The cannabinoid CB2 receptor is necessary for nicotine-conditioned place preference, but not other behavioral effects of nicotine in mice

Whereas cannabinoid CB1 receptors have long been known to contribute to the rewarding effects and dependence liability of many drugs of abuse, recent studies have implicated the involvement of cannabinoid CB2 receptors. Here, we evaluated the role of CB2 receptors in the rewarding properties of nicotine, as assessed in the conditioned place preference (CPP) paradigm and mecamylamine-precipitated withdrawal in nicotine dependent mice. Using complementary pharmacological and genetic approaches, we investigated the involvement of CB2 receptors in nicotine- and cocaine-induced CPP in mice and mecamylamine-precipitated withdrawal in nicotine-dependent mice. We also determined whether deletion of CB2 receptors affects nicotine-induced hypothermia and hypoalgesia. Nicotine-induced (0.5 mg/kg) CPP was completely blocked by selective CB2 antagonist, SR144528 (3 mg/kg) in wild-type mice, and was absent in CB2 (-/-) mice. Conversely, the CB2 receptor agonist, O-1966 (1, 3, 5, 10, 20 mg/kg) given in combination with a subthreshold dose of nicotine (0.1 mg/kg) elicited a place preference. In contrast, O-1966 (20 mg/kg) blocked cocaine (10 mg/kg)-induced CPP in wild type mice, while CB2 (-/-) mice showed unaltered cocaine CPP. CB2 (+/+) and (-/-) nicotine-dependent mice showed almost identical precipitated withdrawal responses and deletion of CB2 receptor did not alter acute somatic effects of nicotine. Collectively, these results indicate that CB2 receptors are required for nicotine-induced CPP in the mouse, while it is not involved in nicotine withdrawal or acute effects of nicotine. Moreover, these results suggest that CB2 receptors play opposing roles in nicotine- and cocaine-induced CPP.