h a t w h i l e TFMPP b i n d s w i t h h i g h e s t a f f i n i t y t o  Indeed,  be  of  o f MCPP on l o r d o s i s  differences  that  in  in  earlier  behaviour  in this  105  laboratory, significant  the drug  was  facilitation  unpublished  data).  5-HT,B a g o n i s t s  found  of  produce  lordosis  Therefore,  facilitates  to  a  slight,  (Mendelson  &  but  Gorzalka,  I suggest that t h e a c t i v a t i o n of  l o r d o s i s , and t h a t  the  differences  i n t h e e f f e c t s o f TFMPP a n d MCPP on l o r d o s i s may be q u a n t i t a t i v e rather  than  qualitative.  EXPERIMENT 9  The  receptor  5-HT3  5-HT r e c e p t o r indicates  h a s been c h a r a c t e r i z e d a s a p e r i p h e r a l  ( B r a d l e y e t a l . , 1 9 8 6 ) . However,  the  e x i s t e n c e o f 5-HT  ( K i l p a t r i c k , Jones & Tyers, possibility  that these  receptors  is  intrahypothalamic antagonist guinea-pig Experiment  ICS  9  binding sites  suggested  by  administration 205-930  I will 5-HT  the of  gastric  1 9 8 8 ) . The  functional  recent the  evidence  i n brain tissue  i n Tyers,  represent  facilitates  evaluate 3  binding sites  i n press, cited  (Costall, K e l l y , Naylor,  of t h e s e l e c t i v e (Fozard,  3  recent  5-HT  report  selective emptying  Tan & T a t t e r s a l l ,  3  that 5-HT  3  i n the  1986).  In  the e f f e c t s of the a d m i n i s t r a t i o n  antagonists  ICS  1984) on l o r d o s i s b e h a v i o u r  205-930  and  MDL  72222  i n estrogen-primed  female  rats.  Methods  Drugs ICS  205-930 a n d MDL  72222  were  obtained  as  gifts  from  106  Sandoz in  a n d M e r r i l l Dow  warm  saline,  approximately  0.3  respectively.  and ml  B o t h d r u g s were d i s s o l v e d  administered  of  intraperitoneally  in  t h e v e h i c l e . D r u g s were a d m i n i s t e r e d  blind. Procedure I n E x p e r i m e n t s 9, t h e d o s e 72222  were  testing  determined  of  each  in  drug,  r e s p o n s e s t o I C S 205-930 a n d MDL  estrogen-treated  females.  10 uq EB 48 h , a n d  56 f e m a l e s r e c e i v e d  e a c h o f 4 g r o u p s o f 14 a n i m a l s r e c e i v e d e i t h e r 5  mg/kg  of  the  experimental  drug  In the  0, 0.05, 0.5,  1 hr p r i o r  or  to behavioural  testing.  Results I n F i g . 9a i t i s a p p a r e n t t h a t t h e 205-930  facilitates  lordosis  l o r d o s i s behaviour appeared in  dose.  confirmed However, the  5  The by  facilitation  dose  of  of l o r d o s i s  Indeed,  to increase steadily with  of  by t h e Newman-Keuls mg/kg  behaviour.  lordosis-facilitating analysis  administration  ICS  effect  variance,  of  levels  o f ICS 205-930 was  F ( 3 , 5 2 ) = 4 . 2 5 4 , p_< .009.  produced  a  t h e range of  doses  72222  evaluated  (Fig. 9b).  Discussion  In Experiment  only  significant  ( g < . 0 5 ) . U n l i k e ICS 2 0 5 - 9 3 0 , MDL  was c o m p l e t e l y i n e f f e c t i v e w i t h i n  of  increases  method i t was d e t e r m i n e d t h a t 205-930  ICS  9, I C S 205-930 was f o u n d t o f a c i l i t a t e  1 07  Fig.  9 a . Mean l o r d o s i s  10 ixq e s t r a d i o l  q u o t i e n t s ± S.E.M. o f f e m a l e s p r i m e d  benzoate  following  d o s e s o f ICS 205-930 30 min p r i o r  t h e a d m i n i s t r a t i o n of to behavioural  testing.  with  varying  108  % i N 3 i i o n o s i s o a y o i Nvaw  109  Fig. 10 Mg  9b. Mean l o r d o s i s estradiol  d o s e s o f MDL  q u o t i e n t s ± S.E.M. o f f e m a l e s p r i m e d  benzoate  f o l l o w i n g the a d m i n i s t r a t i o n of  72222 30 min p r i o r  to behavioural  testing.  with  varying  110  I-  tf>  D)  E CM CM CM CM hCM  o o  o 00  o  ~l O  CD  % iN3iiono s i s o a u o i  O CM  NVBIAI  o  111  lordosis  behaviour.  e f f e c t s of serotonin receptors. progress, HT  It  f i n d i n g suggests that  are at least p a r t i a l l y  i s worth  noting  intrahypothalamic  agonist  3  This  lordosis-inhibiting  has  effect  effect  of the  been  would  of  mediated  by  5-HT  3  i n an e x p e r i m e n t now i n  administration  2-methylserotonin  l o r d o s i s behaviour. This  that  the inhibitory  selective  observed  be  to inhibit  consistent  stimulation  of  with  central  5-HT  found  be i n e f f e c t i v e i n t h i s e x p e r i m e n t . The d i f f e r e n c e s i n  the  e f f e c t s o f ICS 205-930 a n d  partially for  5-HT  due t o d i f f e r e n c e s receptors.  3  72222  tissues  be  ICS  al.,  1985; Round & W a l l i s , 1 9 8 7 ) . T h e s e d i f f e r e n c e s  s u b t y p e s o f 5-HT other in  hand,  by  remains that serotonergic 3  roles  receptors  of  what  (Richardson  have  simply  might  1985).  reflect  On  in  the l i v e r .  in their  and  also as the  brain  resistence to  Of c o u r s e , t h e p o s s i b i l t y  of these drugs. Evaluations antagonists  et  differences  t h e s e d i f f e r e n c e s were due t o d i f f e r e n c e s effects  has  (Richardson  of these drugs t o pass through t h e blood  enzymes  agonists  questions.  205-930  been r e c o g n i z e d  et a l . ,  i n t o b r a i n t i s s u e , or d i f f e r e n c e s  breakdown  5-HT  t h e e f f e c t s of s e r o t o n i n  these d i f f e r e n c e s could  the a b i l i t i e s  barrier  3  least  1000 t i m e s more p o t e n t t h a n MDL 72222 i n  ability  differential  at  was  o f t h e two d r u g s  its  reflect  block  could  i n the a f f i n i t i e s  I n d e e d , i n some  been f o u n d t o be n e a r l y to  MDL  72222  3  I n t e r e s t i n g l y , t h e 5-HT  3  MDL  a  receptors. to  antagonist  5-  should  help  i n non-  of a d d i t i o n a l  .clarify  these  11 2  GENERAL DISCUSSION  In  the present  pizotefin, HT  behaviour the  ketanserin  reversed  quipazine.  noradrenergic  effects  to  central,  was  when  selective  significant effects  found  on  have  5-HT  2  was  considered  5-HT  the drug  inhibited  become  tissue  have  effects  produce the  a  dose  greatly  diminished,  would have d e c l i n e d over  been  concentration-  effect  antagonist  doses  facilitation response  of  after  to  the  of  effects  methysergide 200 m i n , effects  r a t h e r than  lordosis.  At  methysergide  small  30 m i n p r i o r t o b e h a v i o u r a l  o f t h e d r u g were o b s e r v e d  Increasing  or  lordosis.  t h a t t h e i n h i b i t o r y and f a c i l i t a t i v e may  2  antagonist  when t h e s e r o t o n i n - a n t a g o n i z i n g  of m e t h y s e r g i d e a d m i n i s t e r e d  evaluating  5-HT  i s b e l i e v e d t o be most a c t i v e a s  dependent. However, t h e e v a l u a t i o n o f i n c r e a s i n g l y  to  the  dopaminergic  l o r d o s i s . Because t h e c o n c e n t r a t i o n of  plasma and b r a i n  failed  With  t o produce i n h i b i t o r y and f a c i l i t a t i v e  methysergide  in  methysergide  of  i n a t i m e d e p e n d e n t manner. A t 30 m i n  treatment,  the drug  facilitated  lordosis  and p r o g e s t e r o n e .  coadministration  highly  serotonin antagonist  min a f t e r  inhibit  s y s t e m s , was a l s o i n h i b i t e d l o r d o s i s . T h i s  on l o r d o s i s  treatment,  of  found  r e v e r s e d w i t h q u i p a z i n e . The n o n - s e l e c t i v e  methysergide  200  were  by  The  LY53857, a drug w i t h o u t  was  antagonists  2  of m e t i t e p i n e , the l o r d o s i s - i n h i b i t i n g e f f e c t s of  d r u g s were  agonist  t h e 5-HT  a n d m e t i t e p i n e , a n d t h e s e l e c t i v e 5-  i n females primed with estrogen  exception  these  of experiments,  cyproheptadine  antagonist  2  series  i t of  dosedoses  testing  Indeed,  in  methysergide,  facilitative  o n l y 200 min a f t e r  treatment.  5-HT,A  agonists  8-OH  DPAT,  1 13  buspirone, lordosis  ipsapirone,  and  i n estrogen-primed  5-HT,A a g o n i s t s p r o d u c e d estrogen-primed by  gepirone  gepirone  increases  were  and  ipsapirone  or  inhibit  in  lordosis  behaviour  w i t h estrogen and  and  found  in  produced  was f o u n d t o be s i g n i f i c a n t . When  gepirone  of l o r d o s i s . Indeed,  ineffective  primed  to  f e m a l e s . However, o n l y t h e f a c i l i t a t i o n  ipsapirone  inhibition  found  females. At lower doses, a l l of the  a d m i n i s t e r e d t o females primed buspirone,  were  a l l produced  even doses  to  progestereone,  of  facilitate  strong  the drugs  lordosis  w i t h e s t r o g e n were f o u n d t o i n h i b i t l o r d o s i s  that  i n females in  females  p r i m e d w i 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 . The 5-HT,A a n t a g o n i s t BMY 7378 f a c i l i t a t e d However,  lordosis  i n females primed w i t h estrogen a l o n e .  