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

Abstract

BACKGROUND:

To assess GABAA 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 α1-containing GABAA receptors), HZ-166 (positive modulator, preferential efficacy at α2- and α3-containing GABAA receptors), and βCCT (antagonist, preferential affinity for α1-containing GABAA 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 βCCT, but not HZ-166, resulted in significant withdrawal signs.

CONCLUSIONS:

These results are consistent with a role for α1-containing GABAA receptor subtypes in tolerance and dependence observed with chronic alprazolam, although other receptors may be involved in the withdrawal syndrome.

• Authors: Angela N Duke, V V N Phani Babu Tiruveedhula, Dishary Sharmin, Daniel E Knutson, James M Cook, Donna M Platt, James K Rowlett
• Journal: Drug and alcohol dependence (Drug Alcohol Depend) Vol. 228 Pg. 108985 (11 01 2021) ISSN: 1879-0046 [Electronic] Ireland
• PMID: 34500240 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: Copyright © 2021 Elsevier B.V. All rights reserved.

Chemical References

• Receptors, GABA-A
• Benzodiazepines
• Zolpidem
• Midazolam
• Alprazolam

Topics

• Alprazolam (pharmacology)
• Animals
• Benzodiazepines
• Drug Tolerance
• Female
• Macaca mulatta
• Midazolam (pharmacology)
• Receptors, GABA-A (classification)
• Substance Withdrawal Syndrome
• Zolpidem