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.2011 Jan 15;35(1):146-53.
doi: 10.1016/j.pnpbp.2010.10.007. Epub 2010 Oct 20.

Activation of the opioid μ1, but not δ or κ, receptors is required for nicotine reinforcement in a rat model of drug self-administration

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Activation of the opioid μ1, but not δ or κ, receptors is required for nicotine reinforcement in a rat model of drug self-administration

Xiu Liu et al. Prog Neuropsychopharmacol Biol Psychiatry..

Abstract

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 μ1, the δ, and the κ opioid receptors. Male Sprague-Dawley rats were trained in daily 1h 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 μ1 receptors, 0, 5 and 15 mg/kg), naltrindole (selective for δ receptors, 0, 0.5 and 5mg/kg), and 5'-guanidinonaltrindole (GNTI, selective for κ receptors, 0, 0.25 and 1mg/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 μ1, but not the δ or the κ, receptors is required for the reinforcement of nicotine and suggest that opioid neurotransmission via the μ1 receptors would be a promising target for the development of opioid ligands for smoking cessation.

Copyright © 2010 Elsevier Inc. All rights reserved.

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Figures

Figure 1
Figure 1
Effect of naloxonazine, an antagonist selective for the μ1 opioid receptors, on nicotine self-administration behavior. After establishment of stable nicotine self-administration in 25 daily sessions, rats (n=8) were pretreated with naloxonazine 5 hours before the test sessions in a within subject design and counterbalanced manner. The tests were separated by two no-drug pretreatment sessions. The number of lever responses is expressed as mean (±SEM). *p < 0.05, **P < 0.01 significant difference from vehicle (0) condition.
Figure 2
Figure 2
Nicotine self-administration behavior after pretreatment with naltrindole, an antagonist selective for the δ opioid receptors. Rats (n=10) were trained in 25 daily sessions to acquire stable nicotine self-administration. Then, they received an administration of naltrindole 30 min before the test sessions in a within subject design and counterbalanced manner. The tests were separated by two no-drug pretreatment sessions. The number of lever responses is expressed as mean (±SEM).
Figure 3
Figure 3
Nicotine self-administration behavior after pretreatment with GNTI, an antagonist selective for the κ opioid receptors. The tests were conducted after completion of 25 daily nicotine self-administration training sessions and scheduled with two no-drug pretreatment sessions in between. Rats (n=8) were subjected to an administration of GNTI 30 min before the test sessions in a within subject design and counterbalanced manner. The number of lever responses is expressed as mean (±SEM).
Figure 4
Figure 4
Effect of naloxonazine, naltrindole, and GNTI on the number of nicotine infusions. After stable nicotine self-administration was achieved in 25 daily sessions, the tests began. In each respective drug group, rats were subjected to pretreatment with naloxonazine (5 h before the tests), naltrindole or GNTI (30 min before the tests) in a within subject design and counterbalanced manner. There were two no-drug pretreatment sessions inserted between the tests. The doses of these antagonists are in mg/kg. The number of nicotine infusions is expressed as mean (±SEM). *p < 0.05, **P < 0.01 significant difference from respective 0 (vehicle) condition.
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