Pharmacological Studies on the Role of 5-HT_{1 A} Receptors in Male Sexual Behavior of Wildtype and Serotonin Transporter Knockout Rats

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.