GLUCOCORTICOID RECEPTOR-MEDIATED INHIBITION BY CORTICOSTERONE OF 5-HT1A AUTORECEPTOR FUNCTIONING IN THE RAT DORSAL RAPHE NUCLEUS

In the rat brain, the dorsal raphe nucleus contains a large proportion of serotoninergic neurons, which are mostly regulated by somato-dendritic 5-HT1A autoreceptors. This nucleus also possesses intracellular glucocorticoid receptors (GR), which may be involved in the well established modulation of serotonin (5-hydroxytryptamine, 5-HT) metabolism by glucocorticoids. Control by corticosteroids of 5-HT1A receptor-mediated inhibitory control of the firing of serotoninergic neurons in the dorsal raphe nucleus was investigated using an in vitro electrophysiological approach. The spontaneous firing rate of serotoninergic neurons recorded in brain stem slices and its inhibition due to 5-HT1A autoreceptor stimulation by 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) were similar in adrenalectomized rats and sham-operated animals. In vitro pretreatment with corticosterone (30-100 nM) significantly reduced 3-OH-DPAT-induced inhibition of the 5-HT cell discharge in slices from adrenalectomized rats. This effect could be prevented by the GR antagonist, 11 beta-(4-dimethyl-amino-phenyl)-17 beta-hydroxy-17 alpha-(prop-1-ynyl)estra-4,9-dien-3-one (RU 38486, 30 nM), and mimicked by the GR agonist, 11 beta,17 beta-dihydroxy-6-methyl-17 alpha(prop-1-ynyl)androsta-1 ,4,6-trien-3-one (RU 28362, 500 nM). In contrast, the mineralocorticoid receptor (MR) agonist, aldosterone (10 nM), did not alter 8-OH-DPAT-induced inhibition in tissues from adrenalectomized animals. Complementary autoradiographic experiments showed that [H-3]8-OH-DPAT specific binding to 5-HT1A sites in the dorsal raphe nucleus (and the hippocampus) was not significantly altered following adrenalectomy and exposure of brain stem slices to corticosterone. These data suggest that GR are involved in the suppressive effects of high levels of corticosterone on the 5-HT1A receptor-dependent regulation of 5-HT neuronal activity in the rat dorsal raphe nucleus.