Blocking cannabinoid CB1 receptors for the treatment of nicotine dependence: insights from pre-clinical and clinical studies

Abstract

Tobacco use is one of the leading preventable causes of death in developed countries. Since existing medications are only partially effective in treating tobacco smokers, there is a great need for improved medications for smoking cessation. It has been recently proposed that cannabinoid CB(1) receptor antagonists represent a new class of therapeutic agents for drug dependence, and notably, nicotine dependence. Here, we will review current evidence supporting the use of this class of drugs for smoking cessation treatment. Pre-clinical studies indicate that nicotine exposure produces changes in endocannabinoid content in the brain. In experimental animals, N-piperidinyl-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylpyrazole-3-carboxamide (rimonabant, SR141716) and N-(piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (AM251), two cannabinoid CB(1) receptor antagonists, block nicotine self-administration behavior, an effect that may be related to the blockade of the dopamine-releasing effects of nicotine in the brain. Rimonabant also seems efficacious in decreasing the influence of nicotine-associated stimuli over behavior, suggesting that it may act on two distinct neuronal pathways, those implicated in drug-taking behavior and those involved in relapse phenomena. The utility of rimonabant has been evaluated in several clinical trials. It seems that rimonabant is an efficacious treatment for smoking cessation, although its efficacy does not exceed that of nicotine-replacement therapy and its use may be limited by emotional side effects (nausea, anxiety and depression, mostly). Rimonabant also appears to decrease relapse rates in smokers. These findings indicate significant, but limited, utility of rimonabant for smoking cessation.

Figure 1. Rimonabant decreases nicotine self-administration and cue-maintained responding in rats

A) During repeated sessions, animals learned to press a lever to obtain intravenous injections of nicotine and a brief light stimulus was associated with each nicotine injection. This light stimulus progressively gained motivational properties. B) Removing the environmental light stimuli associated with nicotine injection (no-cues condition) dramatically reduced nicotine self-administration by rats, as compared to situation in which nicotine delivery is associated with presentation of these light stimuli (cues condition). Adapted from (Donny et al., 2003) and reproduced with permission from (Le Foll and Goldberg, 2005a). Results are expressed as mean (±SEM) of number of lever-press for saline or nicotine injection per session. C) Rimonabant (SR 141716) administration decreased intravenous nicotine self-administration (a) and responding maintained by nicotine-associated stimuli (b) in rats. Reproduced with permission from (Cohen et al., 2005). D) Rimonabant (SR 141716) administration decreased nicotine-induced dopamine in the shell of the nucleus accumbens, as assessed with microdialysis in awake rats. Reproduced with permission from (Cohen et al., 2002).

Figure 2. Rimonabant blocks nicotine-induced conditioned place preferences (CPP)

A, In order to induce CPP, a box with two discrete chambers, or environments, is usually used. Rats were repeatedly injected with nicotine before being placed in one environment and with saline before being placed in the other environment. Then, in a nicotine-free state, the animals were allowed access to both environments and the amount of time spent in each environment was recorded. Reproduced with permission from (Le Foll and Goldberg, 2005a). B, Nicotine induced significant conditioned place preferences over a large range of doses in rats. Results are expressed as the difference in time in sec spent in the drug-paired side between the post- and the pre-conditioning session. * P <0.05. Adapted from (Le Foll and Goldberg, 2005c) C, Rimonabant (3 mg/kg) blocked the establishment of nicotine-induced conditioned place preference when administered before each conditioning session with nicotine. Reproduced with permission from (Forget et al., 2005). D, Rimonabant administered acutely before the test-session blocked the short term expression of nicotine-induced CPP when the test take place 24h after the last conditioning session, * P < 0.05; ** P<0.01 paired vs unpaired time. + P <0.05 vs nicotine conditioned group without Rimonabant (black diagrams). Reproduced with permission from (Forget et al., 2005). Similar results have been reported by (Le Foll and Goldberg, 2004).

Figure 3. Rimonabant does not affect subjective effects induced by nicotine in rats

A) Description of the drug discrimination paradigm. Rats are trained to press on levers to get food pellets. Rats will be trained to respond on the lever after either saline or training drug injections. During some training sessions after the saline pretreatment, only one lever will allow the animal to get the food pellet (left graph). On other training sessions after the injection of the training drug (e.g nicotine 0.4 mg/kg in B), only lever-presses on the other lever will results in food pellets delivery (middle graph). After training, the rats will press only the saline-associated lever during the saline sessions and only the nicotine-associated lever after injection of nicotine at the training dose (see B). These rats are trained to discriminate the subjective effects induced by nicotine injections (right). B) Dose-effect functions for the discriminative-stimulus effects of nicotine in rats (n = 24) trained to discriminate 0.4 mg/kg nicotine from saline. The percentage of responses on the lever associated with nicotine administration is shown as a function of dose (mg/kg) during tests with various nicotine doses. SR141716 given acutely 60 min before the session did not modify the discrimination of nicotine (no shift of the curve). The arrow indicates that SR141716 alone, at doses of 0.3 and 3 mg/kg, did not produce responding on the nicotine-associated lever, i.e. did not produce any ‘nicotine-like’ effects in those rats. Reproduced with permission from (Le Foll and Goldberg, 2004).