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 neurons of the rat. 2. The effects of THDOC (10 nM - 1 microM) on responses to different concentrations 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 increasing amplitudes (up to 3.9 nA at a holding potential of -20 mV). High doses of THDOC (100 nM-1 microM) induced small inward currents on its own (14+/-3 and 24+/-3 pA, respectively). 4. Simultaneous application of 10 microM GABA with 100 nM or 1 microM THDOC increased current amplitudes by 125 and 128%, respectively. At 10 nM THDOC exerted no consistent effects on GABA currents. 5. Responses to 1 microM 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 microM 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 currents (IPSCs) was reversibly increased from 91+/-10 to 314+/-34 ms (n=3) by the application of THDOC (1 microM). The amplitudes of the IPSCs were not affected by THDOC. 7. 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.
Wetzel
C H
CH
Max-Planck-Institute of Psychiatry, Clinical Institute, Munich, Germany.
Vedder
H
H
Holsboer
F
F
Zieglgänsberger
W
W
Deisz
R A
RA
D000818:Animals; D002478:Cells, Cultured; D018118:Chloride Channels / Q000187:drug effects*; D003900:Desoxycorticosterone / Q000031:analogs & derivatives* / Q000494:pharmacology; D007031:Hypothalamus / Q000187:drug effects* / Q000502:physiology; D051381:Rats; D013569:Synapses / Q000187:drug effects* / Q000502:physiology; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology*
D018118:Chloride Channels; D003900:Desoxycorticosterone; C009413:tetrahydrodeoxycorticosterone; D005680:gamma-Aminobutyric Acid