title: Genetic Deletion of the Nociceptin/Orphanin FQ Receptor in the Rat Confers Resilience to the Development of Drug Addiction.
abstract: The nociceptin (NOP) receptor is a G-protein-coupled receptor whose natural ligand is the NOP/orphanin FQ (N/OFQ) peptide. Evidence from pharmacological studies suggests that the N/OFQ system is implicated in the regulation of several addiction-related phenomena, such as drug intake, withdrawal, and relapse. Here, to further explore the role of NOP system in addiction, we used NOP (-/-) rats to study the motivation for cocaine, heroin, and alcohol self-administration in the absence of N/OFQ function. Conditioned place preference (CPP) and saccharin (0.2% w/v) self-administration were also investigated. Results showed that NOP (-/-) rats self-administer less cocaine (0.25, 0.125, or 0.5 mg/infusion) both under a fixed ratio 1 and a progressive ratio schedule of reinforcement compared with wild-type (Wt) controls. Consistently, cocaine (10 mg/kg, i.p.) was able to induce CPP in Wt but not in NOP (-/-). When NOP (-/-) rats were tested for heroin (20 μg/infusion) and ethanol (10% v/v) self-administration, they showed significantly lower drug intake compared with Wt. Conversely, saccharin self-administration was not affected by NOP deletion, excluding the possibility of nonspecific learning deficits or generalized disruption of reward mechanisms in NOP (-/-) rats. These findings were confirmed with pharmacological experiments using two selective NOP antagonists, SB-612111 and LY2817412. Both drugs attenuated alcohol self-administration in Wt rats but not in NOP (-/-) rats. In conclusion, our results demonstrate that genetic deletion of NOP receptors confers resilience to drug abuse and support a role for NOP receptor antagonism as a potential treatment option for drug addiction.
authors: School of Pharmacy, Pharmacology Unit, University of Camerino, Camerino, Italy.|Committee on the Neurobiology of Addictive Disorders, The Scripps Research Institute, La Jolla, CA, USA.
authors: Marsida
authors: M
authors: Kallupi
authors: School of Pharmacy, Pharmacology Unit, University of Camerino, Camerino, Italy.
authors: Giulia
authors: G
authors: Scuppa
authors: School of Pharmacy, Pharmacology Unit, University of Camerino, Camerino, Italy.|Committee on the Neurobiology of Addictive Disorders, The Scripps Research Institute, La Jolla, CA, USA.
authors: Giordano
authors: G
authors: de Guglielmo
authors: Department of Medical Science, Section of Pharmacology and National Institute of Neuroscience, University of Ferrara, Ferrara, Italy.
authors: Girolamo
authors: G
authors: Calò
authors: Molecular and Cellular Neuroscience Department, The Scripps Research Institute, La Jolla, CA, USA.
authors: Friedbert
authors: F
authors: Weiss
authors: Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, IN USA.
authors: Michael A
authors: MA
authors: Statnick
authors: Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, IN USA.
authors: Linda M
authors: LM
authors: Rorick-Kehn
authors: School of Pharmacy, Pharmacology Unit, University of Camerino, Camerino, Italy.
authors: Roberto
authors: R
authors: Ciccocioppo
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D003042:Cocaine / Q000008:administration & dosage / Q000494:pharmacology*; D019970:Cocaine-Related Disorders / Q000235:genetics*; D004195:Disease Models, Animal; D018765:Dopamine Uptake Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D007858:Learning / Q000187:drug effects*; D009292:Narcotic Antagonists / Q000494:pharmacology*; D051381:Rats; D055647:Rats, Transgenic; D017208:Rats, Wistar; D011957:Receptors, Opioid / Q000235:genetics*; D012646:Self Administration; D000094942:Nociceptin Receptor
chemical_list: D003042:Cocaine; D018765:Dopamine Uptake Inhibitors; D009292:Narcotic Antagonists; D011957:Receptors, Opioid; D000094942:Nociceptin Receptor; C000722285:Oprl1 protein, rat