The cannabinoid antagonist AM251 attenuates nicotine self-administration and nicotine-seeking behaviour in rats

Abstract

The cannabinoid receptor subtype (CB₁) antagonist rimonabant (SR141716) has been shown to decrease nicotine self-administration and attenuate nicotine-evoked dopamine release in the nucleus accumbens; effects that support recent findings on its clinical efficacy as a smoking cessation aid. The present experiments aim to advance our understanding on the role of CB₁ receptors in rodent models of nicotine dependence. AM251, a selective antagonist at CB₁ receptors dose-dependently (1, 3 and 10 mg/kg IP) suppressed intravenous nicotine (0.03 mg/kg per infusion) self-administration in rats during three successive days of pre-treatment. This reduction was short lasting since behaviour was reinstated by suspending AM251 pre-treatment. This was relatively specific to nicotine self-administration since the profile of these reductions produced by AM251 was significantly different from the responses maintained by food pellets. In a model of nicotine-seeking behaviour, rats that had been extinguished by removal of nicotine and associated cues, and presented with a priming dose of nicotine (0.2 mg/kg SC) with the cues, showed robustly reinstated responses to nicotine-seeking behaviour. Acute pre-treatment with AM251 (1–10 mg/kg IP) dose-dependently attenuated the reinstatement effects produced by nicotine and the contingently presented cues. These preclinical findings support the use of rimonabant as a smoking cessation aid and highlight the CB₁ receptor as a viable target to control intake of nicotine and prevent relapse.

Introduction

There is little doubt that tobacco smoking is a major burden to society from various financial and psycho-social perspectives. A scientific case has been made that nicotine is the primary ingredient responsible for maintaining tobacco smoking and inducing dependence (Stolerman and Jarvis, 1995). Tobacco dependence is viewed as a complex disorder (DSM IV) for which there are several treatments available but many smokers find these treatments ineffective. Pharmacological interventions have been restricted to either nicotinic ligands or compounds formerly used as antidepressants (George and O'Malley, 2004), such as bupropion (Zyban™) for which the precise mechanism of action remains unclear (Warner and Shoaib, 2005).

Recent evidence suggests that the endocannabinoid system may play a prominent role in the dependence-producing actions of nicotine (Cohen et al., 2005b, De Vries and Schoffelmeer, 2005). For example, following chronic nicotine treatment, endocannabinoid levels are increased in the limbic forebrain region of rats (Gonzales et al., 2002). These initial observations were applied to nicotine dependence-related measures by examining the cannabinoid CB1 receptor specific antagonist SR141716, now given the proprietary name rimonabant. Pre-treatment with rimonabant attenuated both nicotine self-administration behaviour and nicotine-evoked dopamine release in the nucleus accumbens (NAc) of rats (Cohen et al., 2002). Rimonabant has also been shown to attenuate relapse induced by re-exposure to cocaine-associated cues or cocaine itself, in rats with a history of cocaine self-administration (De Vries et al., 2005), and to attenuate cue-induced reinstatement of nicotine-seeking behaviour in rats (Cohen et al., 2005b) and nicotine-induced conditioned place preference (Le Foll and Goldberg, 2004). Thus, rimonabant may not target a particular substance but rather the motivational aspects associated with drug-taking and drug-seeking behaviours which also extends to natural reinforcers such as sucrose-seeking behaviour that can be suppressed by rimonabant pre-treatment (De Vries et al., 2005).

Recent trials performed with rimonabant (STRATA-US) in smokers motivated to quit produced abstinence rates of 36.2% at 28 days in the study with the 20 mg dose (odds ratio 2.2) compared to 20.6% with placebo (Anthenelli, 2004). Given the benefits of rimonabant on weight gain, some of its efficacy may be linked to the 75% reduction in post-cessation weight gain amongst the quitters (Anthenelli, 2004). This may not be surprising since CB1 receptor antagonists were initially developed to control appetite and rimonabant (Acomplia™) is currently marketed mainly for this purpose.

Endocannobinoids are known to stimulate appetite and ingestive behaviours (see review by Kirkham, 2005). It is thought that CB1 receptors located in the nucleus accumbens and the hypothalamic nuclei mediate these hyperphagic actions of these substances. Blockade of CB1 receptors by rimonabant is known to attenuate stimulated release of extracellular dopamine exerted by various drug reinforcers, and this may be the common factor which underlies the potential of CB1 antagonists as ‘anti-craving’ agents (Cohen et al., 2005a).

The majority of studies examining the role of CB1 receptors in animal models of nicotine dependence have examined rimonabant. This antagonist has generated consistent findings from various rodent models such as the conditioned place preference (Le Foll and Goldberg, 2004) and cue-induced reinstatement models of nicotine-seeking behaviour (Cohen et al., 2005b). Other selective CB1 antagonists have been synthesised and studies are emerging which compare the efficacy of these analogues in various behavioural models. AM251 is a novel CB1 antagonist structurally related to rimonabant and shares similar potency and affinity for CB1 receptors (Gatley et al., 1996, Gatley et al., 1997). Although this compound has been shown to attenuate cocaine-seeking behaviour in rats (Xi et al., 2006), it has so far not been examined for its effects in behavioural models of nicotine dependence.

The present study aims to evaluate the effects of AM251 on nicotine self-administration behaviour and to compare these effects for specificity against responses maintained by food reinforcement. To better understand the nature of any alterations, each dose of AM251 is tested repeatedly over three successive sessions; the number of sessions necessary to observe extinction by saline substitution. The same doses of AM251 are further examined in a model of nicotine-seeking behaviour based upon reinstatement of extinguished responses produced by representation of nicotine and associated cues (Shoaib, 2006).