Bidirectional effects of the neuroactive steroid tetrahydrodeoxycorticosterone on GABA-activated Cl- currents in cultured rat hypothalamic neurons

1 The non-genomic effects of tetrahydrodeoxycorticosterone (THDOC; 5-alpha- pregnane-3-alpha, 21-diol-20-one) were studied in cultured hypothalamic neu rons of the rat. 2 The effects of THDOC (10 nM-1 mu M) on responses to different concentrati ons of exogenously applied GABA and on spontaneous inhibitory postsynaptic currents (IPSCs) were measured with whole-cell voltage clamp recordings. 3 Application of GABA induced inward currents with dose-dependently increas ing amplitudes (up to 3.9 nA at a holding potential of -20 mV). High doses of THDOC (100 nM-1 mu M) induced small inward currents on its own (14+/-3 a nd 24+/-3 pA, respectively). 4 Simultaneous application of 10 mu M GABA with 100 nM or 1 mu M THDOC incr eased current amplitudes by 125 and 128%, respectively. At 10 nM THDOC exer ted no consistent effects on GABA currents. 5 Responses to 1 mu M of GABA were modulated in a bidirectional manner by d ifferent doses of THDOC: 10 nM THDOC reduced the amplitude of GABA response s to 80% (P=0.018, n=15), whereas 100 nM and I mu M THDOC enhanced the GABA response to 115 and 180% (P=0.0007, n=15), respectively. 6 The time constant of decay of spontaneous inhibitory postsynaptic current s (IPSCs) was reversibly increased from 91+/-10 to 314+/-34 ms (n=3) by the application of THDOC (1 mu M). The amplitudes of the IPSCs were not affect ed by THDOC. 7 These data indicate that THDOC modulates GABA responses of h ypothalamic neurons in a bidirectional manner, resulting in a complex tunin g of neuronal excitability in the hypothalamus.