THE NEUROACTIVE STEROID 5-ALPHA-TETRAHYDRODEOXYCORTICOSTERONE INCREASES GABAERGIC POSTSYNAPTIC INHIBITION IN RAT NEOCORTICAL NEURONS IN-VITRO

The neuroactive steroid 5 alpha-pregnane-3 alpha,21-diol-20-one (5 alp ha-tetrahydrodeoxycorticosterone; 5 alpha-THDOC) has been shown to pot entiate GABA-induced chloride currents in cell cultures and subcellula r preparations. In this study, we recorded from pyramidal neurons in a n in vitro slice preparation of the adult rat frontal neocortex using intracellular microelectrodes. 5 alpha-THDOC (10 mu M) increased and p rolonged the inhibitory postsynaptic potential (IPSP). The mean maxima l synaptic conductance of the early, GABA(A) receptor-mediated, IPSP w as enhanced to more than 700%, the one at the maximum of the late, par tially GABA(B) receptor-mediated, IPSP to approximately 400%. The prog esterone/glucocorticoid receptor antagonist RU 38486 did not prevent t he IPSP increase. At a concentration of 1 mu M 5 alpha-THDOC increased only the early IPSP to about 125%. Responses to the iontophoretically applied specific GABA(A) receptor agonist muscimol but not to the spe cific GABA(B) receptor agonist L-baclofen were enhanced by 5 alpha-THD OC (10 mu M). In the giga-seal whole-cell configuration when the GABA( B) receptor-mediated IPSP component was absent due to intracellular pe rfusion, 5 alpha-THDOC (10 mu M) increased IPSPs to a similar extent a s in the conventional microelectrode recordings. Excitatory postsynapt ic potentials, resting membrane potential, input resistance and action potential amplitude were not affected by 5 alpha-THDOC (10 mu M). The se data demonstrate that in neocortical tissue of the rat 5 alpha-THDO C enhances GABAergic inhibition by interacting with postsynaptic GABA( A) receptors while synaptic excitation and parameters of electric exci tability remain unchanged.