The effects of new hypnotic drugs in rats trained to discriminate ethanol

Several new, non-benzodiazepine hypnotic drugs have recently been marketed (zopiclone, zolpidem) or are in development (zaleplon, SX 3228). These compounds act at benzodiazepine (BZ) (omega) receptors but have mechanisms of action which are not identical to those of benzodiazepines; in particular, zolpidem, zaleplon and SX 3228 have been reported to have selectivity for the BZ1 (omega 1) receptor subtype. In the present study the effects of the four hypnotic drugs were investigated in rats trained to discriminate ethanol (1 g/kg). Comparisons were made with pentobarbital and the benzodiazepines, lorazepam and midazolam. The two benzodiazepines and the barbiturate produced dose-related substitution for ethanol. In contrast, zolpidem, zaleplon, SX 3228 and zopiclone gave rise to only partial (maximum effect 50-67%) substitution, even at doses which greatly reduced rates of lever pressing. The limited ethanol-like effects of zolpidem, zaleplon and SX 3228 may be related to the more selective mechanism of action of these compounds. It is not clear why the effects of zopiclone differed from those of the benzodiazepines.