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Sexual behaviour enhancing effects of melatonin Brotto, Lori Anne 1999

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S E X U A L B E H A V I O U R E N H A N C I N G EFFECTS OF M E L A T O N I N by LORI A N N E BROTTO B . S c , The University o f British Columbia, 1997  A THESIS SUBMITTED IN P A R T I A L F U L F I L L M E N T OF THE REQUIREMENTS FOR T H E D E G R E E OF M A S T E R OF ARTS in T H E F A C U L T Y OF G R A D U A T E STUDIES Department of Psychology  We accept this thesis as conforming to the required standard  T H E UNIVERSITY OF BRITISH C O L U M B I A A p r i l 1999 © Lori Anne Brotto, 1999  In presenting this thesis in partial fulfilment  of the  requirements for an advanced  degree at the University of British Columbia, I agree that the Library shall make it freely available for reference and study. I further agree that permission for extensive copying of this thesis for scholarly purposes may be granted by the head of my department  or by  his  or  her  representatives.  It  is  understood  that  copying or  publication of this thesis for financial gain shall not be allowed without my written permission.  Department The University of British Columbia Vancouver, Canada  DE-6 (2/88)  ABSTRACT  Anecdotal reports suggest that melatonin enhances libido i n men. However, controlled trials remain to be published for any species. Accordingly, male rats were chronically treated for 12 weeks with melatonin v i a the drinking water. A l l aspects o f sexual activity, including measures o f both libido and potency, were significantly facilitated. In addition, there was a consistent, progressive reduction in the frequency o f wet dog shake behaviour, suggestive o f a temporal decrement in serotonergic receptor activity. To date, this is the first empirical report of a facilitatory role for melatonin in sexual behaviour.  T A B L E OF CONTENTS Page Abstract  ii  Table o f Contents  iii  List o f Figures  iv  Acknowledgements  v  INTRODUCTION A N D METHODS  1  RESULTS  3  DISCUSSION REFERENCES  :  4 7  iv LIST OF FIGURES Page Figure 1: Effects o f chronic melatonin treatment (3mg/week) on frequency o f ejaculations, copulatory efficiency, and wet dog shakes.  9  ACKNOWLEDGEMENTS  M y sincere thanks go out to my supervisor, Boris Gorzalka, for trusting me and allowing me to make my own decisions, and for his unceasing support, guidance, and humor. Many thanks must go out to the undergraduate students who have helped me conduct this research, and who have shown their continual devotion. I would also like to thank Liisa Galea and Wolfgang Linden, my thesis committee members, for their helpful comments on this thesis. Finally, I must recognize my parents who have been my scaffold throughout my schooling career, and to E d Fontana for all his love and for keeping me sane.  INTRODUCTION A N D METHODS  Melatonin has been postulated to be involved in a number o f behavioural and physiological processes, and controlled clinical trials have established its therapeutic efficacy for specific sleep abnormalities . Whereas melatonin's role in reproductive 1  physiology is reasonably established , its potential function in reproductive behaviour has received only scant attention. Melatonin fluctuations resulting from seasonal variations in light duration have been shown to control pubertal development in several species. Although data linking melatonin to pubertal development in the human remain equivocal , deficiencies in melatonin may be related to impaired sexual functioning in human males. For example, abnormally l o w levels o f melatonin have been reported in men with psychogenic impotence ' , and it has been speculated that dietary melatonin 4  5  supplementation might reverse some aspects o f diseases associated with l o w levels o f melatonin . In addition, there exists an age-related decline in plasma melatonin levels 5  6  coinciding with a steady reduction i n the frequency o f sexual activity, sexual motivation, and potency ' . Furthermore, despite the absence o f randomized control trials, individuals taking melatonin for sleep difficulties have celebrated it's libido-enhancing properties . 9  In addition to its own receptors in the mammalian brain, melatonin interacts directly with receptors from other neurotransmitter systems, or their second messenger responses. Central mechanisms o f action for melatonin have been widely studied, and i n particular, interactions o f melatonin with the serotonergic system have been extensively investigated . For example, Eison et al. (1995) used radioligand binding, 10  11  2  phosphoinositide hydrolysis, and observations o f the serotonergic type 2 A ( 5 - H T ) 2A  receptor-mediated behaviour "Wet D o g Shakes" (WDS) to infer a 5 - H T  2 A  antagonism by  melatonin. W D S correlate positively with increases i n serotonergic activity  12  and have  been considered a reliable behavioural assay o f 5-HT2A receptor activity in vivo  .  