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Background and Purpose:
α-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 GABAA 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.
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.
In cell-attached patch mode, parvocellular neurones fired action potentials spontaneously with an average frequency of 3.6±1.1Hz. Bath application of THDOC reduced this with an EC50 of 67nM (95% confidence limits: 54 to 84nM), Hill coefficient 0.8±0.04, n=5. In whole-cell patch-clamp mode, pressure ejection of GABA evoked inward currents. These were clearly GABAA currents, since they were inhibited by the GABAA receptor antagonist bicuculline, and reversed near the chloride equilibrium potential. THDOC significantly potentiated GABAA currents (1μM 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 1μM 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.
British Journal of Pharmacology (2006) 149, 600–607. doi:10.1038/sj.bjp.0706911