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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 E F F E C T S OF M E L A T O N I N by L O R I A N N E B R O T T O B . S c , The University of British Columbia, 1997 A THESIS S U B M I T T E D I N P A R T I A L F U L F I L L M E N T O F T H E R E Q U I R E M E N T S F O R T H E D E G R E E O F M A S T E R OF A R T S in T H E F A C U L T Y OF G R A D U A T E S T U D I E S Department of Psychology We accept this thesis as conforming to the required standard T H E U N I V E R S I T Y OF B R I T I S H C O L U M B I A A p r i l 1999 © Lor i 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) A B S T R A C T Anecdotal reports suggest that melatonin enhances libido in men. However, controlled trials remain to be published for any species. Accordingly, male rats were chronically treated for 12 weeks with melatonin via the drinking water. A l l aspects of sexual activity, including measures of both libido and potency, were significantly facilitated. In addition, there was a consistent, progressive reduction in the frequency of wet dog shake behaviour, suggestive of 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 C O N T E N T S Page Abstract i i Table of Contents i i i List o f Figures iv Acknowledgements v I N T R O D U C T I O N A N D M E T H O D S 1 R E S U L T S 3 D I S C U S S I O N : 4 R E F E R E N C E S 7 iv LIST O F F I G U R E S Page Figure 1: 9 Effects of chronic melatonin treatment (3mg/week) on frequency of ejaculations, copulatory efficiency, and wet dog shakes. A C K N O W L E D G E M E N T S 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 Li isa 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. I N T R O D U C T I O N A N D M E T H O D S Melatonin has been postulated to be involved in a number of behavioural and physiological processes, and controlled clinical trials have established its therapeutic efficacy for specific sleep abnormalities 1. Whereas melatonin's role in reproductive 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 low levels of melatonin have been reported in men with psychogenic impotence 4 ' 5 , and it has been speculated that dietary melatonin supplementation might reverse some aspects of diseases associated with low levels of melatonin 5 . In addition, there exists an age-related decline in plasma melatonin levels 6 coinciding with a steady reduction in the frequency of sexual activity, sexual motivation, and potency ' . Furthermore, despite the absence of randomized control trials, individuals taking melatonin for sleep difficulties have celebrated it's libido-enhancing properties9. 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 of action for melatonin have been widely studied, and in particular, interactions of melatonin with the serotonergic system have been extensively investigated 1 0. For example, Eison et al. (1995) 1 1 used radioligand binding, 2 phosphoinositide hydrolysis, and observations of the serotonergic type 2 A (5 -HT 2 A ) receptor-mediated behaviour "Wet Dog Shakes" (WDS) to infer a 5 - H T 2 A antagonism by melatonin. W D S correlate positively with increases in serotonergic activity 1 2 and have been considered a reliable behavioural assay of 5-HT2A receptor activity in vivo 13. Further support for a melatonin-serotonin interaction originates from receptor ligand-binding studies which have revealed 5 - H T 2 A receptors in the pineal gland 1 4 . In addition, melatonin pretreatment has been found to attenuate the 5 - H T 2 A agonist, l-(2,5-domethoxy-4-methylphenyl)-2-aminopropane ( D O M ) - induced effects on sleep-wakefulness regulation in the rat 1 5 . Taken together, these studies suggest that melatonin might possess 5 - H T 2 A antagonistic properties. 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 in 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 of human libido and potency have been elucidated in the rat 1 7. Accordingly, sexually proficient, male Long-Evans rats at 9 months of age (500-700g), were given melatonin via the drinking water (.004g/litre) in a manner previously 1 8 * described . This melatonin regimen has been shown to retard the age-related decline in survival rates of 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 of sexual behaviour and W D S , in the presence of 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 of approximately 3 mg/rat. Measures representative of sexual potency (copulatory efficiency and frequencies of 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 of mounts resulting in vaginal penetration to the total number of mounts (with and without intromission). The post-ejaculatory interval was computed as the duration of time, in seconds, between the initial ejaculation, and the following intromission. In addition, the frequency of W D S (defined as a paroxysmal 1 7 rotation of the upper body ) was tallied for the 30 minute observation. R E S U L T S A between-within repeated measures analysis of variance investigating between-treatment differences, and variation over time, was performed on all the data. Statistical analysis revealed that melatonin treatment significantly facilitated all measures of 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 in melatonin-treated animals, suggesting increased l ib ido 1 7 . 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. IB) . A l l three measures point to an enhancement of I n sexual potency . Although some measures of 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 in males treated with melatonin [treatment x week: F ( l 2 , 228) = 1.881, p = .038]. D I S C U S S I O N To date, this is the first empirical report of a facilitatory role for melatonin in sexual behaviour. It has previously been suggested that reproductive behaviour might be inhibited in male rats given high doses of melatonin (8.0 mg/kg) for 30 days 1 9 . This 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 1 9 . However, since behavioural observations were absent, it is not possible to determine whether melatonin inhibited reproductive physiology rather than reproductive behaviour. Furthermore, it should be noted that melatonin levels given in that study were equivalent to a 70kg human consuming 560mg of melatonin - almost 190 times the typical dose used as a sleep aid. W D S are considered to be a robust behavioural assay of 5-HT2A receptor activity 1 3 , and have been used to differentiate males of varying levels o f sexual proficiency 2 0 . The progressive decline in W D S suggests a decrease in 5-HT2A receptor sensitivity after melatonin treatment1 1. Given the negative correlation between 5 - H T 2 A activity and male rat copulatory behaviour 2 1 ' 2 2 , this may account for the increase in sexual behaviour after melatonin treatment. The increase in sexual behavior after chronic melatonin treatment can not be explained by a general facilitation of 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 in the sexually deficient animal. Since behaviours representative of both motivation and potency were enhanced after melatonin treatment in the rat, these results may be applicable to human sexual libido and potency, with melatonin perhaps reversing some aspects of 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. Also , information is required about the toxicity and efficacy of melatonin following chronic administration. 7 R E F E R E N C E S 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 . Mull ins , R . N . Wright, J Pharmacol Exp Ther. 273, 304 (1995). 12. P. Bedard and C.J . Pycock, Neuropharmacol. 16, 663 (1977). 13. A . R . Green and D.J . Heal, in Neuropharmacology of serotonin, A . R . Green, Ed . (Oxford University Press, New 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 . Agmo, Brain Research Protocols 1, 203 (1997). 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. Ha 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 -3-2 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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