this facilitative  h i g h e s t dose.  effect  was no l o n g e r o b s e r v e d a t t h e  BMY 7378 was i n e f f e c t i v e i n  females  primed  with  e s t r o g e n and p r o g e s t e r o n e . The  5-HTTB  agonist  facilitation  of l o r d o s i s  In  primed  females  TFMPP  behaviour  with  produced  a  i n estrogen-primed  estrogen  and  TFMPP  in  inhibition was  females primed  strong females.  progesterone  h i g h e s t d o s e o f TFMPP was e f f e c t i v e . I n t e r e s t i n g l y , of  very  only the  the  effect  w i 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 was  o f l o r d o s i s . The somewhat  weaker 5 - H ^ B a g o n i s t  MCPP  ineffective. Finally,  lordosis range  the  5-HT  i n estrogen-primed  o f d o s e s , t h e 5-HT The r e s u l t s o f  subtype either  antagonist  3  selective inhibition  these  or  205-930  facilitated  f e m a l e s . However, w i t h i n t h e l i m i t e d  a n t a g o n i s t MDL 72222 was i n e f f e c t i v e .  3  drugs  ICS  evaluations suggest  that  facilitation  of  serotonin  serotonin of  receptor  may p r o d u c e  lordosis.  Whether  114  inhibition  or  facilitation  subtype of receptor  produces  5-HT,A r e c e p t o r s a n d , p e r h a p s ,  in  obtained  i n these  the d u a l  role hypothesis  series  of  5-HT,A  lordosis  experiments tend  the  l o r d o s i s of drugs  that  serotonin  receptors behaviour.  The  of Mendelson and G o r z a l k a  first  performed  evaluations  act selectively  receptors.  appears  of  the  at  the  performed i n the e f f o r t  effects  on  subtypes  of  that  antagonists  behaviour.  have  B e c a u s e many o f t h e s e agonists  took  subtypes  of  worthwhile light  place central  to  Indeed,  following  antagonists probable  evaluated  the  e v a l u a t i o n s of serotonin prior  to  serotonin  knowledge.  review  and  and a g o n i s t s  action  of  receptors. Although  on  these  initial agonists  f o r e f f e c t s on l o r d o s i s . antagonists  the c h a r a c t e r i z a t i o n receptors,  i t would  r e - i n t e r p r e t t h e r e s u l t s of these  of present  comprehensive  been  have  t o determine the r o l e of serotonin  i n v e s t i g a t i o n s of Meyerson, a wide v a r i e t y of s e r o t o n i n and  present  I t must be n o t e d , h o w e v e r , t h a t  been  sexual  results  i n the  experiments form o n l y a p o r t i o n of the s t u d i e s  female  to  (1985b).  these  in  3  both t o c o n f i r m and t o extend  the experiments  represent  central  5-HT 2  facilitation  I n many c a s e s ,  that  i n h i b t i o n o f l o r d o s i s . A c t i v a t i o n o f 5-HT ,  5-HT,B a n d , p e r h a p s , p r e s y n a p t i c result  a p p e a r s t o d e p e n d upon w h i c h  i s a c t i v a t e d . These e x p e r i m e n t s s u g g e s t  a c t i v a t i o n of postsynaptic receptors  occurs  Accordingly,  the  and  of the appear  experiments i n  following  is a  r e - e v a l u a t i o n o f t h e e f f e c t s o f 5-HT lordosis  in  terms  of  at specific  s u b t y p e s o f 5-HT  none o f t h e d r u g s d i s c u s s e d  bind e x c l u s i v e l y  to  5-HT r e c e p t o r s , t h e i r  by  serotonergic  systems.  drugs  behaviour  e f f e c t s a p p e a r t o be m e d i a t e d p r i m a r i l y Therefore,  I  have  considered  these  1 15  drugs  only  review  i t becomes a p p a r e n t t h a t  inhibitory been  regard  In t h i s  produce  either  e f f e c t s on l o r d o s i s b e h a v i o u r ,  as has  receptors,  by 5-HT  dual  lordosis.  1985).  5-HT  prejunctional  5-HT,B  that  a r e m e d i a t e d p r i m a r i l y by p o s t facilitatory  autoreceptors  receptors  3  may  effects are  may  mediate  autoreceptors  s e r o t o n i n on l o r d o s i s  activity  facilitate i t is  inhibitory,  facilitatory  and  effects  behaviour.  5-HT a n t a g o n i s t s  b i n d t o b o t h 5-HT, a n d 5-HT  r e c e p t o r s . However, t h e s e d r u g s t e n d f o r 5-HT  receptors  2  t o show v a r y i n g d e g r e e s  (Peroutka,  Lebovitz  degree  to  which  a  5-HT  s u b t y p e s o f t h e 5-HT, r e c e p t o r . quite  selective  affinity HT  5-HT  bind  t h a n t o 5-HT,B  sites.  HT  2  Even  antagonists  binds  drugs tend  considered to  with a markedly higher  e f f e c t i v e n e s s of the c l a s s i c a l  receptors  appears  well  of  in  to the various  bind  to  with  affinity  be high  t o 5-HT,C r e c e p t o r s . M o r e o v e r , i t a p p e a r s t h a t most  antagonists  The  2  antagonist  2  & Snyder,  1 9 8 1 ) . R e c e n t work i n d i c a t e s t h a t d i f f e r e n c e s may a l s o e x i s t the  of  antagonists  classical  preference  i s concluded  on t h e b a s i s o f p r e l i m i n a r y e v i d e n c e ,  suggested that  5-HT r e c e p t o r  It  (Mendelson &  I t i s also concluded that  5-HT^  Finally,  can  r o l e hypotheses  whereas  receptors.  2  serotonergic  serotonin  & Hunter,  somato-dendritic  The  effects.  e f f e c t s of s e r o t o n i n  5-HT,A  mediated  their  i n the recent  1985; W i l s o n  inhibitory synaptic  to  or f a c i l i t a t o r y  suggested  Gorzalka,  at  in  5-  t o 5-HT,A  5-HT a n t a g o n i s t s  e s t a b l i s h e d . However, w h i l e  at  5-  i t is  1 16  clear  t h a t t h e s e d r u g s b i n d t o t h e v a r i o u s s u b t y p e s o f t h e 5-HT,  r e c e p t o r , t h e r e remains antagonists is  some d o u b t  at these s i t e s  as t o t h e i r e f f e c t i v e n e s s  ( H a i g l e r & A g h a j a n i a n , 1974a).  as  There  i n f a c t e v i d e n c e t h a t some c l a s s i c a l 5-HT a n t a g o n i s t s may a c t  as  weak  partial  Aghajanian, highly  agonists  1974a;  selective  studies  methysergide  5-HT  antagonists  2  antagonist.  been  (Haigler  possess  little,  t h e r o l e of s e r o t o n i n  t h e most  Methysergide  antagonists,  receptors  &  i f any,  1985).  investigating  has  5-HT,  P e r o u t k a e t a l . , 1981). However, t h e newer,  agonist a c t i v i t y (Janssen, In  at  commonly  i s one  of  binding with high a f f i n i t y  in lordosis,  employed  receptor  less  selective  the  t o 5-HT , 5-HT,A a n d 52  HT,C r e c e p t o r s , a n d w i t h somewhat l o w e r a f f i n i t y  t o 5-HT,B s i t e s  ( Dr. S.J. Peroutka, personal communication). The  administration  hypothalamus,  of  hippocampus,  methysergide  (Zemlan,  1973;  Zemlan  Crowley,  into  or amygdala f a c i l i t a t e s  estrogen-primed females Ward,  directly  Ward, and  Crowley  Margules,  lordosis i n  and  observed  preoptic area  following (Clemens,  Peripherally lordosis al.,  injection  administered  and  inhibition  methysergide  into  the  1978).  i n estrogen-primed,  1975; H e n r i k  of  Margules,  1975; Foreman a n d  M o s s , 1978; F r a n c k a n d Ward, 1 9 8 1 ) . I n one i n s t a n c e , was  the  Gerall,  methysergide ovariectomized 1976; D a v i s  also  facilitates  females and  (Ward e t  Kohl,  1978;  Foreman a n d M o s s , 1978; R o d r i g u e z - S i e r r a a n d D a v i s , 1979; F r a n c k and  Ward,  1981; H u n t e r  1986a; U l i b a r r i & Y a h r , effects  of  peripherally  et  a l . , 1985; M e n d e l s o n  & Gorzalka,  1987). However, t h e maximal  facilitatory  administered  methysergide  have  been  1 17  reported t o occur 2 t o 6 hr a f t e r Davis  and  maximal  Kohl,  within hr  can  of  intraperitoneally  o c c u r i n 30 m i n a n d may d e c l i n e  i t s p e r i p h e r a l a d m i n i s t r a t i o n , m e t h y s e r g i d e h a s been  estrogen  (Mendelson  i n females primed w i t h and  Gorzalka,  1985; M e n d e l s o n at  the  antagonist, lordosis  low  and  dose  to  times  when  behaviour.  of e s t r o g e n , or w i t h  & Eliasson,  1977; S i e t n i e k s ,  effect  i t i s most  effective  administered  methysergide  It  i s conceivable  of  methysergide  of  inhibit  & G o r z a l k a , 1986a). T o g e t h e r , t h e s e d a t a  peripherally  facilitating  a  1985b),  i n f e m a l e s p r i m e d w i t h a h i g h dose  e s t r o g e n and p r o g e s t e r o n e (Meyerson  that  1973;  & V a s s a r , 1 9 7 5 ) . When e v a l u a t e d 30 m i n t o 1  f o u n d t o be i n e f f e c t i v e  lordosis  effects  methysergide  1 hr ( Sofia  after  et a l ,  1978). P h a r m a c o k i n e t i c d a t a i n d i c a t e t h a t t h e  antiserotonergic  administered  t r e a t m e n t (Zemlan  that  after  suggest  as  a  5-HT  inhibits  the  lordosis-  2 h r i s due t o t h e  a c t i o n of a metabolite. Cinanserin selective  f o r 5-HT  administered  2  et a l . ,  administered peripherally  &  1975).  