Activation of the opioid mu 1, but not delta or Kappa , receptors is required for nicotine reinforcement in a rat model of drug self-administration

• Published in: Progress in neuro-psychopharmacology & biological psychiatry Vol. 35; no. 1; pp. 146 - 153
• Main Authors: Liu, Xiu, Jernigan, Courtney
• Format: Journal Article
• Language: English
• Published: 15.01.2011
• Subjects: Addiction; Antagonists; Drug addiction; Drug development; Drug self-administration; Food; Naloxone; Naltrexone; Naltrindole; Neurotransmission; Nicotine; Opioid receptors; Opioid receptors (type delta); Opioid receptors (type kappa); Reinforcement; Smoking
• ISSN: 0278-5846
• DOI: 10.1016/j.pnpbp.2010.10.007

There has long been an interest in examining the involvement of opioid neurotransmission in nicotine rewarding process and addiction to nicotine. Over the past 3 decades, however, clinical effort to test the effectiveness of nonselective opioid antagonists (mainly naloxone and naltrexone) for smoking cessation has yielded equivocal results. In light of the fact that there are three distinctive types of receptors mediating actions of the endogenous opioid peptides, this study, using a rat model of nicotine self-administration, examined involvement of different opioid receptors in the reinforcement of nicotine by selective blockade of the mu 1, the delta , and the Kappa opioid receptors. Male Sprague-Dawley rats were trained in daily 1 h sessions to intravenously self-administer nicotine (0.03 mg/kg/infusion) on a fixed-ratio 5 schedule. After establishment of stable nicotine self-administration behavior, the effects of the opioid antagonists were tested. Separate groups of rats were used to test the effects of naloxanazine (selective for mu 1 receptors, 0, 5 and 15 mg/kg), naltrindole (selective for delta receptors, 0, 0.5 and 5 mg/kg), and 5'-guanidinonaltrindole (GNTI, selective for Kappa receptors, 0, 0.25 and 1 mg/kg). In each individual drug group, the 3 drug doses were tested by using a within-subject and Latin-Square design. The effects of these antagonists on food self-administering behavior were also examined in the same rats in each respective drug group after retrained for food self-administration. Pretreatment with naloxonazine, but not naltrindole or GNTI, significantly reduced responses on the active lever and correspondingly the number of nicotine infusions. None of these antagonists changed lever-pressing behavior for food reinforcement. These results indicate that activation of the opioid mu 1, but not the delta or the Kappa , receptors is required for the reinforcement of nicotine and suggest that opioid neurotransmission via the mu 1 receptors would be a promising target for the development of opioid ligands for smoking cessation.