Elsevier

Neuropharmacology

Volume 54, Issue 3, March 2008, Pages 564-568
Neuropharmacology

The endogenous OFQ/N/ORL-1 receptor system regulates the rewarding effects of acute cocaine

https://doi.org/10.1016/j.neuropharm.2007.11.003Get rights and content

Abstract

Previous studies have shown that orphanin FQ/nociceptin (OFQ/N), the endogenous ligand of the opioid receptor-like (ORL-1) receptor, reduces the rewarding and addictive properties of cocaine and other drugs of abuse. In the present study, using the conditioned place preference (CPP) paradigm, as an animal model of drug reward, we assessed whether the rewarding action of acute cocaine would be altered in mice lacking the ORL-1 receptor or in wild type mice treated with J-113397, an ORL-1 receptor antagonist, relative to their saline-treated controls. On day 1, mice were tested for their baseline place preferences, in which each mouse was placed in the neutral chamber of a three-chambered CPP apparatus, allowed to freely explore all the chambers and the amount of time that a mouse spent in each conditioning chamber was recorded for 15 min. On days 2–3, mice received once daily alternate-day saline/cocaine (15 or 30 mg/kg) conditioning for 30 min. On day 4, mice were tested for their postconditioning preferences, as described for day 1. In a subsequent study, the effect of J-113397 (3 mg/kg) on the rewarding action of acute cocaine (15 mg/kg) was also examined in wild type mice. Our results showed that mice lacking the ORL-1 receptor expressed greater CPP than their wild type littermates. Furthermore, the rewarding action of cocaine was enhanced in the presence of J-113397 in wild type mice. Together, the present results suggest that the endogenous OFQ/N/ORL-1 receptor system is involved in the rewarding action of acute cocaine.

Introduction

The opioid receptor-like (ORL-1) receptor is a G-protein-coupled receptor that shows high degree of sequence homology to traditional opioid receptors (for review, see Mogil and Pasternak, 2001). Furthermore, the endogenous ligand of the ORL-1 receptor, known as orphanin FQ (Reinscheid et al., 1995) or nociceptin (Meunier et al., 1995), a heptadecapeptide, also shows some degree of sequence homology to endogenous opioid peptides, and in particular to dynorphin A (Reinscheid et al., 1998). The ORL-1 receptor and its endogenous ligand are widely distributed throughout the central nervous system (CNS) and particularly in brain regions involved in motivational and emotional behaviors (Neal et al., 1999a, Neal et al., 1999b). Specifically, in situ hybridization and immunohistochemical studies have demonstrated localization of the ORL-1 receptor in the ventral tegmental area (VTA) (Maidment et al., 2002, Norton et al., 2002), where the cell bodies of the mesolimbic dopaminergic reward circuitry originate. Consistent with its localization, behavioral studies have shown that OFQ/N suppresses basal motor activity (Devine et al., 1996, Lutfy et al., 2001), at least in part, through an action in the VTA (Lutfy et al., 2002, Narayanan et al., 2004).

There is a growing body of evidence implicating the OFQ/N/ORL-1 receptor system in the rewarding and addictive properties of drugs of abuse. For example, intracerebroventricular (ICV) OFQ/N administration has been shown to decrease morphine-stimulated extracellular dopamine in the nucleus accumbens (Nuc Acc) in freely behaving rats (Di Giannuario et al., 1999). In parallel with this, ICV administration of OFQ/N has been reported to block the development of morphine-induced CPP in rats (Ciccocioppo et al., 2000, Murphy et al., 1999). OFQ/N has also been demonstrated to attenuate the acquisition of amphetamine-induced CPP (Kotlinska et al., 2003) and expression of cocaine-induced CPP in rats (Kotlinska et al., 2002). Furthermore, ICV administration of OFQ/N has been shown to attenuate the development of cocaine-induced CPP in mice (Sakoori and Murphy, 2004). However, it is not known whether the rewarding action of cocaine could be altered if the ORL-1 receptor is deleted or blocked pharmacologically using an ORL-1 receptor antagonist. Thus, we examined whether cocaine-induced CPP, an animal model of reward (Bardo and Bevins, 2000), would be altered in mice lacking the ORL-1 receptor or affected in wild type mice treated with J-113397, an ORL-1 receptor antagonist (Kawamoto et al., 1999). Our hypothesis was that if OFQ/N decreases cocaine-induced CPP, then deletion or pharmacological antagonism of the ORL-1 receptor would lead to an increase in cocaine-induced CPP.

Section snippets

Subjects

Male mice were housed 2–4 per cage with free access to food and water in a temperature- and humidity-controlled room on a 12-h light/12-h dark cycle. All experiments were conducted in accordance with the ethical guidelines of the National Institute of Health and approved by the Institutional Animal Care and Use Committee at Western University of Health Sciences (Pomona, CA, USA). All observations were made during the light cycle.

Drugs

Cocaine hydrochloride was obtained from Sigma (St. Louis, MO,

A single alternate-day saline/cocaine (30 mg/kg) conditioning induced CPP in C57BL/6J mice

Fig. 1 illustrates preference of mice towards the vehicle-paired (open bars) and drug-paired (black bars) chambers on the preconditioning day (day 1) and postconditioning day (day 4). A two-factor ANOVA (conditioning chambers and doses of cocaine) of the postconditioning data (day 4) revealed a significant interaction between conditioning chamber and dose (F2,36 = 4.69; p < 0.02). Further analysis of data revealed a significant increase in the amount of time spent in the drug-paired over the

Discussion

Ample evidence suggests that OFQ/N, the endogenous ligand of the ORL-1 receptor, acts to negatively modulate the function of the mesolimbic dopaminergic reward circuitry (Lutfy et al., 2001, Lutfy et al., 2002, Maidment et al., 2002, Murphy and Maidment, 1999, Narayanan et al., 2004, Norton et al., 2002, Zheng et al., 2002) and to attenuate the rewarding and addictive properties of drugs of abuse, such as morphine and cocaine (Ciccocioppo et al., 2000, Di Giannuario et al., 1999, Kotlinska

Acknowledgments

The authors wish to thank Dr. Arbi Nazarian for his suggestions and comments. We also express our gratitude to Dr. Hiroshi Takeshima for generous supply of the ORL-1 receptor heterozygous breeding pairs. The present study was supported in part by the NIDA Grant DA016682.

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