Neurosteroid modulation of arterial baroreflexsensitive neurons in rat rostral ventrolateral medulla.

The major metabolite of progesterone, 3α-OH-dihydroprogesterone (3α-OH-DHP), is the most potent endogenous positive modulator of central nervous system GABAA receptors. Acute intravenous administration of 3α-OH-DHP to virgin female rats potentiates arterial baroreflex sympathoinhibitory responses. The current experiments tested the possibility that circulating 3α-OH-DHP potentiates central GABAergic influences in the rostral ventrolateral medulla (RVLM). The unit activity of spontaneously active, spinally projecting, and arterial pressure-sensitive neurons was recorded in the RVLM of urethan-anesthetized rats. Arterial pressure sensitivity of RVLM neurons was tested before (control) and 10 min after bolus injection (44 μl iv) of 3α-OH-DHP (1.12 μg/kg, n = 19) or vehicle (40% β-cyclodextrin, n = 8). Both threshold pressure and saturation pressure for inhibition of RVLM neurons were decreased after acute administration of a physiological dose of 3α-OH-DHP (1.12 μg/kg iv), which produces plasma concentrations similar to those seen during pregnancy (20-30 ng/ml), suggesting potentiated responsiveness to endogenously released GABA. Following suppression by 3α-OH-DHP, high doses of the inactive stereoisomer 3β-OH-DHP (112-224 μg/kg iv; n = 8) restored unit activity, presumably by displacing 3α-OH-DHP from the neurosteroid binding site on GABAA receptors.