Vanessa Minervini1,2, Alex Disney3, Stephen M Husbands3, Charles P France4,5,6. 1. Department of Pharmacology, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive (Mail Code 7764), San Antonio, TX, 78229, USA. 2. Addiction Research, Treatment and Training (ARTT) Center of Excellence, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA. 3. Department of Pharmacy and Pharmacology, University of Bath, Bath, UK. 4. Department of Pharmacology, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive (Mail Code 7764), San Antonio, TX, 78229, USA. france@uthsca.edu. 5. Addiction Research, Treatment and Training (ARTT) Center of Excellence, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA. france@uthsca.edu. 6. Department of Psychiatry, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA. france@uthsca.edu.
Abstract
RATIONALE: Opioid abuse remains a serious public health problem. The pseudoirreversible mu opioid receptor antagonist methocinnamox (MCAM) might be useful for treating opioid abuse and overdose. Because endogenous opioid systems can modulate cognition and decision-making, it is important to evaluate whether long-term blockade of mu opioid receptors by MCAM adversely impacts complex operant behavior involving memory. OBJECTIVE: This study tested the effects of MCAM in rhesus monkeys responding under a delayed matching-to-sample task, with correct responses reinforced by sucrose pellets. Because MCAM did not alter performance, antagonism of the rate-decreasing effects of morphine was used to confirm that an effective dose of MCAM was administered. Moreover, the muscarinic receptor antagonist scopolamine and the N-methyl-D-aspartate antagonist phencyclidine were studied as positive controls to demonstrate sensitivity of this procedure to memory disruption. RESULTS: Neither MCAM (0.32 mg/kg) nor morphine (1-5.6 mg/kg) impaired delayed matching-to-sample accuracy. Morphine dose-dependently decreased the number of trials completed before MCAM administration, and a single injection of MCAM blocked the behavioral suppressant effects of morphine for at least 7 days. Scopolamine (0.01-0.056 mg/kg) and phencyclidine (0.1-0.56 mg/kg) dose-dependently decreased delayed matching-to-sample accuracy and the number of trials completed. CONCLUSIONS: MCAM did not impair memory (as measured by accuracy in a delayed matching-to-sample task) and did not decrease responding for or consumption of sucrose pellets. This dose of MCAM attenuates self-administration of opioids and reverses as well as prevents opioid-induced respiratory depression. These results provide further support for a favorable adverse effect profile for MCAM.
RATIONALE: Opioid abuse remains a serious public health problem. The pseudoirreversible mu opioid receptor antagonist methocinnamox (MCAM) might be useful for treating opioid abuse and overdose. Because endogenous opioid systems can modulate cognition and decision-making, it is important to evaluate whether long-term blockade of mu opioid receptors by MCAM adversely impacts complex operant behavior involving memory. OBJECTIVE: This study tested the effects of MCAM in rhesus monkeys responding under a delayed matching-to-sample task, with correct responses reinforced by sucrose pellets. Because MCAM did not alter performance, antagonism of the rate-decreasing effects of morphine was used to confirm that an effective dose of MCAM was administered. Moreover, the muscarinic receptor antagonist scopolamine and the N-methyl-D-aspartate antagonist phencyclidine were studied as positive controls to demonstrate sensitivity of this procedure to memory disruption. RESULTS: Neither MCAM (0.32 mg/kg) nor morphine (1-5.6 mg/kg) impaired delayed matching-to-sample accuracy. Morphine dose-dependently decreased the number of trials completed before MCAM administration, and a single injection of MCAM blocked the behavioral suppressant effects of morphine for at least 7 days. Scopolamine (0.01-0.056 mg/kg) and phencyclidine (0.1-0.56 mg/kg) dose-dependently decreased delayed matching-to-sample accuracy and the number of trials completed. CONCLUSIONS:MCAM did not impair memory (as measured by accuracy in a delayed matching-to-sample task) and did not decrease responding for or consumption of sucrose pellets. This dose of MCAM attenuates self-administration of opioids and reverses as well as prevents opioid-induced respiratory depression. These results provide further support for a favorable adverse effect profile for MCAM.
Authors: Lisa R Gerak; Vanessa Minervini; Elizabeth Latham; Saba Ghodrati; Katherine V Lillis; Jessica Wooden; Alex Disney; Stephen M Husbands; Charles P France Journal: J Pharmacol Exp Ther Date: 2019-08-22 Impact factor: 4.030
Authors: John N Bain; Mark A Prendergast; Alvin V Terry; Stephen P Arneric; Mark A Smith; Jerry J Buccafusco Journal: Psychopharmacology (Berl) Date: 2003-05-27 Impact factor: 4.530
Authors: Charles P France; Gerard P Ahern; Saadyah Averick; Alex Disney; Heather A Enright; Babak Esmaeli-Azad; Arianna Federico; Lisa R Gerak; Stephen M Husbands; Benedict Kolber; Edmond Y Lau; Victoria Lao; David R Maguire; Michael A Malfatti; Girardo Martinez; Brian P Mayer; Marco Pravetoni; Niaz Sahibzada; Phil Skolnick; Evan Y Snyder; Nestor Tomycz; Carlos A Valdez; Jim Zapf Journal: Clin Pharmacol Ther Date: 2020-11-29 Impact factor: 6.875