Effects of flesinoxan on corticosteroid receptor expression in the rat hippocampus

Many agents that influence serotonergic neurotransmission modulate expression of hippocampal corticosteroid receptors. We have studied the effect of the specific 5-hydroxytryptamine, 5-HT(1A), receptor agonist flesinoxan on mRNA for glucocorticoid and mineralocorticoid receptors in the hippocampus and dorsal raphe nucleus. Since some responses to 5-HT(1A) receptor stimulation show a strong desensitization, we studied the effect of a single and repeated injections of flesinoxan. Because of the close interrelationship between the serotonergic system and the hypothalamo-pituitary-adrenal axis, we also studied the possible involvement of corticosterone as a mediator of the effects of flesinoxan. We found that a single injection of flesinoxan (3 and 10 mg/kg subcutaneously, s.c.) after 3 h leads to a downregulation of glucocorticoid receptor mRNA in the hippocampus (dentate gyrus and CA1 areas) and dorsal raphe nucleus. This effect does not desensitize after a second treatment over 2 days. Mineralocorticoid receptor mRNA expression remained unaltered. The decrease in hippocampal glucocorticoid receptor mRNA expression occurs independently of circulating corticosterone since flesinoxan reduced glucocorticoid receptor mRNA in the hippocampus of adrenalectomized rats with or without corticosterone replacement. These data indicate that the 5-HT(1A) receptor agonist flesinoxan alters glucocorticoid receptor expression via a direct pathway independently of corticosterone and argues for an intrinsic effect selective for hippocampal glucocorticoid receptor mRNA.