Cannabinoid CB1 receptors are involved in motivational effects of nicotine in rats

Rationale: The endocannabinoid system plays a role in mediating the appetitive value of a variety of reinforcing compounds, either natural rewards or drugs of abuse, but little is known about its involvement in the incentive properties of nicotine. Objectives: The objective of the study is to evaluate whether activation of CB1 cannabinoid receptors is necessary for the establishment and the short- and long-term expression of nicotine-induced conditioned place preference (CPP). This was studied in rats subjected to an unbiased, one-compartment place conditioning procedure, using the selective CB1 receptor antagonist, rimonabant, as a pharmacological tool. Methods: Wistar rats, given previous experience with nicotine in their home cage, were subjected to eight alternating nicotine (0.006-0.6 mg/kg s.c.) and saline pairings with distinct floor textures in an open field and given a test session, with no nicotine injection, in the open field whose floor was covered by two quadrants of the saline-paired texture and two quadrants of the nicotine-paired texture. Rimonabant (0.3-3 mg/kg i.p.) was administered 30 min before each nicotine (0.06 mg/kg) pairing to assess its effect on the establishment of nicotine-CPP. To study the effects of CB1 receptor blockade on short- and long-term expression of nicotine-CPP, rimonabant was administered as a single injection 30 min before the test session, conducted either 24 h, 3 weeks or 12 weeks after the last conditioning session. Results: Rats developed reliable and robust CPP to the 0.06- and 0.125-mg/kg doses of nicotine. Once established, CPP persisted for at least 12 weeks without additional exposure to nicotine and the test apparatus. Pre-pairing injections of rimonabant (3 mg/kg, but not lower doses) prevented the acquisition of nicotine-CPP, and a single pretest administration of rimonabant (3 mg/kg) abolished the expression of nicotine-CPP when the test session took place 24 h after the last conditioning session. However, rimonabant (3 mg/kg) did not antagonize the expression of nicotine-CPP when the test session was conducted 3 or 12 weeks after the acquisition phase. Conclusions: The endocannabinoids are a necessary component in both the perception by rats of the motivational value of nicotine and the short-term capacity of nicotine-paired conditioned stimuli to elicit approach behaviour. In contrast, the acute blockade of CB1 receptors no longer impairs the long-term control of behaviour by nicotine-associated environmental cues. These data provide support to the notion that the blockade of CB1 receptors can oppose tobacco dependence, withdrawal and even relapse, though the time window of efficacy and/or the schedule of administration remain to be established.