Pharmacology and physiology of the serotonin neuronal system in the aging hippocampus and dorsal raphe nucleus

The pharmacology and physiology of the aging serotonin (5-hydroxytryptamine, 5-HT) neuronal system was investigated in the dorsal raphe nucleus (DRN) and hippocampus of male Sprague Dawley and female Fischer 344 rats. The consequences of the acute and chronic exposure to duloxetine, a dual 5-HT and norepinephrine reuptake inhibitor, and a selective 5-HT reuptake inhibitor fluoxetine were compared to elucidate cellular mechanisms of these antidepressants.; Duloxetine inhibited DRN cell firing at significantly lower doses {dollar}rm (EDsb{lcub}50{rcub} = 0.7 pm 0.2 mg/kg; i.v.){dollar} than fluoxetine {dollar}rm (EDsb{lcub}50{rcub} = 5.4 pm 1.9 mg/kg; i.v.).{dollar} In the hippocampus, co-application of 5-HT and fluoxetine, but not duloxetine, potentiated 5-HT inhibitory effects with a significant increase (59%) in the recovery response (RT{dollar}sb{lcub}50{rcub}{dollar} value). In 24-27 mo female rats, but not younger groups, RT{dollar}sb{lcub}50{rcub}{dollar} values significantly increased (68%) with initial duloxetine co-application and returned to baseline levels with prolonged application.; In a model of long-term antidepressant administration (14 days, 1 x daily, 10 mg/kg, i.p.), 5-HT recovery times were significantly increased in the hippocampus of young (73%) and old (104%) fluoxetine groups as compared to age-matched duloxetine and vehicle groups. Co-application of 5-HT with duloxetine significantly increased the RT{dollar}sb{lcub}50{rcub}{dollar} values in the young fluoxetine group with a significant decline (52%) observed in the old versus young fluoxetine groups with continued duloxetine application. In this same drug treatment model DRN cell firing was inhibited at lower doses of fluoxetine in the old {dollar}rm (EDsb{lcub}50{rcub} = 6.6 pm 0.7 mg/kg;{dollar} 2 i.v.) as compared to the young vehicle treated group {dollar}rm (EDsb{lcub}50{rcub} = 3.3 pm 0.9 mg/kg;{dollar} i.v.). Following chronic fluoxetine administration, young animals were less sensitive {dollar}rm (EDsb{lcub}50{rcub} = 12.9 pm 1.5 mg/kg;{dollar} i.v.) to systemic fluoxetine.; The 5-HT receptor characteristics which may underlie the observed changes in cellular electrophysiological responses were examined using quantitative autoradiographic techniques. A decreasing trend in 5-HT{dollar}rm sb{lcub}1A{rcub}{dollar} receptor and 5-HT transporter densities was found in the DRN, with no changes in the hippocampus, with aging and chronic fluoxetine treatment. These studies advance our knowledge of the cellular mechanisms of these agents which may be useful in the treatment of depression.