Endocannabinoid modulation of male rat sexual behavior

Abstract

Rationale

Synthetic and plant-derived cannabinoid CB1 receptor agonists have consistently been shown to impair sexual behavior in male rodents; however, the role of the endocannabinoid system in regulating copulatory processes is largely unknown. The aim of this experiment was to determine the effect of pharmacological facilitation or antagonism of endocannabinoid signaling on male rat sexual behavior.

Materials and methods

Male Long-Evans rats were administered a single injection of either the cannabinoid CB1 receptor antagonist AM251 (1, 2, or 5 mg/kg), the fatty acid amide hydrolase (FAAH) inhibitor URB597 (0.1, 0.3, or 0.5 mg/kg), or the anandamide uptake inhibitor/FAAH inhibitor AM404 (1, 2, and 5 mg/kg), or their respective vehicles, and examined on parameters of appetitive and consummatory sexual behavior.

Results

Inhibition of anandamide metabolism through URB597 had no effect on any parameter of sexual behavior. However, the highest dose of AM404 increased the latency to engage in intromitting behavior, but had no other effect on sexual behavior, suggesting that this effect may be due to the sedative–suppressive effects of this drug. AM251 produced a dose-dependent facilitation of ejaculation, such that the number of intromissions required to achieve ejaculation and the ejaculation latency were reduced by AM251 administration.

Conclusions

These data suggest that antagonism of the CB1 receptor facilitates ejaculatory processes, an effect which may be due to interactions with neuropeptidergic systems in the hypothalamus, and further, suggest a novel target for pharmacological agents aimed at treating ejaculatory-based sexual dysfunction.

This is a preview of subscription content, access via your institution.

Fig. 1
Fig. 2
Fig. 3

References

  1. Bortolato M, Campolongo P, Mangieri RA, Scattoni ML, Frau R, Trezza V, La Rana G, Russo R, Calignano A, Gessa GL, Cuomo V, Piomelli D (2006) Anxiolytic-like properties of the anandamide transport inhibitor AM404. Neuropsychopharmacology 31:2652–2659

    PubMed  Article  CAS  Google Scholar 

  2. Di S, Malcher-Lopes R, Halmos KC, Tasker JG (2003) Nongenomic glucocorticoid inhibition via endocannabinoid release in the hypothalamus: a fast feedback mechanism. J Neurosci 23:4850–4857

    PubMed  CAS  Google Scholar 

  3. Di S, Boudaba C, Popescu IR, Weng FJ, Harris C, Marcheselli VL, Bazan NG, Tasker JG (2005a) Activity-dependent release and actions of endocannabinoids in the rat hypothalamic supraoptic nucleus. J Physiol 569:751–760

    PubMed  Article  CAS  Google Scholar 

  4. Di S, Malcher-Lopes R, Marcheselli VL, Bazan NG, Tasker JG (2005b) Rapid glucocorticoid-mediated endocannabinoid release and opposing regulation of glutamate and gamma-aminobutyric acid inputs to hypothalamic magnocellular neurons. Endocrinology 146:4292–4301

    PubMed  Article  CAS  Google Scholar 

  5. Ferrari F, Ottani A, Giuliani D (2000) Inhibitory effects of the cannabinoid agonist HU 210 on rat sexual behaviour. Physiol Behav 69:547–554

    PubMed  Article  CAS  Google Scholar 

  6. Freund TF, Katona I, Piomelli D (2003) Role of endogenous cannabinoids in synaptic signaling. Physiol Rev 83:1017–1066

    PubMed  CAS  Google Scholar 

  7. Giuffrida A, Rodriguez de Fonseca F, Nava F, Loubet-Lescoulie P, Piomelli D (2000) Elevated circulating levels of anandamide after administration of the transport inhibitor, AM404. Eur J Pharmacol 408:161–168

    PubMed  Article  CAS  Google Scholar 

  8. Gobbi G, Bambico FR, Mangieri R, Bortolato M, Campolongo P, Solinas M, Cassano T, Morgese MG, Debonnel G, Duranti A, Tontini A, Tarzia G, Mor M, Trezza V, Goldberg SR, Cuomo V, Piomelli D (2005) Antidepressant-like activity and modulation of brain monoaminergic transmission by blockade of anandamide hydrolysis. Proc Natl Acad Sci USA 102:18620–18625

    PubMed  Article  CAS  Google Scholar 

  9. Gonzalez S, Romero J, de Miguel R, Lastres-Becker I, Villanua MA, Makryiannis A, Ramos JA, Fernandez-Ruiz (1999) Extrapyramidal and neuroendocrine effects of AM404, an inhibitor of the carrier-mediated transport of anandamide. Life Sci 65:327–336