progesterone,  cinanserin  antagonists  (Leysen & T o l l e n a e r e ,  facilitated  In  peripheral  ineffective  more  1 9 8 2 ) . When  1985). Hunter  et  i n estrogen-primed  1 9 7 5 ) . However, when  t o estrogen-primed females, lordosis  females  administration 1985),  inhibited  a l . , (1985)  also  25  ( E v e r i t t , Fuxe,  primed  (Sietnieks,  substantially  lordosis  1973; Ward e t a l . ,  d i d not f a c i l i t a t e  Jonsson,  appeared  the c l a s s i c a l  receptors  cinanserin  (Zemlan  cinanserin  of  i n t o the medial p r e o p t i c or p o s t e r i o r areas of the  hypothalamus, females  i s one  with  mg/kg  Hokfelt,  estrogen  and  o f 5 mg/kg c i n a n s e r i n whereas  lordosis reported  10  (Hunter that  mg/kg et a l . ,  10  mg/kg  1 18  cinanserin  produced  estrogen-primed receptivity.  a slight  females  However,  with  " r e c e p t i v e " and  statistical  analysis,  regression  toward  very  because  animals into  i s m e r e l y an a r t i f a c t  increase i n l o r d o s i s behaviour i n low  of  the  "non-receptive"  lordosis,  of t h e e x p e r i m e n t a l mean  design,  (see Raible  like  methysergide,  i t s binding t o the various  Engel  &  Kalkman,  1985).  In  5-HT  over  while  that  with  Sietnieks, Other their  estrogen 1985),  and  nonselective whereas  i s somewhat n o n - s e l e c t i v e subtypes  found  lordosis  progesterone  to  facilitate  (Fuxe, e t a l . ,  (Hunter  a n t a g o n i s t s t h a t have  and  pizotefin.  et  with and 1976).  1985)  ,  a l . , 1985 ;  lordosis.  been  evaluated for  Metitepine  mianserin,  cyproheptadine  t o 5-HT  adminstered  2  cyproheptadine inhibited  (Mendelson  and  r e c e p t o r s (Leysen &  systemically  is  somewhat  (Mendelson  &  1985),  pizotefin  bind  Tollenaere,  1982).  t o females primed  and p r o g e s t e r o n e , m e t i t e p i n e ( M e n d e l s o n  1985)  (Hoyer,  i n i t s s e r o t o n e r g i c b i n d i n g (Hoyer, e t a l . ,  preferentially  and  may  e f f e c t s upon l o r d o s i s b e h a v i o u r a r e m e t i t e p i n e , m i a n s e r i n ,  cyproheptadine,  When  1986).  behaviour.  5 mg/kg m e t e r g o l i n e i n h i b i t e d  classical  i s ,a  cinanserin  In females t r e a t e d e i t h e r w i t h e s t r o g e n (Hunter e t a l . , or  to  facilitation  females t r e a t e d c h r o n i c a l l y  0.5 mg/kg t o i n h i b i t  of  prior  Gorzalka,  receptor  e s t r o g e n , 0.05 mg/kg m e t e r g o l i n e was doses  &  i t does n o t e l i m i n a t e t h i s  Metergoline, in  groups  I suspect that t h i s apparent  the  levels  a r b i t r a r y placement of  N o n e t h e l e s s , t h e s e d a t a do i n d i c a t e t h a t inhibit  baseline  and  Gorzalka,  with estrogen  Gorzalka, 1986b;  1986b),  Sietnieks,  l o r d o s i s . A t a d o s e l o w e r t h a n o u r e f f e c t i v e one  and G o r z a l k a ,  1986b),  metitepine  d i d not  inhibit  119  lordosis  (Fernandez-Guasti,  Ahlenius, Hjorth & Larsson,  The p e r i p h e r a l a d m i n i s t r a t i o n o f m i a n s e r i n females t r e a t e d e i t h e r progesterone also  (Hunter  inhibited  progesterone  highly  administration  females  selective  evaluation. of  the  lordosis  Gorzalka,  in  in  in  was  et  higher  (Mendelson  than  found  pirenperone  (Mendelson  lordosis  lordosis  (Mendelson  paper,  a  progesterone  be  a  most 5-HT  in  i t was l o w e r (1985).  In  ( 1 - 1 0 mg/kg), a 5-HT  & 2  2  our  pirenperone own  than at  that  least  antagonist  h a s been f o u n d t o i n h i b i t  Gorzalka,  study found three related lordosis  1985b, 1986b; H u n t e r e t a l . ,  selective antagonist  a l t a n s e r i n d i dnot  i n s t e r o i d - p r i m e d r a t s a t d o s e s up t o 0.2 mg/kg  1985).  potent, 2  single  (Fernandez-  The e r g o l i n e d e r i v a t i v e LY53857 h a s r e c e n t l y been to  and  Intraventricular  recent  effective  Sietnieks  1985) However, t h e 5-HT  (Sietnieks,  antagonist  1985).  and  1985),  in structure t o pirenperone,  inhibit  peripheral  also inhibited  estrogen  Gorzalka,  (Mendelson  and  studies,  females  data). In a  those  ketanserin  Pizotefin  estrogen  a l . , 1 9 8 7 ) . However, w h i l e t h i s d o s e o f  and  behaviour  with  and  ( 0 . 2 5 mg/kg) was r e p o r t e d t o be i n e f f e c t i v e  m i n i m a l l y e f f e c t i v e by studies,  estrogen  a n t a g o n i s t s h a v e become  2  two  Sietnieks,  females primed with  Guasti  In  steroid-primed  1985b;  of pirenperone  5-HT  2  Gorzalka, unpublished  dose  with  1986b).  5-HT -selective  a d m i n i s t r a t i o n of pirenperone and  or  primed  (Mendelson and G o r z a l k a ,  for  inhibited  estrogen,  lordosis in  e t a l . , 1985; S i e t n i e k s , 1 9 8 5 ) .  lordosis  Recently, available  with  inhibited  1987).  and h i g h l y s e l e c t i v e  a n t a g o n i s t s , LY53857  5-HT  2  i s relatively  reported  antagonist. inactive  Unlike at  a.  1 20  adrenergic 1983). 2).  and  dopaminergic  receptors  (Cohen,  I have f o u n d t h a t LY53857 i n h i b i t s  R i t a n s e r i n , a n o t h e r 5-HT  a -adrenergic a c t i v i t y Mendelson whether  2  lordosis  (Experiment  antagonist with-relatively  ( J a n s s e n , 1985), a l s o i n h i b i t s  or  not  5-HT  antagonists  2  receptors,  receptors i s sufficient Until  the  act at  blockade  to inhibit  very r e c e n t l y ,  selective  of  a,  high  affinity  to  adrenergic at  or  5-HT  2  t h e r e have been  no  drugs  acting  as  a t 5-HT1 r e c e p t o r s . The n e w l y selectively  5-HT,A r e c e p t o r s ( Y o c c a e t a l . ,  and 1987).  t h e drug has been found t o r e v e r s e t h e e f f e c t s of t h e  agonist  hippocampal  5-carboxamidotryptamine  tissue.  females, low doses behaviour.  When  on a d e n y l a t e c y c l a s e i n  administered  to  estrogen-primed  o f BMY 7378 were f o u n d t o f a c i l i t a t e  However,  at  h i g h e r doses  reduced. Because  appears  t o be  agonist,  effects  of  a  very  weak  the drug  stimulation  rather  at than  I n t e r e s t i n g l y , a t doses t o h a v e no e f f e c t estrogen  and  partial high  doses  blockade  may of  the  have  BMY 7378 inhibitory  been  5-HT,A  due t o  receptors.  f r o m 0.04 t o 5 mg/kg, BMY 7378 was f o u n d  upon l o r d o s i s b e h a v i o u r i n f e m a l e s p r i m e d  progesterone.  A l t h o u g h t h e 5-HT  3  with  I t i s p o s s i b l e , however, t h a t a t a  h i g h e r d o s e i n h i b i t o r y e f f e c t s may h a v e been  peripheral  lordosis  the l o r d o s i s - f a c i l i t a t i n g  e f f e c t s o f t h e d r u g were s i g n i f i c a n t l y  3  that  lordosis behaviour.  a n t a g o n i s t s of a c t i v i t y  Moreover,  5-HT  little  lordosis (  activity  d e v e l o p e d d r u g BMY 7378 h a s been f o u n d t o b i n d  5-HT,A  & Kurz,  & G o r z a l k a , u n p u b l i s h e d d a t a ) . These d a t a s u g g e s t  dopaminergic  with  Fuller  r e c e p t o r has  been  observed. characterized  as  a  receptor, recent evidence i n d i c a t e s the e x i s t e n c e of  binding  sites  i n brain tissue  ( K i l p a t r i c k , Jones &  Tyers,  121  in  press,  binding  cited  sites  by  the  the  selective  represent  recent  emptying  in  1 9 8 8 ) . The p o s s i b i l i t y  f u n c t i o n a l 5-HT  3  receptors  report that intrahypothalamic  5-HT the  Tattersall,  antagonist  3  of  I C S 205-930  guinea-pig  1986).  administration lordosis  i n Tyers,  In 5  (Costall,  Experiment  that  is  suggested  a d m i n i s t r a t i o n of  facilitates Kelly,  9,  these  gastric  Naylor,  the  Tan &  peripheral  mg/kg I C S 205-930 was f o u n d t o f a c i l i t a t e  i n estrogen-primed  females.  Studies  employing  central  a d m i n i s t r a t i o n o f I C S 205-930 a r e i n p r o g r e s s  i n our l a b o r a t o r y .  Interestingly,  no  facilitatory 1984) .  I  have  could  e f f e c t i v e n e s s of these (Richardson,  be  a  3  indication  a n t a g o n i s t MDL 72222  reflection  of  the  5-HT  3  s e l e c t i v e drugs,  this  discussing  hypothalamic  t h e e f f e c t s o f d r u g s t h a t m i m i c 5-HT, I  areas  inhibited  f e m a l e s ( F o r e m a n & M o s s , 1978a; of while  ventricle  suggestion  agonists  must n o t e t h a t t h e a d m i n i s t r a t i o n o f 5-HT i t s e l f  effect,  receptors  3  as h i g h l y s p e c u l a t i v e .  receptor  injection  (Fozard,  E n g e l , D o n a t s c h & S t a d l e r , 1985). However, p e n d i n g  must be r e g a r d e d  and  of  differential  d r u g s on t h e s u b t y p e s o f 5-HT  the e v a l u a t i o n of other  Before  y e t observed  e f f e c t s o f t h e 5-HT  This  Serotonin  as  10  lordosis  Clemens,  into  preoptic  i n steroid-primed  1978).  