13  Further support for a melatonin-serotonin interaction originates from receptor ligandbinding studies which have revealed 5 - H T  receptors in the pineal g l a n d . In addition, 14  2 A  melatonin pretreatment has been found to attenuate the 5 - H T A agonist, l-(2,52  domethoxy-4-methylphenyl)-2-aminopropane ( D O M ) - induced effects on sleepwakefulness regulation in the r a t . Taken together, these studies suggest that melatonin 15  might possess 5 - H T A antagonistic properties. 2  The rat has become widely used as a model for human copulatory functioning, as sexual arousal in male rats and humans has been shown to possess several physiological similarities  1 6  . For instance, rat penile reflexes following central and pharmacological  manipulation have been utilized to understand erectile functioning i n humans with spinal injuries. Moreover, agents which have been found to enhance erection in rats have successfully been used as therapeutic treatments for human erectile dysfunction. Behaviours representative o f human libido and potency have been elucidated i n the rat . 17  Accordingly, sexually proficient, male Long-Evans rats at 9 months o f age (500-700g), were given melatonin v i a the drinking water (.004g/litre) in a manner previously 1 8 *  described . This melatonin regimen has been shown to retard the age-related decline i n survival rates o f male rats. Following a baseline sexual behaviour test, after which similarly proficient animals were matched and then randomly assigned to either the  3 melatonin or the control condition, males were tested at weekly intervals, for an additional 12 weeks, on measures o f sexual behaviour and W D S , in the presence o f ovariectomized female rats made receptive by lOug estradiol benzoate and 500ug progesterone. Clean water bottles replaced used ones on a weekly basis, and fresh solutions were prepared every 2 days. The average fluid consumption per rat was 0.75 litres/week, which is equivalent to a weekly melatonin intake o f approximately 3 mg/rat. Measures representative o f sexual potency (copulatory efficiency and frequencies o f mounts, intromissions, and ejaculations) and libido (mount, intromission, and ejaculatory latencies, as well as post-ejaculatory intervals) were observed and scored. Copulatory efficiency was defined as the proportion o f mounts resulting in vaginal penetration to the total number o f mounts (with and without intromission). The post-ejaculatory interval was computed as the duration o f time, in seconds, between the initial ejaculation, and the following intromission. In addition, the frequency o f W D S (defined as a paroxysmal 17  rotation o f the upper body ) was tallied for the 30 minute observation.  RESULTS A between-within repeated measures analysis o f variance investigating betweentreatment differences, and variation over time, was performed on all the data. Statistical analysis revealed that melatonin treatment significantly facilitated all measures o f sexual potency and libido, except ejaculatory latency and intromission frequency. Mount and intromission latencies [treatment: F ( l , 19) = 6.626, p = .019 and F ( l , 19) = 4.794, p = .041, respectively], and post-ejaculatory intervals [treatment: F ( l , 13) = 5.718, p = .033] were significantly shorter i n melatonin-treated animals, suggesting increased l i b i d o . 17  4 Mount frequency prior to ejaculation was significantly reduced [treatment: F ( l , 16) = 4.943, p = .041], ejaculation frequency was increased [treatment: F ( l , 19) = 4.455, p = .048] (Fig. 1A), and copulatory efficiency was elevated [treatment: F ( l , 16) = 9.380, p = .007] in males given melatonin (Fig. I B ) . A l l three measures point to an enhancement o f I n  sexual potency  . Although some measures o f sexual behaviour showed significant  increases over time, these effects did not differ between the melatonin and control conditions. Analyses revealed that W D S decreased progressively over time (Fig. 1C), but only i n males treated with melatonin [treatment x week: F ( l 2 , 228) = 1.881, p = .038].  