Neurosteroids are modulators of several receptors and ion channels and are implicated in the pathophysiology of several neuropsychiatric diseases including hepatic encephalopathy (HE). The neurosteroid, allopregnanolone, a positive allosteric modulator of GABA(A) receptors, accumulates in the brains of HE patients where it can potentiate GABA(A) receptor-mediated responses. Attenuation of the effects of neurosteroids on GABA-ergic neurotransmission is therefore of interest for the management of HE. In the present study, we determined the effect of the benzodiazepine partial inverse agonist, Ro15-4513, and the benzodiazepine antagonist, flumazenil on modulation of the GABA(A) mediated chloride currents by allopregnanolone and on spontaneous synaptic activity in cultured hippocampal neurons using the patch-clamp technique. Allopregnanolone (0.03-0.3 microM), dose-dependently potentiated GABA-induced currents, an action significantly reduced by Ro15-4513 (10 microM). In contrast, flumazenil (10 microM) had no effect on the ability of allopregnanolone to potentiate GABA(A) currents but it blocked the effects of Ro15-4513. The frequency of spontaneous synaptic activity was significantly reduced in the presence of allopregnanolone (0.1 microM) from 1.5+/-0.7 to 0.1+/-0.04Hz. This action was partially reversed by Ro15-4513 (10 microM) but was not significantly influenced by flumazenil (10 microM). These findings suggest that the beneficial affects of Ro15-4513 in experimental HE result from attenuation of the effects of neurosteroids at GABA(A) receptors. Our results may provide a rational basis for the use of benzodiazepine inverse agonists in the management and treatment of hepatic encephalopathy in patients with liver failure.
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