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

Abstract

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. 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. Female rats were brought into estrous by hormonal injections before a paced mating sex test. The effects of the 5-HT(1A)/5-HT(7) receptor agonist (+/-)-8-hydroxy-2-(dipropylamino)tetralin hydrobromide (+/-8-OH-DPAT) (0.03-1 mg/kg s.c.) and the 5-HT(1A) 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. Proceptive (darting and hopping) and receptive (lordosis) behaviors were quantified. 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-HT(1A) receptor. 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.