Maintenance on naltrexone + amphetamine decreases cocaine-vs.-food choice in male rhesus monkeys

Abstract

Background Cocaine use disorder remains a significant public health issue for which there are no FDA-approved pharmacotherapies. Amphetamine maintenance reduces cocaine use in preclinical and clinical studies, but the mechanism of this effect is unknown. Previous studies indicate a role for endogenous opioid release and subsequent opioid receptor activation in some amphetamine effects; therefore, the current study examined the role of mu-opioid receptor activation in d-amphetamine treatment effects in an assay of cocaine-vs-food choice. Methods Adult male rhesus monkeys with double-lumen intravenous catheters responded for concurrently available food pellets and cocaine injections (0–0.1 mg/kg/injection) during daily sessions. Cocaine choice and overall reinforcement rates were evaluated during 7-day treatments with saline or test drugs. Results During saline treatment, cocaine maintained a dose-dependent increase in cocaine-vs.-food choice. The mu-opioid receptor agonist morphine (0.032–0.32 mg/kg/h) dose-dependently increased cocaine choice and decreased rates of reinforcement. A dose of the mu-selective opioid receptor antagonist naltrexone (0.0032 mg/kg/h) that completely blocked morphine effects had no effect on cocaine choice when it was administered alone, but it enhanced the effectiveness of a threshold dose of 0.032 mg/kg/h amphetamine to decrease cocaine choice without also enhancing nonselective behavioral disruption by this dose of amphetamine. Conversely, the kappa-selective opioid antagonist norbinalorphimine did not enhance amphetamine effects on cocaine choice. Conclusions These results suggest that amphetamine maintenance produces mu opioid-receptor mediated effects that oppose its anti-cocaine effects. Co-administration of naltrexone may selectively enhance amphetamine potency to decrease cocaine choice without increasing amphetamine potency to produce general behavioral disruption.

Contextual extinction of drug‐associated discriminative stimuli fails to attenuate drug‐vs‐food choice in rhesus monkeys

“…For example, nonpharmacological manipulations such as increasing drug price, increasing the magnitude of the alternative nondrug reinforcer, and punishing cocaine choice all result in decreases of cocaine choice that were of similar magnitude as the present extinction training results (Banks et al, 2013b; Chow & Beckmann, 2020; Johnson et al, 2016; Nader & Woolverton, 1991; Negus, 2003; Negus, 2005; Thomsen et al, 2013). Furthermore, the magnitude of the extinction training effect on cocaine choice in the present study is similar to effects of amphetamine maintenance on cocaine choice in monkeys (Banks et al, 2013a; Moerke et al, 2017) and rats (Thomsen et al, 2013). However, two caveats when interpreting the present results are worth noting.…”

Contextual extinction of drug-associated discriminative stimuli fails to attenuate drug-vs-food choice in rhesus monkeys

“…For example, nonpharmacological manipulations such as increasing drug price, increasing the magnitude of the alternative nondrug reinforcer, and punishing cocaine choice all result in decreases of cocaine choice that were of similar magnitude as the present extinction training results Chow & Beckmann, 2020;Johnson et al, 2016;Nader & Woolverton, 1991;Negus, 2003;Negus, 2005;Thomsen et al, 2013). Furthermore, the magnitude of the extinction training effect on cocaine choice in the present study is similar to effects of amphetamine maintenance on cocaine choice in monkeys (Banks, Blough, Negus, 2013a;Banks, Blough, et al, 2013b;Moerke et al, 2017) and rats (Thomsen et al, 2013). However, two caveats when interpreting the present results are worth noting.…”

Naltrexone maintenance fails to alter amphetamine effects on intracranial self-stimulation in rats.

“…Also, the present results agree with previous findings that naltrexone fails to alter cocaine-induced ICSS facilitation (Pabello et al, 1998). Opioid antagonist treatments also generally fail to alter self-administration of cocaine in research animals (Ettenberg, Pettit, Bloom, & Koob, 1982; Hutsell, Cheng, Rice, Negus, & Banks, 2016; Mello, Mendelson, Bree, & Lukas, 1990; Moerke, Banks, Cheng, Rice, & Negus, 2017; Pettinati et al, 2014; Rowlett, Wilcox, & Woolverton, 1998; Tanda et al, 2016), and Vivitrol failed to alter metrics for cocaine use in a recent clinical trial (Pettinati et al, 2014).…”