Stephanie L Grella1, Douglas Funk2, Kathy Coen3, Zhaoxia Li3, A D Lê4. 1. Neurobiology of Alcohol Laboratory, Centre for Addiction and Mental Health, 33 Russell St., Toronto, Ontario M5S 2S1, Canada; Department of Pharmacology & Toxicology, University of Toronto, Medical Sciences Building, Rm 4207, 1 King's College Circle, Toronto, Ontario M5S 1A8, Canada. 2. Neurobiology of Alcohol Laboratory, Centre for Addiction and Mental Health, 33 Russell St., Toronto, Ontario M5S 2S1, Canada. Electronic address: douglas.funk@camh.ca. 3. Neurobiology of Alcohol Laboratory, Centre for Addiction and Mental Health, 33 Russell St., Toronto, Ontario M5S 2S1, Canada. 4. Neurobiology of Alcohol Laboratory, Centre for Addiction and Mental Health, 33 Russell St., Toronto, Ontario M5S 2S1, Canada; Department of Pharmacology & Toxicology, University of Toronto, Medical Sciences Building, Rm 4207, 1 King's College Circle, Toronto, Ontario M5S 1A8, Canada; Department of Psychiatry, University of Toronto, 250 College Street, 8th Floor, Toronto, Ontario M5T 1R8, Canada.
Abstract
RATIONALE: The correlation between stress and smoking is well established. The mechanisms that underlie this relationship are, however, unclear. Recent data suggest that the kappa-opioid system is involved in the mediation of negative affective states associated with stress thereby promoting drug addiction and relapse. Pharmacological treatments targeting the kappa-opioid system and this mechanism may prove to be useful therapeutics for nicotine addiction in the future. OBJECTIVES: We sought to determine whether there was a stress-specific role of the kappa-opioid system in nicotine seeking behavior. METHOD: Groups of male Long Evans rats were trained to self-administer nicotine intravenously; their operant responding for nicotine was extinguished prior to tests of reinstatement. Pretreatment with systemic injections of the kappa-opioid receptor (KOR) antagonist nor-binaltorphimine (nor-BNI) was given prior to tests of stress (systemic injections of yohimbine (YOH)) or cue-induced reinstatement of nicotine seeking. Systemic injections of the KOR agonist U50,488 were also given in a test for reinstatement of nicotine seeking. RESULTS: Nor-BNI pretreatment at 1h and 24h prior to testing was able to block YOH-induced, but not cue-induced reinstatement of nicotine seeking. U50,488 reinstated nicotine seeking behavior in a dose-dependent manner. CONCLUSIONS: These findings support the hypothesis that the kappa-opioid system is involved in relapse to nicotine seeking induced by stress, but not by conditioned cues. KOR antagonists such as nor-BNI may therefore be useful novel therapeutic agents for decreasing the risk of stress-induced drug relapse.
RATIONALE: The correlation between stress and smoking is well established. The mechanisms that underlie this relationship are, however, unclear. Recent data suggest that the kappa-opioid system is involved in the mediation of negative affective states associated with stress thereby promoting drug addiction and relapse. Pharmacological treatments targeting the kappa-opioid system and this mechanism may prove to be useful therapeutics for nicotine addiction in the future. OBJECTIVES: We sought to determine whether there was a stress-specific role of the kappa-opioid system in nicotine seeking behavior. METHOD: Groups of male Long Evans rats were trained to self-administer nicotine intravenously; their operant responding for nicotine was extinguished prior to tests of reinstatement. Pretreatment with systemic injections of the kappa-opioid receptor (KOR) antagonist nor-binaltorphimine (nor-BNI) was given prior to tests of stress (systemic injections of yohimbine (YOH)) or cue-induced reinstatement of nicotine seeking. Systemic injections of the KOR agonist U50,488 were also given in a test for reinstatement of nicotine seeking. RESULTS:Nor-BNI pretreatment at 1h and 24h prior to testing was able to block YOH-induced, but not cue-induced reinstatement of nicotine seeking. U50,488 reinstated nicotine seeking behavior in a dose-dependent manner. CONCLUSIONS: These findings support the hypothesis that the kappa-opioid system is involved in relapse to nicotine seeking induced by stress, but not by conditioned cues. KOR antagonists such as nor-BNI may therefore be useful novel therapeutic agents for decreasing the risk of stress-induced drug relapse.
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