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-dendr itic 5-HT1A autoreceptors. This nucleus also possesses intracellular g lucocorticoid receptors (GR), which may be involved in the well establ ished modulation of serotonin (5-hydroxytryptamine, 5-HT) metabolism b y glucocorticoids. Control by corticosteroids of 5-HT1A receptor-media ted inhibitory control of the firing of serotoninergic neurons in the dorsal raphe nucleus was investigated using an in vitro electrophysiol ogical approach. The spontaneous firing rate of serotoninergic neurons recorded in brain stem slices and its inhibition due to 5-HT1A autore ceptor stimulation by 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DP AT) were similar in adrenalectomized rats and sham-operated animals. I n vitro pretreatment with corticosterone (30-100 nM) significantly red uced 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-yny l)androsta-1 ,4,6-trien-3-one (RU 28362, 500 nM). In contrast, the min eralocorticoid receptor (MR) agonist, aldosterone (10 nM), did not alt er 8-OH-DPAT-induced inhibition in tissues from adrenalectomized anima ls. Complementary autoradiographic experiments showed that [H-3]8-OH-D PAT 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 sugge st that GR are involved in the suppressive effects of high levels of c orticosterone on the 5-HT1A receptor-dependent regulation of 5-HT neur onal activity in the rat dorsal raphe nucleus.