Long-term exposure to high corticosterone levels attenuates serotonin responses in rat hippocampal CA1 neurons

Recent studies indicated that hyperactivity of the hypothalamopituitary-adr enal system is a considerable risk factor for the precipitation of affectiv e disorders, most notably of major depression. The mechanism by which this hyperactivity eventually leads to clinical symptoms of depression is unknow n. In the present animal study, we tested one possible mechanism, i.e., tha t long-term exposure to high corticosterone levels alters functional respon ses to serotonin in the hippocampus, an important area in the etiology of d epression. Rats were injected daily for 3 weeks with a high dose of cortico sterone; electrophysiological responses to serotonin were recorded intracel lularly from CA1 pyramidal neurons in vitro. We observed that daily injecti ons with corticosterone gradually attenuate the membrane hyperpolarization and resistance decrease mediated by serotonin-1A receptors, We next used si ngle-cell antisense RNA amplification from identified CA1 pyramidal neurons to resolve whether the functional deficits in serotonin responsiveness are accompanied by decreased expression levels of the serotonin-la receptor. I t appeared that expression of serotonin-1A receptors in CA1 pyramidal cells is not altered; this result was supported by in situ hybridization, Expres sion of corticosteroid receptors in the same cells, particularly of the hig h-affinity mineralocorticoid receptor, was significantly reduced after long -term corticosterone treatment. The present findings indicate that prolonge d elevation of the corticosteroid concentration, a possible causal factor f or major depression in humans, gradually attenuates responsiveness to serot onin without necessarily decreasing serotonin-1A receptor mRNA levels in py ramidal neurons. These functional changes may occur by a posttranscriptiona l mechanism or by transcriptional regulation of genes other than the seroto nin-1A receptor gene itself.