Modulation of the decrease in the seizure threshold of pentylenetetrazole in diazepam-withdrawn mice by the neurosteroid 5α-pregnan-3α,21-diol-20-one (alloTHDOC)

The effect of the neurosteroid 5α-pregnan-3α,21-diol-20-one (alloTHDOC) on pentylenetetrazole (PTZ)-induced diazepam-withdrawal seizure was examined in mice. The threshold for PTZ-induced seizure was markedly decreased by discontinuation of chronic diazepam treatment. The decrease in the seizure threshold of PTZ during diazepam withdrawal was significantly attenuated by pretreatment with alloTHDOC (10 and 20 μg/mouse, i.c.v.), which did not affect the seizure threshold of PTZ in chronically vehicle-treated mice. However, the loss of the righting reflex (LRR) induced by other GABA(A) receptor activators (pentobarbital and propofol) did not differ between control and diazepam-withdrawn mice. These findings provide the first demonstration that alloTHDOC may be able to suppress diazepam withdrawal signs, and that the sensitivity to the pharmacological effect of alloTHDOC via GABA(A) receptor may be enhanced in diazepam-withdrawn mice.