However,  the  /ig 5-HT i n t o t h e t h i r d v e n t r i c l e p r o d u c e d no  injection  significantly  of  100  jug 5-HT  facilitated  into  lordosis  either  facilitate  areas  depending  on  which  lateral  (Wilson & Hunter,  1985) . T h e s e f i n d i n g s s u g g e s t t h a t 5-HT c a n lordosis,  the  inhibit  or  of the b r a i n  122  receive  treatment.  LSD  was t h e f i r s t  5-HT a g o n i s t  on  lordosis.  Iri v i t r o b i n d i n g d a t a  LSD  t o the various subtypes  nonselective.  I t binds  H T , 5-HT,A  and  2  affinity  Peripheral females  &  receptors  receptors,  and  with  Meyerson,  Meyerson,  1980).  effects  relatively  high a f f i n i t i e s with  t o 5-  slightly  lower  e t a l . , 1986).  estrogen  and  1972; M e y e r s o n , C a r r e r  Although  lordosisin  progesterone  E l i a s s o n & M e y e r s o n , 1976; E l i a s s o n & M e y e r s o n , &  is  a d m i n i s t r a t i o n o f LSD h a s i n h i b i t e d  treated  Michanek  5-HT  equal  (Engel  for  i n d i c a t e that t h e b i n d i n g of  with roughly  5-HT,C  t o 5-HT,B s i t e s  of  t o be e v a l u a t e d  one  (Eliasson,  & E l i a s s o n , 1974; 1977; S i e t n i e k s  laboratory  has  reported  i n h i b i t o r y e f f e c t s o f LSD i n f e m a l e s t r e a t e d w i t h e s t r o g e n ( Everitt with  e t a l . , 1975), another f a i l e d  relatively  high  doses of t h e drug  to  confirm  alone  this  even  ( S i e t n i e k s & Meyerson,  1980). The of  i n h i b i t o r y e f f e c t s o f LSD h a v e been t a k e n  serotonergic  interpretation agonist  inhibition  ignores  lordosis.  evidence  However,  t h e f a c t t h a t LSD may a c t a s  this  either  an  o r an a n t a g o n i s t , d e p e n d i n g , p e r h a p s , on t h e s u b t y p e o f  5-HT r e c e p t o r . The a b i l i t y of  neurons  and  to inhibit  in  (Middlemiss, HT,A  of  as  o f LSD t o r e d u c e t h e r a t e  t h e d o r s a l raphe  of  (Haigler & Aghajanian,  t h e r e l e a s e of s e r o t o n i n  from  neuron  firing 1974b),  terminals  1982) s u g g e s t s t h a t LSD may a c t a s an a g o n i s t  a t 5-  a n d 5-HT,B r e c e p t o r s , r e s p e c t i v e l y . T h a t t h e d i s c r i m i n a t i o n  of LSD f r o m s a l i n e c a n be b l o c k e d (Janssen, agonist  by s e l e c t i v e  5-HT  2  antagonists  1983) s u g g e s t s t h a t LSD may a c t a s a t l e a s t a p a r t i a l  a t 5-HT  2  r e c e p t o r s . However, LSD h a s been f o u n d t o b l o c k  123  the e x c i t a t o r y , al.,  1981)  Straughn, Briggs, LSD  a n d most l i k e l y ,  effects  1967) a n d  serotonin  reticular  However,  primarily  activity  effects  of  (Sietnieks, finding  an  the  t o suggest  receptors.  that the  5-HT  that the i n h i b i t i o n  increase  in activity  inhibitory  cyproheptadine,  on  the  methysergide, possess  inhibition and  was  2  lordosis-  of  receptors.  of  lordosis  a t 5-HT  reached  effects  Moreover,  i s equal  cyproheptadine Tollenaere,  LSD  which  f o r 5-HT  2  receptors  2  following  1982; H o y e r  et  inhibited lordosis  lordosis i n very  Metergoline,  t o b l o c k LSD, a l l the e f f e c t i v e  metergoline  1985).  Finally,  methysergide,  that Sietnieks'  low doses  LSD.  drug  f o r 5-HT  of the e f f e c t i v e  i n Sietnieks'  by i n c r e a s i n g  t h e 5-  2  drugs  ( P e r o u t k a e t a l . , 1981; L e y s e n &  al.,  pirenperone,  failed  those  by  a n d r e v e r s e d by t h e  by  of  the  a n d m i a n s e r i n h a d no  s i t e s than  the a f f i n i t y  and pirenperone  seems u n l i k e l y  inhibits  lordosis  t o , or g r e a t e r than  cyproheptadine, mianserin  of  by  LSD were r e d u c e d  and p i r e n p e r o n e ,  mianserin,  higher a f f i n i t y  cinanserin. sites  5-HT,  of t h e c l a s s i c a l and s e l e c t i v e  antagonists metergoline, methysergide,  2  Bradley,  a n t a g o n i s t a l t a n s e r i n . H o w e v e r , i n t h e same s t u d y  2  effect  it  postsynaptic  1985). T h i s c o n c l u s i o n  that  cinanserin,  HT  to  (Roberts &  (Boakes,  a t s p e c i f i c p o p u l a t i o n s of c e n t r a l  i s due  5-HT  the cortex  et  LSD may be p a r t i a l l y due t o b l o c k a d e o f  I t h a s been s u g g e s t e d LSD  by  i n view of t h e e f f e c t s  inhibiting  in  (Peroutka  t h a t t h e i n h i b i t o r y e f f e c t s of  a n t a g o n i s t s , i t i s tempting  2  mediated  2  formation  & Dray, 1970). I suspect  a r e mediated  5-HT  of  5-HT  like  metergoline,  (1985)  study.  data provide evidence  a c t i v i t y a t 5-HT ( 5 - 2 0 uq/kq)  LSD,  2  and Thus,  t h a t LSD  receptors.  appears t o f a c i l i t a t e  124  lordosis  in estrogen-treated  Sietnieks  &  Meyerson,  attributed  to i n h i b i t i o n  upon a u t o r e c e p t o r s reduction  of  in  1983).  the  facilitation  of  treatment  (Aghajanian,  f o r as  of  begin  l o n g as  3  hr  of LSD  &  induced  after  whereas raphe LSD,  in  the  the  short-lived  this raphe  phenomenon.  t h e i r normal  patterns  administration  1968). In c o n t r a s t , may  treatment  a  might  e n t i r e l y to  intravenous  by LSD  have been  of  activity  Sheard,  1975;  through a c t i o n  effect  to recover the  al.,  dorsal  c a n n o t be due  is a relatively  Foote  lordosis  et  However,  the  neuronal  f i r i n g w i t h i n 5 minutes a f t e r  facilitation  raphe. in  by LSD of  I n d e e d , r a p h e n e u r o n s may  LSD  effects  dorsal  lordosis  following  of  These  lordosis-facilitating  reduction  of  Everitt  activity  m e c h a n i s m . The LSD  (  of s e r o t o n e r g i c a c t i v i t y  the  neuronal  contribute to  females  persist  (Sietnieks  the  undiminished &  Meyerson,  1983) . Recently,  i t has  been f o u n d t h a t v e r y  10 Mg/kg) e n h a n c e t h e a b i l i t y o f glutamate-induced nucleus  (McCall & Aghajanian,  appears  to  be  Reiffenstein, in the a  mediated  1 9 8 6 b ) . The  f a c i a l nucleus  time  course  lordosis that  excitation  by LSD  prolonged The  of  (5-  to  facilitate  the  serotonin  of m o t o r n e u r o n s i n t h e 1980). T h i s by  5-HT  was  effect  (Sietnieks  enhancement,  hallucinogenic  effect  be  o f low  phenylalkylamines  &  activity  f o r over 4 hr, f a c i l i t a t i o n of  1983). These data  s e r o t o n e r g i c a c t i v i t y may  lordosis-facilitating  serotonin  serotonergic  rather  facial  (Penington  found to p e r s i s t  & Meyerson,  rat  of  receptors  2  enhancement o f LSD  d o s e s o f LSD  s i m i l a r to t h a t observed i n the  postsynaptic  inhibition  by  low  than  suggest  presynaptic  responsible for doses of  the  LSD.  2,5-dimethoxy-4-  1 25  methylamphetamine  (DOM), 2 , 4 , 5 - t r i m e t h o x y a m p h e t a m i n e  dimethoxy-4-methylphenylethylamine a l s o been f o u n d t o f a c i l i t a t e inhibit LSD,  attributed Fuxe,  to  nor  significant raphe  low  doses,  ( E v e r i t t & Fuxe,  reductions  DOM  in  serotonergic a c t i v i t y  (Penington  been  Reiffenstein, excitatory  like  found  1986b)  effect  to  of  to  been  sites  have  primed  1986a)  doses  of  and  has  dorsal  (Penington  &  receptor-mediated  2  of t h e f a c i a l  motor  o f DOM a n d TMA f o r  f o r 5-HT,  i n which these drugs produced  of l o r d o s i s  doses  DOM  of mescaline 1 2 - f o l d h i g h e r  1982) t h a n t h e i r a f f i n i t i e s  (Everitt  the  N,N,dimethyltryptamine MeODMT),  5-HT  the a f f i n i t i e s  drugs' r e l a t i v e a f f i n i t i e s Low  Aghajanian,  f o u n d t o be 3 0 - f o l d h i g h e r (Shannon e t  1984), and t h e a f f i n i t y  & Tollenaere,  the  and  s e r o t o n i n on n e u r o n s  5-HT  inhibition  Reiffenstein,  enhance,  mimic  interest,  of  and  &  (Everitt &  LSD, m e s c a l i n e ( M c C a l l & A g h a j a n i a n ,  n u c l e u s . Of f u r t h e r  range  1 9 7 7 ) . As w i t h  e f f e c t s on s e r o t o n e r g i c a u t o r e c e p t o r s i n t h e  has  2  and t o  e f f e c t s o f t h e p h e n y l a l k y l a m i n e s have been  . Interestingly,  1980)  the  at  a n d m e s c a l i n e have  1 9 7 7 ) . However, n e i t h e r m e s c a l i n e ( H a i g l e r  1973)  al.,  lordosis  l o r d o s i s a t h i g h e r doses  the f a c i l i t a t o r y  (DOMPE),  (TMA), 2,5-  females. High doses  f o r 5-HT  2  a n d 5-HT,  sites.  reflect  tryptamine derivatives  5-methoxydimethyltryptamine  these  The  f a c i l i t a t i o n and to  also f a c i l i t a t e of  sites.  