Vilazodone does not inhibit sexual behavior in male rats in contrast to paroxetine: A role for 5-HT1A receptors?

Vilazodone (VLZ) is a selective serotonin reuptake inhibitor (SSRI) and 5-HT 1A receptor partial agonist approved for the treatment of major depressive disorder in adults. In preclinical studies, VLZ had significantly lower sexual side effects than SSRIs and reduced serotonin transporter (SERT) levels in forebrain regions. In the current study, once-daily paroxetine (PAR, 10 mg/kg), VLZ (10 mg/kg), PAR + buspirone (BUS, 3 mg/kg; a 5-HT 1A partial agonist), or vehicle (VEH) was administered to male rats for 2 weeks then switched for 7 days (eg, PAR switched to VLZ, PAR + BUS, or VEH). Sexual behavior (eg, ejaculation frequency and latency) was evaluated 1-hr postdose on days 1, 7, 14, and 21. After 2 weeks, treatment with PAR but not VLZ resulted in a significant decrease in sexual behavior. In a 30-min test, the range of ejaculation frequency was 3.08–3.5 with VLZ and 1.00–1.92 with PAR ( P < 0.05 vs VEH). After switching from PAR to VEH, PAR + BUS, or VEH, sexual behaviors were normalized to control levels. In contrast, the switch from VLZ to PAR resulted in reduced sexual behaviors. This preclinical study showed that unlike PAR, an SSRI with no 5-HT 1A receptor activity, initial treatment with VLZ did not result in sexual side effects at therapeutically relevant doses. Results in male rats switched from PAR to VLZ or PAR + BUS strongly suggest that activation of 5-HT 1A receptors may mitigate the sexual side effects associated with conventional SSRIs. • Administration of paroxetine reduced sexual behavior in male rats. • This effect was not found with paroxetine + buspirone or vilazodone. • Adding buspirone to paroxetine reversed the deficits in sexual behavior. • Switching from paroxetine to vilazodone also reversed deficits in sexual behavior. • Drugs with 5-HT 1A partial agonism may mitigate SSRI-induced sexual dysfunction.