Treatment of cycling female rats with fluoxetine induces desensitization of hypothalamic 5-HT1A receptors with no change in 5-HT2A receptors

Abstract Although women constitute the majority of patients who receive treatment with selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine, most animal studies of SSRIs are conducted on males. The present study investigated whether long-term treatment of cycling female rats with fluoxetine alters their estrous cycle and the sensitivity of hypothalamic serotonin (5-HT) 5-HT 1A and 5-HT 2A receptor systems. Adult female rats received daily injections of fluoxetine (10 mg/kg, i.p.) for three consecutive estrous cycles ( 15.2±0.2 days) with the first injection beginning on metestrus (when circulating estrogen levels are low and stable). Fluoxetine did not alter basal plasma estradiol levels at metestrus, nor did it alter the pattern of estrous cyclicity. Rats treated with fluoxetine showed a loss in body weight. On the morning of metestrus of the fourth cycle (18 h after the last fluoxetine injection), the rats were injected with a sub-maximal dose of the 5-HT 1A agonist (±)-8-hydroxy-2-dipropylaminotetralin (8-OH-DPAT, 50 μg/kg, s.c.) or a maximal dose of the 5-HT 2A agonist [(±)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane HCl] (DOI). Plasma levels of oxytocin, ACTH and corticosterone were measured as peripheral indicators of hypothalamic 5-HT 1A and 5-HT 2A receptor sensitivity. Injecting 8-OH-DPAT to saline pretreated rats produced a significant increase in plasma oxytocin (299%), ACTH (1456%) and corticosterone (170%) levels but not in plasma prolactin or renin concentrations. Greater increases in plasma levels of these hormones were observed after injecting DOI. Fluoxetine treatment completely blocked the oxytocin, ACTH and corticosterone responses to 8-OH-DPAT, but did not inhibit the effect of DOI on any hormone, thus confirming that fluoxetine treatment did not produce a deficit in the functioning of corticotropin releasing hormone or oxytocin containing neurons. These results indicate that in cycling female rats, fluoxetine treatment desensitizes hypothalamic post-synaptic 5-HT 1A receptor signaling. Understanding the pharmacological effects of fluoxetine in females may lead to more effective treatment of women with mood disorders.