Tolerance and dependence following chronic alprazolam treatment: quantitative observation studies in female rhesus monkeys
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In order to understand mechanisms underlying tolerance and dependence following chronic benzodiazepine treatments, quantitative and reproducible behavioral models of these phenomena are required.
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.
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.
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).
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.
KeywordsBenzodiazepine Tolerance Dependence Alprazolam Primate Sedation
Supported by NIH/NIDA grant DA043204, DA011792, and AA016179.
Compliance with ethical standards
Research protocols were approved by the Institutional Animal Care and Use Committee at Harvard Medical School.
Conflict of interest
The authors declare that they have no conflict of interest.
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