Effects of the kappa opioid agonist U50,488 and the kappa opioid antagonist nor-binaltorphimine on choice between cocaine and food in rhesus monkeys

Negus, S. Stevens

doi:10.1007/s00213-004-1878-7

Cited by 72 publications

(40 citation statements)

References 38 publications

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“…We have shown previously that norBNI alone does not alter cocaine vs. food choice (Hutsell et al, 2016; Negus, 2004), and the dose of norBNI used in the present study (10 mg/kg) has been shown previously to produce selective kappa antagonist effects for up to two weeks (Ko et al, 1998). Taken together, these results suggest that kappa receptor antagonism is not sufficient to enhance amphetamine-induced reductions in cocaine vs. food choice, and provide further support for the conclusion that effects of naltrexone were mediated by its antagonism of mu rather than kappa receptors.…”

Section: Discussionsupporting

confidence: 49%

“…Finally, the effects of 0.032 mg/kg/h amphetamine were also determined alone or in combination with the kappa antagonist norbinaltorphimine (norBNI) (10 mg/kg administered IM once on the first day of amphetamine treatment). The single-dose treatment regimen was based on previous studies to indicate that 10 mg/kg norBNI produces kappa antagonist effects for at least two weeks and does not alter cocaine vs. food choice when administered alone (Hutsell et al, 2016; Ko et al, 1998; Negus, 2004). Only one monkey received all treatments; other monkeys exhausted their catheterization sites, and these monkeys had to be replaced over the course of the study.…”

Section: Methodsmentioning

confidence: 99%

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

Moerke

Banks

Cheng

et al. 2017

Drug and Alcohol Dependence

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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.

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Section: Discussionsupporting

confidence: 49%

Section: Methodsmentioning

confidence: 99%

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

Moerke

Banks

Cheng

et al. 2017

Drug and Alcohol Dependence

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“…Previous research has found that U50,488 decreases the number of total arm entries, which is thought to be an index of locomotor activity [33], in rats examined in the elevated plus maze [19, 34]. U50,488 has also been shown to decrease operant response rates [35]. In the current study, U50,488 injections led to an increase in responding on the previously ethanol-associated lever despite these motor-suppressive effects, suggesting that stimulation of KORs plays a significant role in the reinstatement of ethanol seeking.…”

Section: Discussionmentioning

confidence: 99%

nor-BNI Antagonism of Kappa Opioid Agonist-Induced Reinstatement of Ethanol-Seeking Behavior

Harshberger

Gilson

Gillett

et al. 2016

Journal of Addiction

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Recent work suggests that the dynorphin (DYN)/kappa opioid receptor (KOR) system may be a key mediator in the behavioral effects of alcohol. The objective of the present study was to examine the ability of the KOR antagonist norbinaltorphimine (nor-BNI) to attenuate relapse to ethanol seeking due to priming injections of the KOR agonist U50,488 at time points consistent with KOR selectivity. Male Wistar rats were trained to self-administer a 10% ethanol solution, and then responding was extinguished. Following extinction, rats were injected with U50,488 (0.1–10 mg/kg, i.p.) or saline and were tested for the reinstatement of ethanol seeking. Next, the ability of the nonselective opioid receptor antagonist naltrexone (0 or 3.0 mg/kg, s.c.) and nor-BNI (0 or 20.0 mg/kg, i.p.) to block U50,488-induced reinstatement was examined. Priming injections U50,488 reinstated responding on the previously ethanol-associated lever. Pretreatment with naltrexone reduced the reinstatement of ethanol-seeking behavior. nor-BNI also attenuated KOR agonist-induced reinstatement, but to a lesser extent than naltrexone, when injected 24 hours prior to injections of U50,488, a time point that is consistent with KOR selectivity. While these results suggest that activation of KORs is a key mechanism in the regulation of ethanol-seeking behavior, U50,488-induced reinstatement may not be fully selective for KORs.

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“…Two findings argue against this possibility. First, cocaine vs. food choice in this procedure is sensitive to many other manipulations that are thought to influence the relative reinforcing strength of cocaine, including magnitude of the drug and food reinforcers, fixed-ratio values for the drug and food choices, non-contingent food delivery, punishment of food or drug choice, treatment with monoamine releasers, and social rank (Negus, 2003; 2004; 2005a; 2005b; Czoty et al , 2005). Second, opioid withdrawal in opioid-dependent rhesus monkeys produces a robust increase in choice of opioid agonists over food (Spragg, 1940; Griffiths et al, 1975; Negus, 2006; Negus and Rice, 2009).…”

Section: Discussionmentioning

confidence: 99%

Effects of Extended Cocaine Access and Cocaine Withdrawal on Choice Between Cocaine and Food in Rhesus Monkeys

Banks

Negus

2009

Neuropsychopharmacol

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Chronic drug use may lead to sufficient drug intake to produce dependence and the emergence of abstinence signs during withdrawal. Although withdrawal can increase the reinforcing effects of some drugs (e.g. opioids), the impact of withdrawal on the reinforcing effects of stimulants like cocaine is less clear. This study used a novel cocaine-versus-food choice procedure to examine the relative reinforcing strength of cocaine before, during and after exposure to graded levels of extended cocaine access. Responding in four rhesus monkeys was maintained by cocaine (0–0.1 mg/kg/inj) and food delivery under a concurrent-choice schedule during daily 2hr sessions. Under baseline conditions, cocaine maintained a dose-dependent increase in cocaine choice. Subsequently, subjects were exposed to and withdrawn from periods of extended cocaine access, which was accomplished by implementing daily 21-hr supplemental sessions of cocaine self-administration in addition to daily choice sessions. During supplemental sessions, cocaine (0.1 mg/kg/inj) was available under a fixed-ratio 10/time out X schedule, and the duration of the time out was varied from 30 min to 7.5 min. Cocaine intake increased 10-fold to more than 11 mg/kg/day during exposure to supplemental sessions with the shortest post-injection time out. However, parameters of cocaine choice were not significantly affected either during or after extended cocaine access. These results do not support the hypothesis that cocaine withdrawal increases the reinforcing strength of cocaine. This differs from results with the opioid agonist heroin and suggests that withdrawal may play different roles in maintenance of opioid and stimulant abuse.

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Effects of the kappa opioid agonist U50,488 and the kappa opioid antagonist nor-binaltorphimine on choice between cocaine and food in rhesus monkeys

Abstract: These results suggest that continuous treatment with U50,488 produces a kappa receptor-mediated increase in the relative reinforcing effects of cocaine in comparison with food.

Cited by 72 publications

References 38 publications

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

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

nor-BNI Antagonism of Kappa Opioid Agonist-Induced Reinstatement of Ethanol-Seeking Behavior

Effects of Extended Cocaine Access and Cocaine Withdrawal on Choice Between Cocaine and Food in Rhesus Monkeys

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