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  • Title: Effects of a cannabinoid receptor (CB) 1 antagonist AM251 on behavioral sensitization to nicotine in a rat model of novelty-seeking behavior: correlation with hippocampal 5HT.
    Author: Bhatti AS, Aydin C, Oztan O, Ma Z, Hall P, Tao R, Isgor C.
    Journal: Psychopharmacology (Berl); 2009 Mar; 203(1):23-32. PubMed ID: 18936914.
    Abstract:
    RATIONALE: There are marked individual differences in the efficacy of mainstream nicotine cessation agents in preventing relapse. A rat model of novelty-seeking phenotype was reported to have predictive value for psychostimulant taking behavior where locomotor reactivity to novelty is used to rank high (HR, highest 1/3) versus low (LR, lowest 1/3) responsiveness to novelty in outbred rats. We tested the hypothesis that a cannabinoid receptor (CB) 1 antagonist that is in clinical trials for smoking cessation may reverse behaviorally sensitizing effects of nicotine in HRs and repeated nicotine-induced elevations in hippocampal 5HT. MATERIALS AND METHODS: Adolescent LRHR rats underwent intermittent behavioral sensitization to nicotine regimen with or without a CB1 receptor antagonist AM251 or bupropion treatment following nicotine training during 1 week of nicotine-free period. Expression of behavioral sensitization to nicotine was assessed in response to a low-dose nicotine challenge. Using the same sensitization regimen and therapeutic treatments, hippocampal 5HT levels were measured via in vivo microdialysis in response to the nicotine challenge. RESULTS: HR but not LR animals showed behavioral sensitization to a low-dose nicotine challenge following intermittent nicotine training and 1 week of injection-free period. AM251 (5 mg/kg, i.p.) but not bupropion administration during injection-free period successfully reversed locomotor sensitization to nicotine challenge in HRs. AM251 treatment also reversed nicotine-induced elevations in extracellular 5HT in the HR hippocampal hilus. CONCLUSION: These data suggest that CB1 antagonists may prevent locomotor sensitization to nicotine and reverse nicotine-induced elevations in hippocampal 5HT in high novelty seekers.
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