Serotonin Transporter Null Mutation and Sexual Behavior in Female Rats: 5-HT1A Receptor Desensitization

Abstract

Introduction Serotonin plays a key role in sexual behavior. In serotonin transporter (SERT) knockout rats (−/−), basal extracellular 5-HT levels are considerably increased, indicating a serotonergic disturbance. Heterozygous SERT(+/−) rats express 50% of SERT in comparison to wild-type rats and may therefore model the s/s phenotype of the human SERT promoter (5-HTTLPR) polymorphism. Aim In the present study, we used both homozygote and heterozygote SERT knockout and wild-type rats (+/+) to study the putative role of the SERT in female sexual behavior. Methods Female rats were brought into estrous by hormonal injections before a paced mating sex test. The effects of the 5-HT1A/5-HT7 receptor agonist (±)-8-hydroxy-2-(dipropylamino)tetralin hydrobromide (±8-OH-DPAT) (0.03–1 mg/kg s.c.) and the 5-HT1A receptor antagonist WAY-100635 (0.1–1–mg/kg i.p.) on sexual behaviors of the females were tested separately and in a selected combination of both in all three genotypes. Main Outcome Measures Proceptive (darting and hopping) and receptive (lordosis) behaviors were quantified. Results Basal proceptive and receptive sexual activities were not different between SERT+/+, +/− and −/− female rats. The dose–effect curve after ±8-OH-DPAT for these activities was clearly shifted to the right in SERT−/− animals compared to other genotypes. WAY-100635 alone had no effect on sexual behavior in any genotype, but was able to antagonize the ±8-OH-DPAT-induced decrease in sexual activities indicating the involvement of the 5-HT1A receptor. Conclusions The absence (−/−) or reduced (+/−) expression of SERT does not affect basal sexual activity in female rats in a paced mating situation. The data indicate a desensitized 5-HT1A receptor in the SERT−/−, but not in the SERT+/− females. Under normal basal conditions, desensitized 5-HT1A receptors apparently do not play a role in female sexual behavior of the SERT−/−. However, upon activation of the 5-HT1A receptor in “normal” females (SERT+/+ and SERT+/−), a hyposexual behavior is induced.

Chronic Paroxetine Treatment Does Not Affect Sexual Behavior in Hormonally Sub-Primed Female Rats Despite 5-HT1A Receptor Desensitization

“…Based on the fact that the role of 5-HT 1A receptors is different in females, it could be that 5-HT 1A receptor desensitization in women just prevents sexual side effects. This hypothesis is in line with the findings in our previous study with SERT knockout rats [18].…”

“…One week was used as washout period to prevent accumulation. The doses of (±)8‐OH‐DPAT and WAY‐100635 were based on our previous study performed in wild‐type and SERT knockout rats on the same background strain [18]. WAY‐100635 alone was not tested this time because it did not show any effects on female sexual behavior in previous studies [18].…”

“…This leads to elevated extracellular 5-HT levels which, in turn, stimulate autoreceptors and postsynaptic 5-HT receptors. In a previous study, we investigated the importance of the serotonin transporter (SERT) on sexual behavior using SERT knockout rats [18]. The main difference between SERT knockout rats and rats that are chronically administered with SSRIs is that the knockouts have an altered serotonergic system from conception.…”

Pharmacology of serotonin and female sexual behavior

“…Consistent with this is a recent report that systemic treatment with 8-OH-DPAT reduced proceptivity and also reduced the time females spent in the male’s compartment in a pacing paradigm (Snoeren et al, 2010; Snoeren et al, 2011a; Snoeren et al, 2011b). Because both effects were attenuated by the 5-HT 1A receptor antagonist, WAY100635 (Snoeren et al, 2010; Snoeren et al, 2011b), a 5-HT 1A receptor-mediated effect was implicated. Therefore, the collective findings indicate that 5-HT 1A receptor agonists may negatively affect both consummatory and appetitive/precopulatory effects of female sexual behavior and most evidence is consistent with a location of the relevant receptors that is postsynaptic to 5-HT neurons.…”

“…In addition, since 8-OH-DPAT inhibits sexual behavior in rats that are missing the serotonin transporter (Olivier et al, 2011; Snoeren et al, 2010), the drug’s ability to produce inhibition does not appear to be dependent on changes in reuptake of 5-HT. However, in a recent study with marmoset monkeys, 16 weeks of treatment with 8-OH-DPAT was reported to increase mRNA for the serotonin transporter in the DRN (Aubert et al, 2013).…”