    PubMed  Article  CAS  Google Scholar 

  10. Gorzalka BB, Hill MN (2006) Cannabinoids, sexual behavior and reproduction. Annu Rev Sex Res 17:132–161

    Google Scholar 

  11. Gorzalka BB, Hanson LA, Brotto LA (1998) Chronic stress effects on sexual behavior in male and female rats: mediation by 5-HT2A receptors. Pharmacol Biochem Behav 61:405–412

    PubMed  Article  CAS  Google Scholar 

  12. Hill MN, Gorzalka BB (2005) Is there a role for the endocannabinoid system in the etiology and treatment of melancholic depression? Behav Pharmacol 16:333–352

    PubMed  Article  CAS  Google Scholar 

  13. Hirasawa M, Schwab Y, Natah S, Hillard CJ, Mackie K, Sharkey KA, Pittman QJ (2004) Dendritically released transmitters cooperate via autocrine and retrograde actions to inhibit afferent excitation in rat brain. J Physiol 559:611–624

    PubMed  Article  CAS  Google Scholar 

  14. Hughes AM, Everitt BJ, Lightman SL, Todd K (1987) Oxytocin in the central nervous system and sexual behavior in male rats. Brain Res 414:133–137

    PubMed  Article  CAS  Google Scholar 

  15. Hull EM, Muschamp JW, Sato S (2004) Dopamine and serotonin: influences on male sexual behavior. Physiol Behav 83:291–307

    PubMed  CAS  Google Scholar 

  16. Mackie K (2005) Distribution of cannabinoid receptors in the central and peripheral nervous system. Handbook Exp Pharmacol 168:299–325

    Article  CAS  Google Scholar 

  17. Marsicano G, Lutz B (1999) Expression of the cannabinoid receptor CB1 in distinct neuronal subpopulations in the adult mouse forebrain. Eur J Neurosci 11:4213–4225

    PubMed  Article  CAS  Google Scholar 

  18. Martinez-Gonzalez D, Bonilla-Jaime H, Morales-Otal A, Henriksen SJ, Velazquez-Moctezuma J, Prospero-Garcia O (2004) Oleamide and anandamide effects on food intake and sexual behavior of rats. Neurosci Lett 364:1–6

    PubMed  Article  CAS  Google Scholar 

  19. Melis MR, Succu S, Mascia MS, Argiolas A (2004) Antagonism of cannabinoid CB1 receptors in the paraventricular nucleus of male rats induces penile erection. Neurosci Lett 359:17–20

    PubMed  Article  CAS  Google Scholar 

  20. Melis MR, Succu S, Mascia MS, Sanna F, Melis T, Castelli MP, Argiolas A (2006) The cannabinoid receptor antagonist SR-141716A induces penile erection in male rats: involvement of paraventricular glutamic acid and nitric oxide. Neuropharmacology 50:219–228

    PubMed  Article  CAS  Google Scholar 

  21. Murphy LL, Gher J, Steger RW, Bartke A (1994) Effects of delta 9-tetrahydrocannabinol on copulatory behavior and neuroendocrine responses of male rats to female conspecifics. Pharmacol Biochem Behav 48:1011–1017

    PubMed  Article  CAS  Google Scholar 

  22. Patel S, Roelke CT, Rademacher DJ, Cullinan WE, Hillard CJ (2004) Endocannabinoid signaling negatively modulates stress-induced activation of the hypothalamic–pituitary–adrenal axis. Endocrinology 145:5431–5438

    PubMed  Article  CAS  Google Scholar 

  23. Pattij T, de Jong TR, Uitterdijk A, Waldinger MD, Veening JG, Cools AR, van der Graaf PH, Olivier B (2005) Individual differences in male rat ejaculatory behaviour: searching for models to study ejaculation disorders. Eur J Neurosci 22:724–734

    PubMed  Article  Google Scholar 

  24. Piomelli D, Tarzia G, Duranti A, Tontini A, Mor M, Compton TR, Dasse O, Monaghan EP, Parrott JA, Putnam D (2006) Pharmacological profile of the selective FAAH inhibitor KDS-4103 (URB597). CNS Drug Rev 12:21–38

    PubMed  Article  CAS  Google Scholar 

  25. Schlicker E, Kathmann M (2001) Modulation of transmitter release via presynaptic cannabinoid receptors. Trends Pharmacol Sci 22:565–572

    PubMed  Article  CAS  Google Scholar 

  26. Schuel H, Burkman LJ (2005) A tale of two cells: endocannabinoid-signaling regulates functions of neurons and sperm. Biol Reprod 73:1078–1086

