Inhibition by α-tetrahydrodeoxycorticosterone (THDOC) of pre-sympathetic parvocellular neurones in the paraventricular nucleus of rat hypothalamus

Background and Purpose: alpha-tetrahydrodeoxycorticosterone (THDOC) is an endogenous neuroactive steroid which increases in plasma and brain concentration during stress. It has both positive and negative modulatory effects on GABA activated GABA(A) currents, dependent upon the dose. We investigated the effects of THDOC on spinally-projecting ''pre-sympathetic'' neurones in the parvocellular subnucleus of the hypothalamic paraventricular nucleus (PVN), to determine whether it activates or inhibits these neurones, and by what mechanism. Experimental Approach: Rat spinally-projecting (parvocellular) PVN neurones were identified by retrograde labelling and the action of THDOC investigated with three modes of patch-clamp: cell-attached action current, whole-cell voltage-clamp and cell-attached single-channel recording. Key Results: In cell-attached patch mode, parvocellular neurones fired action potentials spontaneously with an average frequency of 3.6 +/- 1.1 Hz. Bath application of THDOC reduced this with an EC50 of 67nM (95% confidence limits: 54 to 84nM), Hill coefficient 0.87 +/- 0.04, n = 5. In whole-cell patch-clamp mode, pressure ejection of GABA evoked inward currents. These were clearly GABA(A) currents, since they were inhibited by the GABAA receptor antagonist bicuculline, and reversed near the chloride equilibrium potential. THDOC significantly potentiated GABA(A) currents (1 mu M THDOC: 148 +/- 15% of control, n = 5, p <= 0.05, ANOVA). Single-channel analysis showed no differences in conductance or corrected mean open times in the presence of 1 mu M THDOC. Conclusions and Implications: THDOC inhibited parvocellular neuronal activity without showing any evidence of the bidirectional activity demonstrated previously with cultured hypothalamic neurones. Our data are consistent with the hypothesis that THDOC acts by potentiating the post-synaptic activity of endogenously released GABA.