Tolerance and dependence following chronic alprazolam treatment in rhesus monkeys: Role of GABAA receptor subtypes

Background: To assess GABA(A) receptor subtypes involved in benzodiazepine tolerance and dependence, we evaluated the ability of subtype-selective and non-selective ligands to substitute for (i.e., produce "cross-tolerance") or precipitate withdrawal during chronic alprazolam treatment. Methods: Four female rhesus monkeys (Macaca mulatta) were implanted with chronic intravenous catheters and administered alprazolam (1.0 mg/kg every 4 h). Following 14+ days of chronic alprazolam, acute administration of selected doses of non-selective and subtype-selective ligands were substituted for, or administered with, alprazolam, followed by quantitative behavioral observations. The ligands included alprazolam and midazolam (positive modulators, non-selective), zolpidem (positive modulator, preferential affinity for alpha 1-containing GABAA receptors), HZ-166 (positive modulator, preferential efficacy at alpha 2-and alpha 3-containing GABA(A) receptors), and SCCT (antagonist, preferential affinity for alpha 1-containing GABA(A) receptors). Results: Acutely, alprazolam and midazolam both induced observable ataxia along with a mild form of sedation referred to as "rest/sleep posture" at a lower dose (0.1 mg/kg, i.v.), whereas at a higher dose (1.0 mg/kg, i.v.), induced deep sedation and observable ataxia. With chronic alprazolam treatment, observable ataxia and deep sedation were reduced significantly, whereas rest/sleep posture was unchanged or emerged. Zolpidem showed a similar pattern of effects, whereas no behaviors engendered by HZ-166 were changed by chronic alprazolam. Administration of SCCT, but not HZ-166, resulted in significant withdrawal signs. Conclusions: These results are consistent with a role for alpha 1-containing GABA(A) receptor subtypes in tolerance and dependence observed with chronic alprazolam, although other receptors may be involved in the withdrawal syndrome.