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Tolerance and dependence following chronic alprazolam treatment: quantitative observation studies in female rhesus
Angela N Duke1,2,3, Donna M Platt1,2, James K Rowlett4,5
1Department of Psychiatry and Human Behavior, University of Mississippi Medical Center, 2500 North State Street, Jackson, MS, 39216, USA.
Rationale:
In order to understand mechanisms underlying tolerance and dependence following chronic benzodiazepine treatments, quantitative and reproducible behavioral models of these phenomena are required.
Objectives:
This research evaluated the ability of chronic treatment with a commonly prescribed benzodiazepine, alprazolam, to induce tolerance to sedative effects and physical dependence using a novel set of behavioral measurements in rhesus monkeys.
Methods:
Four female rhesus monkeys (Macaca mulatta) were implanted with chronic intravenous catheters and administered i.v. alprazolam (1.0 mg/kg every 4 h, 38 days total). Quantitative observation measures were obtained during the 38 days of treatment. Acute administration of the benzodiazepine receptor antagonist flumazenil (0.1, 0.3 mg/kg, i.v.) was given to assess precipitated withdrawal. On day 39, saline was substituted for alprazolam and withdrawal signs were assessed for 7 days.
Results:
Maximal sedation ("deep sedation") was evident on day 1 but was not significantly different from baseline levels by day 4 and was absent for the remainder of the 38 days of treatment. A milder form of sedation, "rest/sleep posture," emerged by day 3 and did not decline over 38 days. Cessation of alprazolam treatment resulted in significant withdrawal signs (nose rub, vomit, procumbent posture, tremor/jerk, rigid posture) that dissipated by day 3. These signs also were observed with flumazenil (0.3 mg/kg).
Conclusions:
Chronic alprazolam treatment resulted in rapid tolerance to some behaviors (e.g., deep sedation) but no tolerance to others (e.g., rest/sleep posture). Physical dependence was observed via both spontaneous and precipitated withdrawal. Based on previous research, these phenomena may reflect differential plasticity at GABAA receptor subtypes.