1977) seems  hallucinogenic  (DMT),  psilocybin  & Fuxe,  (Leysen  drugs  lordosis are  (5-  i n estrogen-  inhibitory  in  females  primed  w i t h e s t r o g e n or w i t h e s t r o g e n and p r o g e s t e r o n e  (Everitt  & Fuxe,  1977). Tryptamine  to  bind with highest a f f i n i t y  al.,  1981).  Within  this  d e r i v a t i v e s have been  t o 5-HT,  receptors  c l a s s of r e c e p t o r s ,  thought  (Peroutka  et  5-MeODMT a n d DMT  1 26  show a m a r k e d s e l e c t i v i t y  f o r 5-HT,A  Thus t h e f a c i l i t a t o r y and i n h i b i t o r y tryptamines  could  be  somato-dendritic receptors, that  at  least  facilitate  psilocybin)  e f f e c t of serotonin Aghajanian,  1980).  facilitating  DMT  the  piperazine  mimics  Thus  i t  a t 5-HT  was  to  first  5-HT,A  primed with estrogen  & Davis,  1 9 7 9 ) . However, i n l a t e r were  and progesterone  Gorzalka, with  1985b)  estrogen  quipazine  has  alone also  subsequently  facilitate,  that  binds  the  been  to  with  at  moderately and  with  (Hoyer e t a l . ,  inhibit  studies  et  found  lordosis in  (Rodriguez-Sierra  comparable  doses  i n females t r e a t e d  of with &  l o r d o s i s i n females t r e a t e d al.,  to  1985).  that  Interestingly,  facilitate  r a t s (Kow, Zemlan &  observed  females  be  ( A r e n d a s h & G o r s k i , 1982; M e n d e l s o n  (Hunter  &  lordosis-  could  low  lordosis,  Pfaff,  doses  w h e r e a s d o s e s o v e r 9 mg/kg may i n h i b i t  estrogen-primed  (McCall  receptors,  2  and p r o g e s t e r o n e  and t o f a c i l i t a t e  l i m i t e d degree, i n s p i n a l have  nucleus  receptors.  2  f o u n d t o be i n e f f e c t i v e  of  neural excitatory  receptors  reported  females  estrogen  appears  derivative quipazine  affinity  1985). Q u i p a z i n e  quipazine  the  motor  t o 5 - H T T C , 5 - H T T B , a n d 5-HT  lower  5-HT,A  metabolite  e f f e c t s of h a l l u c i n o g e n i c tryptamines  high a f f i n i t y slightly  postsynaptic  ( the active  facial  l e a s t p a r t i a l l y due t o a c t i v i t y The  due t o a c t i v i t y a t  However, a t doses c o m p a r a b l e t o t h o s e  and  in  1986).  e f f e c t s of t h e N-methylated  and  lordosis, psilocin  enhances,  (Peroutka,  partially  autoreceptors  respectively.  sites  (Mendelson  &  of  to a  1979).  I  quipazine  lordosis in  Gorzalka,  unpublished  data). Quipazine  is  active  at  somato-dendritic  5-HT,A  127  autoreceptors facilitate  &  lordosis  inhibiting  de  by  Montigny,  reducing  action  as  a  weak  antagonist  corticosterone  with the s e l e c t i v e 1983).  In  5-HT  2  5-HT  of  lordosis-  antagonists  cyproheptadine, 1986a).  and  These  of  a g o n i s t DOM w i l l  2  2  pirenpirone,  surprising. subpopulation  with  LY53857  elevates treatment  (Cohen  et a l . , trained to  a l s o respond t o  pizotefin  ketanserin,  (Mendelson  suggest 5-HT  2  antagonists  that  these  drugs  Interestingly, o f 5-HT  2  &  quipazine  importantly,  by  t h e 5-  methysergide,  Gorzalka,  quipazine  receptors,  and  affinity  1985b,  facilitates  attenuates  restoring activity  receptors, the suggestion  effectively  quipazine  i s r e v e r s e d by  1 9 8 3 ) . P e r h a p s most  r e c e p t o r s . I n v i e w o f t h e much h i g h e r 5-HT  5-HTTB  the l o r d o s i s - i n h i b i t i n g e f f e c t s of  findings  5-HT  1982), However,  g e n e r a l i z a t i o n s t u d i e s , animals  l o r d o s i s by s t i m u l a t i n g effects  through i t s  agonist. Quipazine  2  antagonist  2  Young, & R o s e n c r a n s ,  quipazine attenuates  for  i t may  prejunctional  l e v e l s , and t h i s  5-HT  stimulus  respond t o the (Glennon,  at  (Martin & Sanders-Bush,  appears t o a c t p r i m a r i l y as a  2  activity  thus  r e l e a s e of 5 - H T i n c e r t a i n a r e a s  the  autoreceptors  HT  the  ,  s e r o t o n e r g i c p a t h w a y s . A t h i g h e r d o s e s , q u i p a z i n e may  enhancing  serum  1983)  l o r d o s i s by a c t i v a t i n g p o s t s y n a p t i c 5 - H T , A r e c e p t o r s , o r  inhibit by  (Blier  of  t o these  antagonists  that quipazine could  f o r 5-HT  recent  data  binding  2  indicate  binding s i t e s possesses  sites  is  that  a  a conformational  f o r 5-HT  Titeler,  h a s been f o u n d t o b i n d w i t h q u i t e  affinity (Lyon  1987). Q u i p a z i n e to  the agonist  binding  agonists  compete  state with high a f f i n i t y  2  (Lyon,  s t a t e o f t h e 5-HT  e t a l . , 1987). At m o d e r a t e l y h i g h doses,  the  Davis  2  &  high  receptor  quipazine  might  128  be  expected  is  worth  similar  t o d i s p l a c e 5-HT  noting to  that  DOM  DMT,  bind  5-MeODMT,  with  b i n d i n g ' s t a t e o f t h e 5-HT  antagonists  2  very  and  sites. I t  phenylalkylamines  high a f f i n i t y t o the agonist  receptor  2  from these  (Lyon e t a l . , 1987).  The p i p e r a z i n e MK 212 f a c i l i t a t e s l o r d o s i s , a n d t h i s has  been a t t r i b u t e d t o s t i m u l a t i o n o f 5-HT  Hunter,  1985).  MK  212  (Clineschmidt, McGuffin, of  5-HT  agonists  2  studies  show  low  a  very  receptors  ( Engel  determine  receptors  drugs  have  also  with  become  8-OH-DPAT,  primed  progesterone  the  and  progesterone  high  i n drug studies  and o t h e r  2  of  5-HT  interest binding  selectivity  to  state  for  5-H^A  The h i g h l y s e l e c t i v e  5-HT,A  slightly  less  with  estrogen,  & Gorzalka,  lordosis  facilitate  (Mendelson & G o r z a l k a ,  irfhibit with  females  lisuride primed  lordosis I986d).  in  Because  lordosisin  &  small doses of  with  ipsapirone  estrogen-primed  1986; E i s o n , E i s o n , S t a n l e y  1986)  estrogen and  drugs  & Riblet,  and  females  reduce  s e r o t o n e r g i c neurons i n t h e d o r s a l raphe  Hutson & Curzon,  Larsson,  (Peroutka,  doses,  both  partial  estrogen and  Hjorth  1986c,d). Extremely  5-HT,A a g o n i s t in  selective  or  Fernandez-Guasti,  ( S i e t n i e k s , 1985). A t lower  of  typical  binding  be  i p s a p i r o n e , and gepirone  somewhat s e l e c t i v e  activity  the  (Ahlenius,  inhibit  very  available.  either  Mendelson  gepirone  manner  o f MK 212 f o r 5-HT  e t a l . , 1986). I t would  agonists buspirone,  1986;  affinity  response  for quipazine  1 9 8 4 ) . However,  &  receptor.  2  Recently,  females  1977) i n a  i t substitutes  (Lucot,  (Wilson  the head-twitch  t h e a f f i n i t y o f MK 212 f o r t h e a g o n i s t  o f t h e 5-HT  agonist  & Pflueger,  and  discrimination  produces  receptors  2  effect  the  (Dourish, 1986) t h e  129  lordosis-facilitating activity It  e f f e c t s of  at somato-dendritic i s of  interest  i p s a p i r o n e , and gepirone ineffective lordosis  in  the  5-HT,A to  &  primed  Gorzalka,  5-HT,A  unpublished  agonists data)  1980) a n d  methyltryptamine  receptors  5-HT has  quipazine.  a  support  our  effects  progesterone  DPAT  (Mendelson (Hlinak,  LSD 5-HT  &  1987;  (Sietnieks agonist  &  a to  be  upon  treatment  with  recent  suggestion  that  of  activity  at  5-HT,A  I986d).  1-(3-trifluoromethylphenyl)piperazine  serotonergic binding p r o f i l e  similar  t o that of  TFMPP  inhibits  the  K +  r e l e a s e o f 5-HT f r o m h y p o t h a l a m i c s y n a p t o s o m e s ( M a r t i n  trained  1982).  In  stimulus  quipazine,  the  generalization  t o r e s p o n d t o TFMPP w i l l  agonists m-chlorophenylpiperazine 5-HT  2  agonist  studies,  respond t o the  5-HTTB  (MCPP) a n d RU24969, b u t n o t t o DOM,  or  8-OH DPAT (Cunningham & A p p e l ,  Young, 1984). P e r i p h e r a l lordosis  inhibit  However, TFMPP a p p e a r s t o a c t p r i m a r i l y a s an a g o n i s t  Sanders-Bush,  agonist  buspirone,  alone  and  agonist  receptors. Unlike quipazine,  5-HTTB  to  l o r d o s i s or are  lisuride  dependent  the  agonist  of  Sano & Wade, 1975) a l s o a p p e a r or  enhances  8-OH  uncharacterized  (Mendelson & G o r z a l k a ,  The  animals  by  These d a t a  progesterone  &  (Espino,  enhanced  progesterone.  induced  doses  estrogen  and  Meyerson,  the  due  The l o r d o s i s - i n h i b i t i n g e f f e c t s  1 9 8 5 ) , t h e 5-HT,A a c t i v e  at  that  with  I986d).  be  autoreceptors.  