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

Rationale

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.

Objective

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.

Methods

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.

Results

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.

Conclusions

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.