Fluoxetine Treatment of Prepubescent Rats Produces a Selective Functional Reduction in the 5-HT2A Receptor-mediated Stimulation of Oxytocin

Various childhood mood disorders are being treated with serotonin selective reuptake inhibitors (SSRIs) such as fluoxetine (Prozac(R)), yet limited data are available on their effects on serotonergic systems prior to maturation. This study investigated the effects of chronic fluoxetine treatment on 5-HT2A serotonin receptor-mediated neuroendocrine responses in young male rats. Prepubescent male rats were treated with saline or fluoxetine (10 mg/kg/day, i.p.) for 14 days, a treatment regimen producing maximal changes in postsynaptic 5-HT2A function in adults. Eighteen hours post-treatment, the rats received saline or increasing doses (0.5, 2.0, or 5.0 mg/kg, i.p.) of the 5-HT2 receptor agonist (+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane HCl ((+/-)-DOI). Trunk blood was obtained to determine changes in oxytocin, ACTH, corticosterone, and renin responses. Fluoxetine produced a small ( approximately 6%) but significant reduction in body weight gain, but no changes were observed in basal hormone levels. In both saline- and fluoxetine-treated rats, (+/-)-DOI increased plasma oxytocin levels in a dose-dependent manner. However, the magnitude of the oxytocin responses to all doses of (+/-)-DOI were markedly attenuated ( approximately 50%) in the fluoxetine-treated rats, indicating a functional reduction in the E(max) of 5-HT(2A) receptor-mediated oxytocin responses. In contrast, fluoxetine did not alter the (+/-)-DOI-induced increases in plasma ACTH, corticosterone, or renin. These data provide the first demonstration of selective neuroadaptive responses in 55-HT2A serotonin receptor function due to prepubescent treatment with fluoxetine. These data may be clinically relevant with respect to the use of selective serotonin reuptake inhibitors in children and adolescents.