DISCUSSION  To date, this is the first empirical report o f a facilitatory role for melatonin i n sexual behaviour. It has previously been suggested that reproductive behaviour might be inhibited in male rats given high doses o f melatonin (8.0 mg/kg) for 30 d a y s . This 19  suggestion was based entirely on evidence that the pregnancy rate for dams paired with melatonin-treated males was significantly lower than that for dams paired with control males . However, since behavioural observations were absent, it is not possible to 19  determine whether melatonin inhibited reproductive physiology rather than reproductive behaviour. Furthermore, it should be noted that melatonin levels given i n that study were equivalent to a 70kg human consuming 560mg o f melatonin - almost 190 times the typical dose used as a sleep aid.  W D S are considered to be a robust behavioural assay o f 5-HT2A receptor activity , and 13  have been used to differentiate males o f varying levels o f sexual proficiency . The 20  progressive decline in W D S suggests a decrease in 5-HT2A receptor sensitivity after melatonin treatment . Given the negative correlation between 5 - H T A activity and male 11  2  rat copulatory behaviour ' , this may account for the increase i n sexual behaviour after 21  22  melatonin treatment.  The increase in sexual behavior after chronic melatonin treatment can not be explained by a general facilitation o f motor activity. In fact, it has been found that rats treated with melatonin exhibited less spontaneous movements, and spent more time in a frozen posture  . Therefore, the increase in sexual behavior is more likely explained by  processes which directly affect sexual, and not necessarily other, behaviors. Taken together, the results demonstrate that melatonin enhances sexual performance, and that these results may be explained, in part, by a 5-HT2A antagonism.  The implications for these findings are clear. Given the facilitatory effect on sexually proficient rats, it seems reasonable to speculate that melatonin might exert even greater improvements i n the sexually deficient animal. Since behaviours representative o f both motivation and potency were enhanced after melatonin treatment i n the rat, these results may be applicable to human sexual libido and potency, with melatonin perhaps reversing some aspects o f sexual dysfunction or increasing sexual motivation in human males. It is evident, however, that further rigorously controlled investigations are required to  6 elucidate the mechanisms by which melatonin might enhance sexual functioning. A l s o , information is required about the toxicity and efficacy o f melatonin following chronic administration.  7 REFERENCES  1. J.E. Chase and B . E . Gidal, Ann. Pharmacother.  31, 1218 (1997).  2. A . Cagnacci and A . Volpe, Journal of Endocrinology  Invest. 19, 382 (1996).  3. R . J . Reiter, Ann. Med. 30, 103 (1998). 4. G . Grugni et al, Horm Metab Res. 26, 440 (1994). 5. C P . Maurizi, Southern Medical Journal 77, 1516 (1984). 6. F. Waldhauser, G . Weiszenbacher, E . Tatzer, B . Gisinger, M . Waldhauser, M . Schemper, H . Frisch, J. Clin. Endocrinol. Metab. 66, 648 (1988). 7. A . C . Kinsey, W . B . Pomeroy, C . E . Martin, in Sexual behavior in the human male ( W . B . Saunders Company, London, 1948), pp. 226-238. 8. A . Weizman, R. Weizman, J. Hart, B . Maoz, H . Wijsenbeek, M . B . David, J. Am. Geriat. 31,485 (1983). 9. W . H . Bergstrom and D . O . Hakanson, Advances in Pediatrics, 45, 91 (1998). 10. J . M . Miguez, F.J. Martin, M . Aldegunde, Neurochem. Res. 22, 87 (1997). 11. A . S . Eison, R . P . Freeman, V . B . Guss, U . L . Mullins, R . N . Wright, J Pharmacol Ther. 273, 304 (1995). 12. P. Bedard and C.J. Pycock, Neuropharmacol.  16, 663 (1977).  13. A . R . Green and D.J. Heal, i n Neuropharmacology  of serotonin, A . R . Green, E d .  (Oxford University Press, N e w York, 1985), pp. 326-365. 14. P. Govitrapong, V . Prapapanich, M . Ebadi, J. Pineal Res. 11, 182 (1991). 15. C . Dugovic, J.E. Leysen, A . Wauquier, Neurosci. Lett. 104, 320 (1989). 16. J . G . Pfaus, Horm Behav. 30, 187 (1996). 17. A . A g m o , Brain Research Protocols 1, 203 (1997).  Exp  8  18.. Oaknin-Bendahan, Y . Anis, I. N i r , N . Zisapel, NeuroReport  6, 785 (1995).  19. K . Yamada, K . Maruyama, S. Mogami, N Miyagawa, M . Tsuboi, Chem. Pharm. Bull. 40, 2222 (1992). 20. N . V . Watson and B . B . Gorzalka, Pharmacol Biochem Behav. 37, 825 (1990). 21. M . M . Foreman, J.L. H a l l , R . L . Love, Life Sci. 45, 1263 (1989). 22. B . B . Gorzalka, L . A . Hanson, L . A . Brotto, Pharmacol. Biochem. Behav. 61, 405 (1998). 23. J.I. Chuang and M . T . L i n , J. Pineal Res. 17, 11 (1994).  # Melatonin • Control  T  T 4 T  ^1  4-  32 H 0  Base  1-4  5-8  9-12  Weeks FIG. 1. Effects of chronic melatonin treatment (3mg/week) on frequency of ejaculations, copulatory efficiency, and wet dog shakes. Values represent means +/- S.E.M. of 4 week intervals (except baseline values).  

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