Role of 5-HT1A receptors in fluoxetine-induced lordosis inhibition

Fluoxetine (Prozac®), a selective serotonin reuptake inhibitor (SSRI), is an antidepressant that is also prescribed for several other disorders such as anorexia, bulimia, and premenstrual dysphoria, all of which are prevalent in females. However, fluoxetine also produces sexual side effects both in male and female patients, the mechanisms of which are unknown. In rats, serotonin (5-HT), acting via 5-HT1A receptors, reduces female rat sexual behavior. Fluoxetine's block of the serotonin transporter (SERT) leads to elevation of extracellular 5-HT and consequent activation of 5-HT1A receptors, which may contribute to disruption of sexual activity. The following experiments were designed to test this hypothesis in female Fischer rats. In the first experiment, the 5-HT1A receptor antagonist, WAY100635, was used to test the hypothesis that fluoxetine-induced lordosis inhibition occurs via activation of 5-HT1A receptors. In the second experiment, the effect of 9 days of daily 10 mg/kg fluoxetine administration on sensitivity to 8-OH-DPAT-induced lordosis inhibition was examined. In the third experiment, the ability of progesterone to reduce the potency of fluoxetine in lordosis inhibition was studied. Three major findings emerged from these studies: (1) The 5-HT1A receptor antagonist, WAY100635, attenuated effects of an acute fluoxetine injection on lordosis behavior: (2) subchronic treatment with fluoxetine reduced the potency of the 5-HT1A receptor agonist, 8-OH-DPAT, as an inhibitor of lordosis behavior: and (3) progesterone, previously reported to attenuate effects of 8-OH-DPAT, reduced the potency of an acute fluoxetine treatment. These findings reinforce earlier suggestions that 5-HT1A receptors contribute to fluoxetine-induced sexual side effects and that adaptation of these receptors occurs with repeated fluoxetine treatment. In summary, while the present findings implicate 5-HT1A receptors in fluoxetine-induced sexual dysfunction, additional mechanisms may also be involved. Although fluoxetine has greatest affinity for SERT, fluoxetine is not completely selective for SERT and also elevates extracellular nonadrenaline and dopamine, albeit with a slower time course than seen for elevations in 5-HT. Therefore, additional studies are clearly needed in both animal models and in the human population before definite conclusions about the mechanisms responsible for SSRI-induced sexual dysfunction can be clarified.

Research supported by NIH HD28419, by TWU REP and by the Department of Biology.