Role of gamma-aminobutyric acid type A (GABA_A) receptor subtypes in acute benzodiazepine physical dependence-like effects: Evidence from squirrel monkeys responding under a schedule of food presentation

Rationale: Assays of schedule-controlled responding can be used to characterize the pharmacology of benzodiazepines and other GABA_A receptor modulators, and are sensitive to changes in drug effects that are related to physical dependence. Objective: The present study used this approach to investigate the role of GABA_A receptor subtypes in mediating dependence-like effects following benzodiazepine administration. Methods: Squirrel monkeys (n = 6) were trained on a fixed-ratio schedule of food reinforcement. Initially, the response rate-decreasing effects of chlordiazepoxide (0.1-10 mg/kg; nonselective GABA_A receptor agonist), zolpidem (0.032-1.0 mg/kg; α1 subunit-containing GABA_A subtype-preferring agonist), and HZ-166 (0.1-10 mg/kg; functionally selective α2 and α3 subunit-containing GABA_A receptor agonist) were assessed. Next, acute dependence-like effects following single injections of chlordiazepoxide, zolpidem, and HZ-166 were assessed with flumazenil (0.1-3.2 mg/kg; nonselective GABA_A receptor antagonist). Finally, acute dependence-like effects following zolpidem administration were assessed with βCCt and 3-PBC (0.1-3.2 mg/kg and 0.32-10 mg/kg, respectively; α1 subunit-containing GABA_A receptor antagonists). Results: Chlordiazepoxide, zolpidem, and HZ-166 produced dose- and time-dependent decreases in response rates, whereas flumazenil, βCCT, and 3-PBC were ineffective. After the drug effects waned, flumazenil produced dose-dependent decreases in response rates following administration of 10 mg/kg chlordiazepoxide and 1.0 mg/kg zolpidem, but not following any dose of HZ-166. Further, both βCCT and 3-PBC produced dose-dependent decreases in response rates when administered after 1.0 mg/kg zolpidem. Conclusions: These data raise the possibility that α1 subunit-containing GABA_A receptors play a major role in physical dependence-related behaviors following a single injection of a benzodiazepine.