The endogenous OFQ/N/ORL-1 receptor system regulates the rewarding effects 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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Nociceptin receptor activation does not alter acquisition, expression, extinction and reinstatement of conditioned cocaine preference in mice
2016, Brain ResearchCitation Excerpt :Recently, we demonstrated that administration of the selective NOP receptor agonist SR-8993 impaired consolidation of fear memories in animal models of post-traumatic stress disorder (Andero et al., 2013). Given that previous studies identified a role for nociceptin in the rewarding properties of cocaine (Kotlinska et al., 2002; Marquez et al., 2008; Rutten et al., 2010), and that similar neural mechanisms are known to be involved in stress- and reward-related behaviors (Koob and Kreek, 2007), we sought to determine whether SR-8993 would also affect behaviors related to cocaine reward and reinstatement. Using a conditioned place preference (CPP) procedure, we found that SR-8993 when injected 30 min or 2 h before testing did not significantly affect acquisition and expression of cocaine CPP when mice were conditioned 7.5 or 15 mg/kg of cocaine, nor did SR-8993 affect extinction, stress- or cocaine-induced reinstatement of CPP.
The Nociceptin Receptor as an Emerging Molecular Target for Cocaine Addiction
2016, Progress in Molecular Biology and Translational ScienceCitation Excerpt :Given that OFQ/N is considered an antiopioid peptide in the brain25,182 and that it regulates the activity of beta-endorphin-containing neurons in the hypothalamic arcuate nucleus,30 which provide opioidergic inputs to the VTA and NAc,183,184 we propose that OFQ/N may exert some of its inhibitory action on cocaine reward by blocking the action of beta-endorphin. Interestingly, we have observed that the rewarding action of acute cocaine was enhanced in mice lacking NOPr,72 which is opposite of what is observed in mice lacking beta-endorphin, that is, reduced rewarding action of acute cocaine.151 The two peptides (beta-endorphin and OFQ/N) exert opposite effects on the mesolimbic dopaminergic neurons causing, respectively, an increase185 or decrease26 in extracellular accumbal dopamine.
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2013, European Journal of PharmacologyThe rewarding action of acute cocaine is reduced in β-endorphin deficient but not in μ opioid receptor knockout mice
2012, European Journal of PharmacologyCitation Excerpt :The assignment of mice to the conditioning chambers was counterbalanced. The choice of the dose of cocaine and duration of conditioning were based on our previous studies (Marquez et al., 2008a, 2008b). Mice lacking the μ opioid receptor and their wild-type littermates/controls were tested for preconditioning place preference on day 1, received conditioning on days 2 and 3, and then tested for postconditioning place preference on day 4, as described above.
Pharmacological blockade or genetic knockout of the NOP receptor potentiates the rewarding effect of morphine in rats
2011, Drug and Alcohol Dependence