Effects of flesinoxan on corticosteroid receptor expression in the rat hippocampus

Many agents that influence serotonergic neurotransmission modulate expressi on of hippocampal corticosteroid receptors. We have studied the effect of t he specific 5-hydroxytryptamine, 5-HT1A, receptor agonist flesinoxan on mRN A for glucocorticoid and mineralocorticoid receptors in the hippocampus and dorsal raphe nucleus. Since some responses to 5-HT1A receptor stimulation show a strong desensitization, we studied the effect of a single and repeat ed injections of flesinoxan. Because of the close interrelationship between the serotonergic system and the hypothalamo-pituitary-adrenal axis, we als o studied the possible involvement of corticosterone as a mediator of the e ffects 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 gluc ocorticoid receptor mRNA in the hippocampus (dentate gyrus and CAI areas) a nd dorsal raphe nucleus. This effect does not desensitize after a second tr eatment over 2 days. Mineralocorticoid receptor mRNA expression remained un altered. The decrease in hippocampal glucocorticoid receptor mRNA expressio n occurs independently of circulating corticosterone since flesinoxan reduc ed glucocorticoid receptor mRNA in the hippocampus of adrenalectomized rats with or without corticosterone replacement. These data indicate that the 5 -HT1A receptor agonist flesinoxan alters glucocorticoid receptor expression via a direct pathway independently of corticosterone and argues for an int rinsic effect selective for hippocampal glucocorticoid receptor mRNA. (C) 2 000 Elsevier Science B.V. All rights reserved.