| Autor: |
Esquivel-Franco DC; Groningen Institute for Evolutionary Life Sciences, University of Groningen, Groningen, Netherlands.; Programa de Doctorado en Ciencias Biomédicas, Universidad Nacional Autónoma de México, Mexico City, Mexico.; Instituto de Investigaciones Biomédicas (IIB), Universidad Nacional Autónoma de México, Mexico City, Mexico., de Boer SF; Groningen Institute for Evolutionary Life Sciences, University of Groningen, Groningen, Netherlands., Waldinger M; Department of Pharmacology & Physiology, College of Medicine, Drexel University, Philadelphia, PA, United States., Olivier B; Groningen Institute for Evolutionary Life Sciences, University of Groningen, Groningen, Netherlands.; Department of Psychopharmacology, Utrecht Institute for Pharmaceutical Sciences, Science Faculty, Utrecht University, Utrecht, Netherlands.; Department of Psychiatry, School of Medicine, Yale University, New Haven, CT, United States., Olivier JDA; Groningen Institute for Evolutionary Life Sciences, University of Groningen, Groningen, Netherlands. |
| Abstrakt: |
Brain serotonin (5-HT) neurotransmission plays an important role in male sexual behavior and it is well established that activating 5-HT 1 A receptors in rats facilitate ejaculatory behavior. However, the relative contribution of 5-HT 1 A somatodendritic autoreceptors and heteroreceptors in this pro-sexual behavior is unclear. Moreover, it is unclear whether the contribution of somatodendritic 5-HT 1 A autoreceptors and postsynaptic 5-HT 1 A heteroreceptors alter when extracellular 5-HT levels are chronically increased. Serotonin transporter knockout (SERT -/- ) rats exhibit enhanced extracellular 5-HT levels and desensitized 5-HT 1 A receptors. These rats model neurochemical changes underlying chronic SSRI-induced sexual dysfunction. We want to determine the role of presynaptic versus postsynaptic 5-HT 1 A receptors in the pro-sexual effects of 5-HT 1 A receptor agonists in SERT +/+ and in SERT -/- rats. Therefore, acute effects of the biased 5-HT 1 A receptor agonists F-13714, a preferential 5-HT 1 A autoreceptor agonist, or F-15599, a preferential 5-HT 1 A heteroreceptor agonist, and S15535 a mixed 5-HT 1 A autoreceptor agonist/heteroreceptor antagonist, on male sexual behavior were assessed. A clear and stable genotype effect was found after training where SERT +/+ performed sexual behavior at a higher level than SERT -/- rats. Both F-15599 and F-13714 induced pro-sexual activity in SERT +/+ and SERT -/- animals. Compared to SERT +/+ , the F13714-dose-response curve in SERT -/- rats was shifted to the right. SERT +/+ and SERT -/- rats responded similar to F15599. Within both SERT +/+ and SERT -/- rats the potency of F-13714 was much stronger compared to F-15599. S15535 had no effect on sexual behavior in either genotype. In SERT +/+ and SERT -/- rats that were selected on comparable low sexual activity (SERT +/+ 3 or less ejaculations and SERT -/- 5 or less ejaculations in 10 weeks) S15535 also did not influence sexual behavior. The two biased compounds with differential effects on 5-HT 1 A auto- and hetero-receptors, exerted pro-sexual activity in both SERT +/+ and SERT -/- rats. Applying these specific pharmacological tools has not solved whether pre- or post-synaptic 5-HT 1 A receptors are involved in pro-sexual activity. Moreover, the inactivity of S15535 in male sexual behavior in either genotype was unexpected. The question is whether the in vivo pharmacological profile of the different 5-HT 1 A receptor ligands used, is sufficient to differentiate pre- and/or post-synaptic 5-HT 1 A receptor contributions in male rat sexual behavior.
(Copyright © 2020 Esquivel-Franco, de Boer, Waldinger, Olivier and Olivier.) |
