The neuroactive steroid 5 alpha-tetrahydrodeoxycorticosterone increases GABAergic postsynaptic inhibition in rat...

The neuroactive steroid 5 alpha-pregnane-3 alpha, 21-diol-20-one (5 alpha-tetrahydrodeoxycorticosterone; 5 alpha-THDOC) has been shown to potentiate GABA-induced chloride currents in cell cultures and subcellular preparations. In this study, we recorded from pyramidal neurons in an in vitro slice preparation of the adult rat frontal neocortex using intracellular microelectrodes. 5 alpha-THDOC (10 microM) increased and prolonged the inhibitory postsynaptic potential (IPSP). The mean maximal synaptic conductance of the early, GABAA receptor-mediated, IPSP was enhanced to more than 700%, the one at the maximum of the late, partially GABAB receptor-mediated, IPSP to approximately 400%. The progesterone/glucocorticoid receptor antagonist RU 38486 did not prevent the IPSP increase. At a concentration of 1 microM 5 alpha-THDOC increased only the early IPSP to about 125%. Responses to the iontophoretically applied specific GABAA receptor agonist muscimol but not to the specific GABAB receptor agonist L-baclofen were enhanced by 5 alpha-THDOC (10 microM). In the giga-seal whole-cell configuration when the GABAB receptor-mediated IPSP component was absent due to intracellular perfusion, 5 alpha-THDOC (10 microM) increased IPSPs to a similar extent as in the conventional microelectrode recordings. Excitatory postsynaptic potentials, resting membrane potential, input resistance and action potential amplitude were not affected by 5 alpha-THDOC (10 microM). These data demonstrate that in neocortical tissue of the rat 5 alpha-THDOC enhances GABAergic inhibition by interacting with postsynaptic GABAA receptors while synaptic excitation and parameters of electric excitability remain unchanged.