Introduction. Sexual dysfunction, as a result of selective-serotonin reuptake inhibitor (SSRI) treatment among women, is relatively common and is a factor in medication compliance. The mechanisms that underlie these side-effects of SSRIs are not well-understood. SSRIs can alter activity of catabolic enzymes that are involved in progesterone's conversion to 5α-pregnan-3α-ol-20-one (3α,5α-THP). 3α,5α-THP plays a key role in female reproductive physiology and behavior.
Aims. This study aimed to determine whether 3α,5α-THP, in the midbrain ventral tegmental area (VTA) may be a potential mechanism for fluoxetine's reduction in sexual responding of female rodents. We hypothesized that if fluoxetine induces decrements in sexual responding in part through actions of 3α,5α-THP, then fluoxetine will inhibit sexual receptivity concomitant with reducing 3α,5α-THP levels, effects which can be reversed by 3α,5α-THP administration.
Methods. Experiment 1 investigated effects of acute systemic fluoxetine [20 mg/kg intraperitoneal (IP)] and/or 3α,5α-THP [500 µg, subcutaneous (SC)] administration on sexual responding of ovariectomized, hormone-primed rats. Experiment 2 examined effects of 3α,5α-THP administration to the midbrain VTA (100 ng) on fluoxetine-induced decrements in lordosis of ovariectomized, hormone-primed rats and hamsters.
Main Outcome Measures. Sexual responding was determined in rats and hamsters. For rats, the percentage of times that the lordosis response occurred following mounting by a sexually-vigorous male (lordosis quotients) was utilized. For hamsters, lateral displacement, the pelvic movement that females will make to facilitate intromissions by a male hamster, was utilized.
Results. Fluoxetine significantly reduced lordosis, and this was reversed SC 3α,5α-THP. Intra-VTA 3α,5α-THP attenuated fluoxetine's detrimental effects on lordosis quotients and lateral displacement of rats and hamsters, respectively.
Conclusions. Thus, fluoxetine's effects to disrupt female sexual responses may involve its effects on progestogens in the midbrain VTA. Frye CA, and Rhodes ME. Fluoxetine-induced decrements in sexual responses of female rats and hamsters are reversed by 3α,5α-THP. J Sex Med 2010;7:2670–2680.