Dehydroepiandrosterone (DHEA) and its metabolites, DHEA-sulphate (DHEA-S) and androsterone, have neurosteroid activity. In this study, we examined whether DHEA, DHEA-S and androsterone, can influence serotonin (5-HT) neuronal firing activity via modulation of γ-aminobutryic acid (GABAA) receptors. The firing of presumed 5-HT neurones in a slice preparation containing rat dorsal raphe nucleus was inhibited by the GABAA receptor agonists 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridinyl-3-ol (THIP) (25 μM) and GABA (100 μM). DHEA (100 and 300 μM) and DHEA-S (1, 10 and 100 μM) caused a rapid and reversible attenuation of the response to THIP. DHEA (100 μM) and DHEA-S (100 μM) also attenuated the effect of GABA. Androsterone (10 and 30 μM) markedly enhanced the inhibitory response to THIP (25 μM). The effect was apparent during androsterone administration but persisted and even increased in magnitude after drug wash-out. The data indicate that GABAA receptor-mediated regulation of 5-HT neuronal firing is sensitive to negative modulation by DHEA and its metabolite DHEA-S is sensitive to positive modulation by the metabolite androsterone. The effects of these neurosteroids on GABA A receptor-mediated regulation of 5-HT firing may underlie some of the reported behavioural and psychological effects of endogenous and exogenous DHEA.
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