Enhanced sucrose pellet consumption induced by benzodiazepine-type drugs in squirrel monkeys: role of GABAA receptor subtypes.

Rationale: Benzodiazepine agonists characteristically increase food intake in humans and non-human subjects, and the underlying mechanisms of this effect are not understood completely.

Objective: Compounds with selectivity for GABAA receptor subtypes were used to evaluate the role of GABAA receptors containing alpha1 and alpha5 subunits (alpha1GABAA and alpha5GABAA receptors, respectively) in benzodiazepine-induced increases in sucrose pellet consumption.

Materials And Methods: Adult male squirrel monkeys (N=4-6), maintained under free-feeding conditions, were administered with intramuscular injections of the nonselective benzodiazepines diazepam and alprazolam, the alpha1GABAA-preferring compounds zolpidem and zaleplon, or the alpha5GABAA-preferring agonist QH-ii-066 before daily 10-min periods when sucrose pellets were available. In a separate experiment, observable behavioral effects (e.g., ataxia and procumbent posture) were quantified after administration of alprazolam, zaleplon, and QH-ii-066. To further assess the roles of GABAA receptor subtypes, zolpidem-induced increases in pellet consumption were re-evaluated after pretreatment with nonselective antagonist flumazenil, the alpha1GABAA-preferring antagonist beta-carboline-3-carboxylate-t-butyl ester (BCCT), or QH-ii-066.

Results: Alprazolam, diazepam, zolpidem, and zaleplon but not QH-ii-066 significantly increased sucrose pellet consumption. In addition, all agonists decreased locomotion and environment-directed behavior as well as engendered ataxia and procumbent posture. For all compounds except QH-ii-066, these behaviors occurred at doses similar to those that increased pellet consumption. Flumazenil and BCCT, but not QH-ii-066, antagonized zolpidem-induced increases in pellet consumption in a surmountable fashion.

Conclusion: These results suggest that the alpha1GABAA receptor subtype plays a key role in benzodiazepine-induced increases in consumption of palatable food, whereas the alpha5GABAA receptor subtype may not be involved in this effect.