The nongenomic effects of tetrahydrodeoxycorticosterone (THDOC; 5-alpha-pregnane-3-alpha, 21-diol-20-one) were studied in cultured hypothalamic neurons of the rat.
The effects of THDOC (10 nM–1 μM) on responses to different concentrations of exogenously applied GABA and on spontaneous inhibitory postsynaptic currents (IPSCs) were measured with whole-cell voltage clamp recordings.
Application of GABA induced inward currents with dose-dependently increasing amplitudes (up to 3.9 nA at a holding potential of −20 mV). High doses of THDOC (100 nM–1 μM) induced small inward currents on its own (14±3 and 24±3 pA, respectively).
Simultaneous application of 10 μM GABA with 100 nM or 1 μM THDOC increased current amplitudes by 125 and 128%, respectively. At 10 nM THDOC exerted no consistent effects on GABA currents.
Responses to 1 μM of GABA were modulated in a bidirectional manner by different doses of THDOC: 10 nM THDOC reduced the amplitude of GABA responses to 80% (P=0.018, n=15), whereas 100 nM and 1 μM THDOC enhanced the GABA response to 115 and 180% (P=0.0007, n=15), respectively.
The time constant of decay of spontaneous inhibitory postsynaptic currents (IPSCs) was reversibly increased from 91±10 to 314±34 ms (n=3) by the application of THDOC (1 μM). The amplitudes of the IPSCs were not affected by THDOC.
These data indicate that THDOC modulates GABA responses of hypothalamic neurons in a bidirectional manner, resulting in a complex tuning of neuronal excitability in the hypothalamus.
British Journal of Pharmacology (1999) 127, 863–868; doi:10.1038/sj.bjp.0702597