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

Megan J Moerke; Matthew L Banks; Kejun Cheng; Kenner C Rice; S Stevens Negus

doi:10.1016/j.drugalcdep.2017.09.020

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

Drug Alcohol Depend. 2017 Dec 1:181:85-93. doi: 10.1016/j.drugalcdep.2017.09.020. Epub 2017 Oct 13.

Authors

Megan J Moerke¹, Matthew L Banks², Kejun Cheng³, Kenner C Rice⁴, S Stevens Negus⁵

Affiliations

¹ Department of Pharmacology and Toxicology, Virginia Commonwealth University, 410 N. 12th St., Richmond, VA 23298, USA. Electronic address: megan.moerke@vcuhealth.org.
² Department of Pharmacology and Toxicology, Virginia Commonwealth University, 410 N. 12th St., Richmond, VA 23298, USA. Electronic address: matthew.banks@vcuhealth.org.
³ Drug Design and Synthesis Section, National Institute on Drug Abuse and National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD 20852, USA; Office of Pharmaceutical Quality, The Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD 20993, USA. Electronic address: kejun.cheng@fda.hhs.gov.
⁴ Drug Design and Synthesis Section, National Institute on Drug Abuse and National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD 20852, USA. Electronic address: kennerr@nida.nih.gov.
⁵ Department of Pharmacology and Toxicology, Virginia Commonwealth University, 410 N. 12th St., Richmond, VA 23298, USA. Electronic address: sidney.negus@vcuhealth.org.

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 (0-0.1mg/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 (0.032-0.32mg/kg/h) dose-dependently increased cocaine choice and decreased rates of reinforcement. A dose of the mu-selective opioid receptor antagonist naltrexone (0.0032mg/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 0.032mg/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.

Keywords: Amphetamine; Choice; Cocaine; Morphine; Naltrexone; Rhesus monkey.

MeSH terms

Administration, Intravenous
Animals
Choice Behavior / drug effects*
Cocaine / administration & dosage
Cocaine / pharmacology*
Dextroamphetamine / pharmacology*
Dose-Response Relationship, Drug
Drug Interactions
Food
Macaca mulatta
Male
Morphine / pharmacology
Naltrexone / analogs & derivatives
Naltrexone / pharmacology*
Receptors, Opioid, mu / agonists
Receptors, Opioid, mu / antagonists & inhibitors
Reinforcement, Psychology
Self Administration

Substances

Receptors, Opioid, mu
norbinaltorphimine
Naltrexone
Morphine
Cocaine
Dextroamphetamine

Abstract

MeSH terms

Substances

Grants and funding