ISONIAZID-INDUCED INHIBITION OF GABAERGIC TRANSMISSION ENHANCES NEUROSTEROID CONTENT IN THE RAT-BRAIN

Isoniazid (375 mg/kg, s.c.), a drug that decreases GABA(A) receptor-me diated transmission, elicited a time-dependent increase of neuroactive steroid (pregnenolone, progesterone and allotetrahydro-deoxycorticost erone) concentrations in rat brain and plasma. This treatment also tim e-dependently increased the plasma concentration of corticosterone. Br ain and plasma neuroactive steroid levels peaked between 40 and 120 mi n after isoniazid administration, respectively, and returned to contro l values by 5 hr. Acute foot shock stress mimicked the effect of isoni azid by increasing in a time-dependent manner the same neuroactive ste roids both in brain and plasma. Abecarnil (0.3 mg/kg, i.p.), a beta-ca rboline derivative with anxiolytic properties, antagonized the effect of both isoniazid and foot shock on brain and plasma neuroactive stero ids and on plasma corticosterone level. These data indicate that an in hibition of central GABAergic transmission enhances the concentrations of THDOC and its precursors pregnenolone and progesterone in the rat brain and plasma as well as the plasma levels of corticosterone. This finding suggests that GABA exerts a tonic inhibitory action on the mec hanisms involved in the regulation of the synthesis and release of the se neuroactive steroids in the central nervous system and plasma. Copy right (C) 1996 Elsevier Science Ltd.