Many substances which act at the GABA-benzodiazepine-chloride receptor complex (GBC), such as benzodiazepine agonists, antagonists, and inverse agonists, barbiturates, and GABA agonists and antagonists, are known to interact with the behavioral effects resulting from both acute and chronic administration of ethanol. In biochemical experiments, endogenous steroids have recently been shown to have potent actions at the GBC. Some of these steroids act like hypnotic barbiturates while others act like the GABA antagonist picrotoxin. There have as yet been no behavioral studies of the interactions of these substances with ethanol, and very few studies of the behavioral effects of these compounds by themselves outside the anesthetic to convulsant spectrum.
The aim of this proposal is to determine the effects of these compounds alone and on the actions of ethanol. Dose-response curves for various steroids alone and on the acute effects of ethanol will be generated. A Stoelting activity monitor will be used to assess motor activity, the dowel test will be used to assess ataxia, a rating scale will be used to assess intoxication, duration of loss of righting reflex will be measured, and change in body temperature will be measured. For purposes of comparison and to help define the mechanism of action, the interaction of the steroids with the benzodiazepine diazepam and the hypnotic barbiturate pentobarbital will also be assessed in the same behavioral tests as used with ethanol. Interactions of various steroids with the chronic effects of ethanol will be assessed by evaluating their influences on signs of withdrawal in mice exposed to a liquid diet containing ethanol. Cross-tolerance or sensitivity to the effects of the steroids will also be determined after withdrawal signs have terminated.