note  Sietnieks,  (TFMPP)  may  that e i t h e r f a c i l i t a t e  females  selective  Gorzalka,  either  drugs  i n females primed w i t h both estrogen  (Mendelson of  these  administration  the  selective  5-HT,A  1986; G l e n n o n , McKenny & of  TFMPP  facilitates  i n estrogen-primed females(Experiment 8 ) . In a d d i t i o n ,  1 30  I have v e r y  r e c e n t l y o b s e r v e d t h a t 0.03 mg/kg o f t h e p u t a t i v e 5-  HT,B a g o n i s t CGS 12066B ( N e a l e , F a l l o n , B o y a r , Stone, Glaeser,  Sinton  estrogen-primed  females  d a t a ) . Together, these autoreceptors  & Williams, (  data  reported  to  suggest  &  Gorzalka,  that  unpublished  prejunctional  mediate l o r d o s i s - f a c i l i t a t i n g  inhibit  Martin,  1987) f a c i l i t a t e s l o r d o s i s i n  Mendelson  apparent c o n t r a d i c t i o n t o t h i s  Wasley,  possibility,  S-H^B  e f f e c t s o f 5-HT. I n RU  24969  l o r d o s i s (Hunter & W i l s o n ,  has  been  1985). However,  w h e r e a s RU 24969 h a s o f t e n been c h a r a c t e r i z e d a s a s e l e c t i v e HT,B  a g o n i s t , the drug binds  5-HT,A Indeed,  receptors  with nearly equal  (Tricklebank,  a t doses t h a t  inhibit  Middlemiss  RU 24969 m i m i c s t h e h y p o t h e r m i c e f f e c t o f t h e agonist  8-OH  DPAT  high a f f i n i t y to  &  l o r d o s i s (Wilson  Neill,  1986).  & Hunter, 5-HT,A  ( T r i c k l e b a n k e t a l . , 1986). Recent  is  the  (Kennett,  possibility  Dourish  & Curzon,  that higher  facilitated  lordosis  postsynaptic this  5-HT,B  sites. at  doses  serotonergic  evidence as p r e -  1987). T h e r e f o r e ,  there  d o s e s o f 5-HT,B a g o n i s t s  could  produce l o r d o s i s - i n h i b i t i n g e f f e c t s through postsynaptic  1985),  selective  s u g g e s t s t h a t 5-HT,B r e c e p t o r s may e x i s t p o s t - a s w e l l synaptically  5-  However, that  stimulation  action  the  at  fact  that  appeared tends  certain  to  TFMPP produce  t o argue  against  possibility.  Conclusions  In r e v i e w i n g it  becomes  facilitate  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  apparent  that  the expression  serotonin  can  and  either  of l o r d o s i s behaviour  in  agonists  inhibit the  or  female  131  rat.  It  serotonin  appears  that  a r e mediated  receptors.  It  the  lordosis-inhibiting  primarily  conclusion  forebrain  means,  I  levels,  lordosis.  On  the  f u r t h e r suggest that  lordosis-facilitating  m e d i a t e d p r i m a r i l y by to  5-HT  important again  role  agonist  There  5-HT  Giblin  formation  & Pfaff,  mediate neural (Haigler recently  &  receptors  3  2  receptors  2  play  2  a  tempting possessing  particularly  receptors  receptors.  I might  tend  also to  I therefore  cannot  at certain  stimulation  facilitates  lordosis  of  populations  (  the  excitatory effects 1974a;  of  5-HT  serotonin  Peroutka  et  medullary  Cohen, S c h w a r t z -  1987). Moreover, i t appears t h a t  antagonist formation  administration  of  LY  may  lordosis.  that  Aghajanian,  preliminary  in  2  receptors this  53857  inhibits  quipazine  into  directly  into  lordosis, this  area  area  a l . , 1981). Very  I have found t h a t t h e a d m i n i s t r a t i o n of s m a l l doses  5-HT  reticular  of  t h e s e e f f e c t s . Of c o u r s e ,  that a c t i v i t y  enhances  i s evidence  reticular  the  of  s t a t e may  5-HTTC  the p o s s i b i l i t y  5-HT,C receptors  or s u r g i c a l  e f f e c t s of s e r o t o n i n .  note that drugs s e l e c t i v e f o r 5 - H T  eliminate of  binding  to  depletion  r e c e p t o r s . Moreover, i t i s  2  (cited  e f f e c t s o f s e r o t o n i n a p p e a r t o be  i n mediating  bind with high a f f i n i t y  basis  f o r e b r a i n 5-HT  suggest that the subpopulation  a high a f f i n i t y  forebrain.  by e i t h e r c h e m i c a l  m e d i a t e some o f t h e l o r d o s i s - i n h i b i t i n g The  i n the  receptors  1985b) i n d i c a t i n g t h a t s i m p l e  serotonin  facilitates  evidence,  t h e 5-HT!A  primarily  of  5-HT,A  i s c o n s i s t e n t with the v a r i e t y of reports  in Mendelson & Gorzalka, of  post-synaptic  i s tempting t o suggest that  that mediate these e f f e c t s e x i s t This  by  effects  of  the medullary whereas  the  i s facilitatory  132  (unpublished  data).  reports  facilitation  of  forebrain  serotonin,  facilitating neural  I n view o f t h e s e r e s u l t s , and of  I  effects  of  serotonin a t 5-HT  at  5-HT  receptors  2  been s u g g e s t e d t h a t receptors  co-exist,  5-HT  2  o f 5-HT, r e c e p t o r s .  appears  to  Sprouse  by  activity  at  Conversely,  &  forebrain activity  adjacent  5-HT,A a t 5-HT  2  2  antagonists  activity  5-HT,A  a t 5-HT,  1987).  5-HT  be  would i n h i b i t  e f f e c t s of  the  forebrain.  l o r d o s i s by f r e e i n g  from  receptors.  I t i s i n t e r e s t i n g to consider  the modulating  i n a f f e c t i n g l o r d o s i s might vary  also  effects  serotonergic  forebrain.  suggest  I further  that  2  of that  agonists  as a f u n c t i o n  activity. a t somato-dendritic  facilitate  lordosis-inhibiting  2  that  receptors  may  2  receptors  I t may  in  lordosis  t h i s w o u l d be due t o r e d u c t i o n s  autoreceptors  5-HT  can f a c i l i t a t e l o r d o s i s  receptors  Evidence suggests that a c t i v i t y  Ostensibly,  I t has  at  lordosis-inhibiting  l e v e l s of s e r o t o n e r g i c  autoreceptors  which  t o modulate t h e  t h i s m e c h a n i s m , t h e a p p a r e n t e f f e c t i v e n e s s o f 5-HT  of b a s e l i n e  As  by  lordosis.  may s e r v e  receptors  the  antagonists  2  lordosis-  mechanism  I n some a r e a s ,  Rasmussen,  attenuating  5-HT  the  might f a c i l i t a t e  receptors  s e l e c t i v e s t i m u l a t i o n o f 5-HT indirectly  d e p l e t i o n of  i n the brainstem.  d i m i n i s h the e f f e c t s of a c t i v i t y  (Aghajanian,  many  a r e m e d i a t e d p r i m a r i l y by receptors  2  the  i n a r e a s o f t h e b r a i n where 5-HT, a n d  activity  and  that  i s t e m p t i n g t o o f f e r an a d d i t i o n a l  activity  by  following  hypothesize  excitatory activity  It  lordosis  of  behaviour.  i n the a c t i v i t y  pathways activity  o f t h e 5-HT,B t y p e f a c i l i t a t e s  w i t h t h e a c t i v a t i o n of a u t o r e c e p t o r s  5-HT,A  ascending at  of  t o the  prejunctional  lordosis activity.  o f t h e 5-HT,A t y p e ,  the  133  activation  o f p r e j u n c t i o n a l 5-HT,B r e c e p t o r s  reduction  of  activity  serotonergic  pathways.  in  I n summary, I h y p o t h e s i z e or  facilitate  effects HT,A  in  effects  are  further  suggest  3  the  mediated  autoreceptors  HT  lordosis-inhibiting  s e r o t o n i n can e i t h e r  I suggest that  the  inhibit  inhibitory  o f s e r o t o n i n a r e m e d i a t e d p r i m a r i l y by p o s t - s y n a p t i c  receptors  Finally,  certain  that  l o r d o s i s behaviour.  would r e s u l t i n t h e  by  that  in  forebrain, 5-HT  the  raphe  receptors  2  activity  whereas  at  the  i n the brainstem.  may  facilitate  on t h e b a s i s o f p r e l i m i n a r y e v i d e n c e ,  receptors  may m e d i a t e i n h i b i t o r y , a n d  autoreceptors  facilitatory  facilitatory  somato-dendritic  nuclei  effects  of  5-  I  5-HT,A lordosis.  I s u g g e s t t h a t 5-  prejunctional serotonin  S-HT^B  on l o r d o s i s  behaviour.  IMPLICATIONS FOR UNDERSTANDING EFFECTS OF SEROTONERGIC DRUGS ON HUMAN BEHAVIOUR  The  reproductive  different earlier,  from  on  behaviour of  exposure  magnitude and nature through  her  levels.  physical expression the  human  to  the  estrogen.  female  c y c l e , the sexual  largely  There  are  of s e x u a l  independent also  rat  is  entirely  I n c o n t r a s t , whereas t h e  of her sexual m o t i v a t i o n  menstrual  f e m a l e a p p e a r s t o be estrogen  considerably  t h a t o f t h e human f e m a l e . F o r e x a m p l e , a s n o t e d  the sexual  dependent  b i o l o g y of t h e female r a t i s  may v a r y  activity of  somewhat  o f t h e human  fluctuations i n  d i s t i n c t differences i n the  behaviour  i n the  female. For example, t h e r e f l e x i v e  female  r a t and  l o r d o s i s response  134  has  no o b v i o u s c o u n t e r p a r t i n t h e  might  be  noted  human  that the stimulation  female.  (generally  insertions  of  the  uncharacteristic  less male's  the  the female  greatest  ten  well-spaced  and  2 or 3 seconds i n d u r a t i o n )  penis,  of t h a t e x p e r i e n c e d  t h e human f e m a l e . F i n a l l y , that  than  i t  r e c e i v e d by t h e f e m a l e r a t  i n c o p u l a t i o n , which might i n c l u d e s i x t o short-lived  Moreover,  would  be  decidedly  (or a t l e a s t expected!)  