Different types of GABA_A receptors may mediate the anticonflict and response rate-decreasing effects of zaleplon, zolpidem, and midazolam in squirrel monkeys

Abstract.

Rationale: The role of different types of GABA_A receptors in mediating anticonflict and response rate-decreasing effects of benzodiazepines in primate species is not known. Objective: To examine the behavioral effects of the benzodiazepine-site, GABA_A agonists zolpidem, zaleplon, and midazolam in the presence of two antagonists, flumazenil and β-carboline-3-carboxylate-t-butyl ester (β-CCt) in squirrel monkeys. Methods: Two schedules of operant responding were used: (1) a multiple fixed-ratio (FR) schedule of food presentation involving punished and nonpunished behavior, and (2) an FR schedule of stimulus shock-termination. Results: Midazolam (0.03–1.0 mg/kg), zolpidem (0.1–3.0 mg/kg), and zaleplon (0.1–3.0 mg/kg) increased rates of punished responding and decreased rates of nonpunished responding under the multiple schedule. Pretreatment with flumazenil (0.3–1.0 mg/kg) antagonized the anticonflict and response rate-decreasing effects of all three agonists. Pretreatment with β-CCt (3–10 mg/kg) antagonized the anticonflict and rate-decreasing effects of midazolam, as well as the rate-decreasing effects of zolpidem and zaleplon. However, β-CCt did not antagonize the anticonflict effects of zolpidem and zaleplon; instead, these effects of zolpidem and zaleplon were apparently enhanced in the presence of β-CCt. Under the schedule of stimulus shock-termination, both flumazenil and β-CCt antagonized zolpidem and zaleplon; however, the effects of β-CCt were less consistent than the effects of flumazenil. Conclusion: In nonhuman primates, different types of GABA_A receptors may mediate the anticonflict and the response rate-decreasing effects of the nonselective GABA_A agonist midazolam and the selective GABA_A1 agonists zolpidem and zaleplon.