    PubMed  CAS  Google Scholar 

  27. Scorticati C, Fernandez-Solari J, De Laurentiis J, Mohn C, Prestifilippo JP, Lasaga M, Seilicovich A, Billi S, Franchi A, McCann SM, Rettori V (2004) The inhibitory effect of anandamide on luteinizing hormone-releasing hormone secretion is reversed by estrogen. Proc Natl Acad Sci USA 101:11891–11896

    PubMed  Article  CAS  Google Scholar 

  28. Shrenker P, Bartke A (1985) Suppression of male copulatory behavior by delta 9-THC is not dependent on changes in plasma testosterone or hypothalamic dopamine or serotonin content. Pharmacol Biochem Behav 22:415–420

    PubMed  Article  CAS  Google Scholar 

  29. Stoneham MD, Everitt BJ, Hansen S, Lightman SL, Todd K (1985) Oxytocin and sexual behaviour in the male rat and rabbit. J Endocrinol 107:97–106

    PubMed  Article  CAS  Google Scholar 

  30. Succu S, Mascia MS, Sanna F, Melis T, Argiolas A, Melis MR (2006) The cannabinoid CB1 receptor antagonist SR 141716A induces pennile erection by increasing extra-cellular glutamic acid in the paraventricular nucleus of male rats. Behav Brain Res 169:274–281

    PubMed  Article  CAS  Google Scholar 

  31. Tyrey L (1992) Delta-9-tetrahydrocannabinol attenuates luteinizing hormone release induced by electrochemical stimulation of the medial preoptic area. Biol Reprod 47:262–267

    PubMed  Article  CAS  Google Scholar 

  32. van Gaal LF, Rissanen AM, Scheen AJ, Ziegler O, Rossner S, RIO Europe Study Group (2005) Effects of the cannabinoid-1 receptor blocker rimonabant on weight reduction and cardiovascular risk factors in overweight patients: 1-year experience from the RIO-Europe study. Lancet 365:1389–1397

    PubMed  Article  CAS  Google Scholar 

  33. Waldinger MD, Hengeveld MW, Zwinderman AH, Olivier B (1998) Effect of SSRI antidepressants on ejaculation: a double blind, randomized, placebo-controlled study with fluoxetine, fluovoxamine, paroxetine and sertraline. J Clin Psychopharmacol 18:274–281

    PubMed  Article  CAS  Google Scholar 

  34. Waldinger MD, Zwinderman AH, Olivier B (2001) SSRIs and ejaculation: a double-blind, randomized, fixed-dose study with paroxetine and citalopram. J Clin Psychopharmacol 21:556–560

    PubMed  Article  CAS  Google Scholar 

  35. Wang H, Dey SK, Maccaronne M (2006) Jekyll and Hyde: two faces of cannabinoid signaling in male and female fertility. Endocrin Rev 27:427–448

    Article  CAS  Google Scholar 

  36. Wenger T, Toth BE, Juaneda C, Leonardelli J, Tramu G (1997) The effects of cannabinoids on the regulation of reproduction. Life Sci 65:695–701

    Article  Google Scholar 

  37. Witkin JM, Tzavara ET, Davis RJ, Li X, Nomikos GG (2005) A therapeutic role for cannabinoid CB1 receptor antagonists in major depressive disorders. Trends Pharmacol Sci 26:609–617

    PubMed  Article  CAS  Google Scholar 

  38. Witt DM, Insel TR (1994) Increased fos expression in oxytocin neurons following masculine sexual behavior. J Neuroendocrinol 6:13–18

    PubMed  Article  CAS  Google Scholar 

Download references

Acknowledgment

This research was supported by a Natural Sciences and Engineering Research Council of Canada (NSERC) operating grant to BBG and a Michael Smith Foundation for Health Research postgraduate trainee award and a NSERC Canadian Graduate Scholarship to MNH. The authors would like to thank Shirley Sarkodee-Adoo, Morag Yule, Rajinder Gill, and Eda Karacabeyli for their technical assistance.

Author information

Affiliations

Authors

Corresponding author

Correspondence to Boris B. Gorzalka.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Gorzalka, B.B., Morrish, A.C. & Hill, M.N. Endocannabinoid modulation of male rat sexual behavior. Psychopharmacology 198, 479–486 (2008). https://doi.org/10.1007/s00213-007-0901-1

Download citation

Keywords

  • Copulation
  • Ejaculation
  • Oxytocin
  • Anandamide
  • 2-AG
  • Hypothalamus
  • Sex