of c o u r s e , i t should  be  by  emphasized  d i f f e r e n c e s between t h e s e x u a l b e h a v i o u r of  r a t a n d t h a t o f t h e human f e m a l e  rich emotional, social,  l i e i n the extremely  a n d c o g n i t i v e c o m p o n e n t s o f human s e x u a l  behaviour. In view  of the extreme d i f f e r e n c e s  of t h e female relevance  r a t and t h e human f e m a l e , one m i g h t  the  effects  behaviour  contribute  lordosis  directly of  understanding could  of t h e  s e r o t o n e r g i c drugs in  general.  to human  our  role  female  of  First,  serotonin  the  sexual present  on l o r d o s i s may of  sexual behaviour.  of the e f f e c t s of s e r o t o n e r g i c  possibily  sexual  I believe  on human f e m a l e  understanding  the  Indeed, drugs  a on  l e a d t o t h e d e v e l o p m e n t o f an a n i m a l  model of t h e of s e r o t o n e r g i c m o d u l a t i o n women. I n v i e w  the  t h e p r e s e n t d a t a may  of the e f f e c t s of s e r o t o n e r g i c drugs  neuropharmacology thorough  of  a n d human b e h a v i o u r  evaluation  female  However, d e s p i t e t h e s e o b v i o u s d i f f e r e n c e s  be o f r e l e v a n c e t o t h e u n d e r s t a n d i n g the  question  o f human  t h a t t h e r e a r e a t l e a s t t h r e e ways i n w h i c h  and  behaviours  present d a t a might h o l d f o r t h e u n d e r s t a n d i n g of  the r o l e of s e r o t o n i n i n the modulation behaviour.  i n the sexual  of s e x u a l  behaviour  in  of the s e r i o u s l a c k of i n f o r m a t i o n c o n c e r n i n g t h e  neuropharmacology  of  human,  particularly  female,  sexual  135  behaviour, value.  a s u c c e s s f u l animal  Second,  understanding drugs  and  the  of  model  present  potential  would  data  be  of  may p r o v i d e  interactions  substantial  a basis f o r the  between  serotonergic  t h e g o n a d a l s t e r o i d hormones i n humans. T h i r d ,  d a t a may a l l o w  further insight  i n t o p o t e n t i a l sex d i f f e r e n c e s i n  humans i n t h e r e s p o n s e s t o s e r o t o n e r g i c Although  great  neuropharmacology  drugs.  s t r i d e s h a v e b e e n made i n u n d e r s t a n d i n g of  a f f e c t i v e behaviour,  very  little  the  i s known  a b o u t t h e n e u r o p h a r m a c o l o g y o f human s e x u a l b e h a v i o u r . it  these  Moreover,  a p p e a r s t h a t most o f what i s known a b o u t t h e e f f e c t s o f d r u g s  on human s e x u a l b e h a v i o u r mechanical  aspects  of  i s known i n r e g a r d s male  sexual  ejaculation. Relatively l i t t l e drugs  on  sexual  motivation  to  behaviour,  i s known  about  or s a t i s f a c t i o n  the  somewhat  erection the  and  effects  of  i n e i t h e r males or  females. In s p i t e of a r e l a t i v e there  l a c k o f i n f o r m a t i o n on d r u g  i s evidence t o suggest that the sexual behaviour  females  i s at least p a r t i a l l y  under s e r o t o n e r g i c  e x a m p l e , women r e c e i v i n g t h e monoamine o x i d a s e phenelzine, depression libido  tranylcypromine,  experience thought  orgasm  to  enzymatic  anorgasmia, &  produce t h e i r  breakdown  neurotransmitters. e f f e c t i v e n e s s of facts  that  (Shen  suggest  of  that  Sata,  (MAO)  inhibitors  1983).  loss MAO  of  loss  of  ability  to  inhibitors  are  t h e r a p e u t i c e f f e c t s by p r e v e n t i n g t h e serotonin  and  the  catecholeamine  w i t h MAO  i n h i b i t o r s , the  neurotransmitters  the  human  influence. For  to experience  i s , the  Following treatment these  of  and i s o c a r b o x i d e as t r e a t m e n t s f o r  have f r e q u e n t l y been r e p o r t e d  and  effects,  sexually  i s enhanced.  These  i n h i b i t o r y e f f e c t s of these  1 36  d r u g s may be a t l e a s t p a r t i a l l y types  of  serotonergic  antidepressant  drugs,  nortriptyline  and  reported  to  (Buffurn,  1986).  thought t o neurons  serotonin  HT  their  Seeman,  in  human  tricyclic  females  have l o n g by  (and t o  that  occurs  preventing some  degree  (re-uptake)  concentrations  of s e r o t o n i n  the  effects  of the  of  the t r i c y c l i c  ability  t o block  low  affinity  little,  i f any, sexual  known  serotonergic  (Tang  of  &  behaviour  administration  at  5-HT  2  a t 5-  receptors.  desipramine, serotonin  of  a drug  and  with  r e c e p t o r s , appears t o produce  2  impairment  (Buffum,  i s the fact  that  1986). the  substance  on t h e s t r e e t a s a ' l o v e d r u g  (Naranjo,  t o 5-  systems, i t  of sexual  the  activity  reuptake  a n d h a s been c o n s i d e r e d stimulant  high a f f i n i t y  1983). In view of t h e  antidepressant  f o r 5-HT  further interest been  with  known  i s due t o i n c r e a s e s o f a c t i v i t y  blockade  been  recovery  drugs i n t e r a c t with  rather  has  anorgasmia  appear t o a c t as a n t a g o n i s t s  antidepressants  little  sexual  higher  been  a r e e n h a n c e d . More r e c e n t l y i t h a s become  HT, r e c e p t o r s a n d  1978)  effects  serotonin  imipramine,  and  antidepressants  t o suggest that the i n h i b i t i o n  Interestingly,  tricyclic  frequently  libido  1980; S t o l z , M a r z d e n & M i d d l e m i s s ,  tempting  which  in  drugs a l s o b i n d w i t h r e l a t i v e l y  is  Of  also  w i t h t a r g e t neurons and  ways i n w h i c h t h e s e  with  receiving  i t s r e l e a s e . When t h e  r e c e p t o r s , where t h e y  2  have  therapeutic  i s blocked,  neurotransmitter these  tricylic  in certain  amitriptyline,  decreases  recovering  remain i n c o n t a c t  that  including  These  after  Women  clomipramine,  produce  noradrenalin) of  activity.  experience  from  be due t o i n c r e a s e s  by some r e s e a r c h e r s  Shulgin  & Sargent,  to  MDA,  ' (Gawin, a c t as  1967), a l s o  a  binds  137  with r e l a t i v e l y  high a f f i n i t y  Rosencrans,  1982).  to  5-HT  However,  receptors  2  unlike  (Glennon  the  tricyclic  a n t i d e p r e s s a n t s , MDA a p p e a r s t o a c t a s an a g o n i s t a t 5-HT (Glennon  &  Rosencrans,  hallucinogenic harmala  shrub  medicines  1982; S h a n n o n ,  harmala  alkaloids,  1980).  derived  affinity  Susilo,  Nick  indoleamine  to &  5-HT  Hill,  and  2  receptors  1985).  In  e f f e c t s t h r o u g h s t i m u l a t i o n o f 5-HT Rosencrans,  effects  of  to  to  reverse  antagonists  faciliate the  rat,  pirenpirone  serotonin  the harmala  theory  that  produce  their  ( G l e n n o n , Young &  If  harmala  2  alkaloids  and  alkaloid  in  this  are at least  harmine  speculative,  is  effects  ketanserin  has  been  of  the  (Mendelson  5-HT  2  & Gorzalka,  i ti s tempting  to  suggest  i n t h e human f e m a l e , a s i n t h e f e m a l e  serves a dual role this  sexually  receptors. In this context  indeed  i n the modulation the case,  serotonergic c o n t r o l of l o r d o s i s behaviour proposed  Bruning,  l o r d o s i s behaviour i n t h e female r a t and  t h e above d a t a t h a t  behaviour.  receptors  2  lordosis-inhibiting  I986e). Although h i g h l y from  the  hallucinogens  due t o s t i m u l a t i o n o f 5-HT  i t must be n o t e d t h a t t h e reported  of  folk  moderately  1983), i t i s c o n c e i v a b l e t h a t t h e a l l e g e d  stimulating partially  with  (Rommelspacher, view  phenylalkylamine  i n the  1978). Moreover,  some h a r m a l a a l k a l o i d s have been f o u n d t o b i n d high  mildly  t h e Perqanum  , h a v e a l s o been u s e d a s a p h r o d i s i a c s  o f I n d i a and t h e M i d d l e E a s t (Gawin,  sites  2  The  from  St  dissertation  may  be  understanding and p r e d i c t i n g t h e e f f e c t s of  then in of  of  sexual  t h e model o f  the some  female r a t value  serotonergic  in  drugs  on human f e m a l e s e x u a l b e h a v i o u r . The  present  s e r i e s o f s t u d i e s may a l s o be o f r e l e v a n c e i n  138  understanding  the  behaviour  opening  by  s e r o t o n e r g i c drugs It  i s common  use  i n humans  However, used  effects  of  the  possibility  drugs  knowledge t h a t t h e e f f e c t s are  first  evaluated  on  human  of i n t e r a c t i o n s  a n d t h e hormones e s t r o g e n  and  between  progesterone.  of drugs d e s t i n e d f o r  i n experimental  animals.  what i s r a r e l y c o n s i d e r e d i s t h e f a c t t h a t t h e a n i m a l s  i n these e v a l u a t i o n s a r e almost  seems t h a t t h e f l u c t u a t i o n s the  serotonergic  invariably  male a n i m a l s . I t  i n hormone l e v e l s t h a t  characterize  e s t r o u s c y c l e s of f e m a l e s , and t h e b e h a v i o u r a l changes t h a t  accompany t h e s e sources  of  fluctuations, variance  Unfortunately, evaluating  this  potential  are  in  bias  looked  standard  as  unwelcome  behavioural  eliminates  interactions  upon  the  paradigms.  