Angela N Duke1, V V N Phani Babu Tiruveedhula2, Dishary Sharmin2, Daniel E Knutson2, James M Cook2, Donna M Platt3, James K Rowlett4. 1. Harvard Medical School, New England Primate Research Center, One Pine Hill Drive, Southborough, MA, 01772, USA. 2. Department of Chemistry and Biochemistry, University of Wisconsin-Milwaukee, Milwaukee Institute of Drug Discovery, Milwaukee, WI, 53211, USA. 3. Harvard Medical School, New England Primate Research Center, One Pine Hill Drive, Southborough, MA, 01772, USA; Department of Psychiatry and Human Behavior, University of Mississippi Medical Center, 2500 North State Street, Jackson, MS, 39216, USA. 4. Harvard Medical School, New England Primate Research Center, One Pine Hill Drive, Southborough, MA, 01772, USA; Department of Psychiatry and Human Behavior, University of Mississippi Medical Center, 2500 North State Street, Jackson, MS, 39216, USA. Electronic address: jrowlett@umc.edu.
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.
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: Nancy A Ator; John R Atack; Richard J Hargreaves; H Donald Burns; Gerard R Dawson Journal: J Pharmacol Exp Ther Date: 2009-09-29 Impact factor: 4.030
Authors: S L Huskinson; D M Platt; M Brasfield; M E Follett; T E Prisinzano; B E Blough; K B Freeman Journal: Psychopharmacology (Berl) Date: 2020-05-06 Impact factor: 4.530