Abstract
Brain serotonin (5-HT) neurotransmission plays an important role in male sexual behavior and it is well established that activating 5-HT1A receptors in rats facilitate ejaculatory behavior. However, the relative contribution of 5-HT1A somatodendritic autoreceptors and heteroreceptors in this pro-sexual behavior is unclear. Moreover, it is unclear whether the contribution of somatodendritic 5-HT1A autoreceptors and postsynaptic 5-HT1A heteroreceptors alter when extracellular 5-HT levels are chronically increased. Serotonin transporter knockout (SERT–/–) rats exhibit enhanced extracellular 5-HT levels and desensitized 5-HT1A receptors. These rats model neurochemical changes underlying chronic SSRI-induced sexual dysfunction. We want to determine the role of presynaptic versus postsynaptic 5-HT1A receptors in the pro-sexual effects of 5-HT1A receptor agonists in SERT+/+ and in SERT–/– rats. Therefore, acute effects of the biased 5-HT1A receptor agonists F-13714, a preferential 5-HT1A autoreceptor agonist, or F-15599, a preferential 5-HT1A heteroreceptor agonist, and S15535 a mixed 5-HT1A 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-HT1A 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-HT1A 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-HT1A receptor ligands used, is sufficient to differentiate pre- and/or post-synaptic 5-HT1A receptor contributions in male rat sexual behavior.
Highlights
The serotonergic system plays an important modulatory role in sexual behavior (Uphouse and Guptarak, 2010; Olivier et al, 2019)
(±) 8-OH-DPAT has 5-HT7 R agonistic effects (Thomas et al, 1999), this mechanism cannot explain the pro-sexual effects because other 5-HT1A receptor agonists without 5-HT7 R agonistic activity, display pro-sexual effects (Snoeren et al, 2014). 5-HT1A receptors are present as presynaptic inhibitory autoreceptors on soma and dendrites of raphé serotonergic neurons projecting to many forebrain areas (Fernandez-Guasti et al, 1992; Le Poul et al, 1995; Marek, 2010; Altieri et al, 2013)
In contrast to 8OH-DPAT, both F15599 (Newman-Tancredi et al, 2009) and F15714 (Assié et al, 2006) are devoid of 5-HT7 receptor activity. We studied both compounds in a dose-response study in male rat sexual behavior. Another high-affinity (Ki = 1.8 nM) 5-HT1A receptor ligand, S-15535 acts in vivo as a preferential agonist at presynaptic autoreceptors and as antagonist at post-synaptic 5HT1A heteroreceptors (Millan et al, 1993; Carli et al, 1999).This compound is an interesting tool to study in male sexual behavior as it may shed further light on the complex role of 5-HT1A receptors in male rat sexual behavior
Summary
The serotonergic system plays an important modulatory role in sexual behavior (Uphouse and Guptarak, 2010; Olivier et al, 2019). Systemic acute administration of non-selective 5-HT1A receptor agonists like (±)-8-OH-DPAT and flesinoxan (activation of pre- and post-synaptic receptors) leads to decreased serotonergic release, but at the same time to activation of post-synaptic 5-HT1A heteroreceptors (Müller et al, 2007; Lladó-Pelfort et al, 2012). To further explore the role of pre- and post-synaptic 5-HT1A receptors in male sexual behavior, more recently developed selective and high-affinity 5-HT1A receptor agonists are useful. These so-called “biased” or “functionally selective” agonists (Newman-Tancredi, 2011; Garcia-Garcia et al, 2014) display selectivity for either pre- or post-synaptic 5HT1A receptors.
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