possibility  of  between drugs and t h e o v a r i a n  hormones. Because  the  dependent  upon  evaluation  of  full  expression  exposure the  to  effects  the  of  of  lordosis  female  drugs  on  sex  behaviour hormones,  lordosis  p r o v i d e s an i d e a l o p p o r t u n i t y t o e v a l u a t e p o t e n t i a l interactions.  In  the s e l e c t i v e inhibited which primed  behaviour  drug/hormone  6 i t was f o u n d t h a t h i g h d o s e s o f  b e h a v i o u r . However, low doses o f t h e s e  facilitated  lordosis  w i t h b o t h e s t r o g e n and p r o g e s t e r o n e . that  the  From  i n females  these  lordosis-inhibiting effects  data  the  s h o u l d be n o t e d t h a t s e r o t o n e r g i c d r u g s treatment  of a v a r i e t y  primed i t was  of these  a r e e n h a n c e d by p r o g e s t e r o n e . W i t h t h e s e p o s s i b i l i t i e s it  drugs,  o r were i n e f f e c t i v e i n f e m a l e s  with estrogen alone, i n h i b i t e d l o r d o s i s  suggested  the  5-HT,A a g o n i s t s b u s p i r o n e , i p s a p i r o n e a n d g e p i r o n e  lordosis  either  Experiment  is  in  drugs mind  a r e now p r e s c r i b e d i n  of a f f e c t i v e d i s o r d e r s .  Indeed, t h e  139  selective  5-HT,A a g o n i s t  available  i n Canada  buspirone  as  a  treatment  p r o g e s t e r o n e does enhance t h e sites,  then  anxiolytic  effects  i t i s conceivable  e f f e c t s of these  psychotherapeutic  has  to of  that  drugs.  effectiveness  just  relieve anxiety. I f agonists  at  possibility  these  drugs  concern  and  progesterone  levels  should  be  t o t h e m e d i c a l c o m m u n i t y . However, t o  knowledge  this  possibility  has  not  5-HT,A  been  that  the  might  through the menstrual c y c l e as a f u n c t i o n of changing estrogen  become  i t might a l s o a l t e r t h e  The of  recently  vary  levels  of  of c o n s i d e r a b l e the  best  addressed  of  my  i n the  literature. I t may a l s o be r e c a l l e d t h a t 5-HT,A a g o n i s t s p r o d u c e effects  on  b e h a v i o u r by m i m i c k i n g t h e e f f e c t s o f s e r o t o n i n . I f  e s t r o g e n a n d p r o g e s t e r o n e do agonists,  their  then  modulate  the  effects  i t i s reasonable t o suggest  of  5-HT,A  t h a t t h e s e hormones  modulate the a c t i v i t i e s of s e r o t o n i n i t s e l f  a t 5-HT,A r e c e p t o r s .  Therefore,  i n view of  activity  receptors  may  anxiety  in  the  some  evidence  way  ( D o u r i s h e t a l . , 1986),  be  that  involved  receptors  by  5-HT,A  i n the experience of  the r e s u l t s of Experiment  lead to the suggestion that abnormalities i n the 5-HT,A  at  progesterone  may  be  6 also  modulation  involved  p a t h o g e n e s i s o f mood d i s o r d e r s a s s o c i a t e d w i t h t h e  of  i n the  premenstrual  syndrome. Finally,  when  experiments  now  possibility  that  to  taken  i n progress,  of  the  with  present  the data  t h e r e may be s e x d i f f e r e n c e s  s e r o t o n e r g i c d r u g s . As  effects  together  receptor  with  subtype  female selective  rats, drugs  results raise  of the  i n the responses studies on  on t h e  the sexual  140  b e h a v i o u r o f male r a t s have o n l y several  c a s e s t h e r e have a p p e a r e d  the effects- of c e r t a i n the  recently  However,  subtype-selectiveserotonergic  5-HT,A a g o n i s t 8-OH DPAT i n h i b i t s 8) b u t f a c i l i t a t e s  drugs  r a t s . The f a c t  l o r d o s i s behaviour  sexual behaviour  Experiment  sex d i f f e r e n c e s  8)  suggests that  i n the responses  in  females  i n male r a t s ( a s  sexual  the  behaviour  agonists and  in  effects  t o t h e newly  of  facilitate  rats.  available  behaviour  d a t a ) . Indeed,  , these drugs  occurs  sufficient  t o completely  behaviour  in  at  male  1987)  inhibit  receptor,  at least  It  in  the  S-H^D  i n areas throughout  the  other  5-HT,B  (Experiment 8 expression  of  lordosis  5 times higher than  be  expression noted  brain  is  human  of  those sexual  that the  tissue.  receptor, the  of  & Gorzalka, unpublished  the  must  human  t h e r e a r e sex  facilitation  eliminate  rats.  and  i n females  (Mendelson  doses  r e c e p t o r does not occur  concentrations  TFMPP  i n t h e c a s e o f TFMPP,  behaviour  analagous  Whereas  i n males  5-HTTA  5 - H T T B - s e l e c t i v e d r u g s on t h e  l o r d o s i s behaviour  unpublished data)  sexual  of  female  i n humans t h e r e may a l s o be  s e l e c t i v e a n x i o l y t i c s . Evidence a l s o suggests that differences  on  that the  w e l l as t h e male s e x u a l b e h a v i o u r of t e s t o s t e r o n e t r e a t e d rats;  in  t o be d r a m a t i c d i f f e r e n c e s i n  s e x u a l b e h a v i o u r of male and female  (Experiment  begun.  5-HTTB  However, found  brain  an  i n dense  (Palacios,  A t p r e s e n t , t h e f u n c t i o n o f t h e 5-HT,D r e c e p t o r i n humans  remains  unknown. However, i t i s r e a s o n a b l e t o  function  of  will  developed  be  therapeutic differences  these receptors w i l l to  purposes.  alter  assume  that  be e l u c i d a t e d , a n d t h a t  their  activity  for  the drugs  specific  I n v i e w o f what a p p e a r t o be d r a m a t i c s e x  i n the responses  t o 5-H^B  agonists i n the  rat,  i t  141  is  reasonable  differences  to  suspect  that  there  could  also  be  i n the responses t o 5-HT,D-selective drugs that  sex may  become a v a i l a b l e i n t h e f u t u r e .  Summary  In  this  dissertation  I  have  evaluated  the  e f f e c t s on  l o r d o s i s b e h a v i o u r of drugs t h a t a c t s e l e c t i v e l y  at  subtypes  evaluating the  of  central  serotonin  receptors.  e f f e c t s o f t h e s e d r u g s I was a b l e the  dual  role hypothesis  behaviour  (Mendelson  statement of t h e dual receptors  both t o confirm  of serotonergic Gorzalka,  and t o  extend  modulation of l o r d o s i s  1985b).  r o l e hypothesis  known  In  the  original  i t was p r o p o s e d t h a t  5-HT,  mediate the l o r d o s i s - i n h i b i t i n g e f f e c t s of s e r o t o n i n ,  w h e r e a s 5-HT serotonergic series  &  By  the  of  2  receptors activity.  mediate l o r d o s i s - f a c i l i t a t i n g From e v i d e n c e  experiments  i t was  gathered  concluded  in  that  e f f e c t s of  the  present  the l o r d o s i s -  i n h i b i t i n g e f f e c t s o f s e r o t o n i n a r e m e d i a t e d p r i m a r i l y by t h e 5HT,A  subtype of r e c e p t o r .  a t c e n t r a l 5-HT The at  present 5-HT  2  3  s i t e s might a l s o  data  receptors  indicated  that  autoreceptors  I t was f u r t h e r s u g g e s t e d t h a t inhibit  tended t o c o n f i r m facilitates  the hypothesis  lordosis.  stimulation  lordosis  of  However,  lordosis  facilitating  e f f e c t s of s t i m u l a t i o n of  of  autoreceptors  would  activity  of  lordosis-inhibiting  activity  these  somato-dendritic  facilitate  subtypes  behaviour.  that  a n d 5-HT,B p r e j u n c t i o n a l a u t o r e c e p t o r s behaviour.  activity  Ostensibly,  be  5-HT,A  might  the  data  also  lordosis-  the  5-HT,A  due  to decreases i n the  serotonergic  and  pathways.  5-HT,B  The  142  question  of  receptors  5-HTTB  The was  what, i f a n y r o l e m i g h t be p l a y e d r e m a i n s t o be d e t e r m i n e d .  e v a l u a t i o n of l o r d o s i s behaviour  performed with animals  administered  the  f e m a l e s e x hormones e s t r o g e n  and  of  d r u g e f f e c t s under d i f f e r i n g  steroid  opportunity  to  effects  the  of  steroids.  evaluate  concluded  of  that  particularly  existing  the  those  effects active  e n h a n c e d by e x p o s u r e t o Finally, implications effects  in  the  of  provided the  in  the  between  effects  r a t may the effects  behaviour  of  the e f f e c t s may  closing  serotonergic  drugs,  s i t e s , may be  behaviours  of  I  discussed  the  be  of  sexual  I suggested  behaviour  o f some u s e i n u n d e r s t a n d i n g  of  serotonergic  model  some  e v a l u a t i o n of t h e  drugs  on  in  and even  the  sexual  suggested that the e v a l u a t i o n of  to  the  examine  sexual  behaviour  interactions  s e r o t o n e r g i c d r u g s a n d t h e s t e r o i d s e x hormones a s w e l l differences  by  i t was  section  o f s e r o t o n e r g i c d r u g s on a  and  the l i t e r a t u r e  a s a g o n i s t s a t 5-HT,A  women. 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