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. Preclinical studies indicate that nicotine exposure produces changes in endocannabinoid content in the brain. In experimental animals, Rimonabant (SR141716) and AM251, two cannabinoid CB 1 receptor antagonists, block nicotine selfadministration 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 doesn't 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.

Cannabinoid Discrimination and Antagonism by CB1Neutral and Inverse Agonist Antagonists

“…The CB 1 inverse agonist rimonabant, in addition to serving as an antagonist in pharmacological studies of cannabinergic drugs, showed initial promise as a novel type of therapeutic for appetitive suppression and smoking cessation (Pacher et al, 2006;Padwal and Majumdar, 2007;Le Foll et al, 2008;Rigotti et al, 2009). However, reports of gastrointestinal side effects and mood-depressant actions (Després et al, 2005;Van Gaal et al, 2005;Traynor, 2007) cut short its use in clinical populations, leaving the future development of this class of drugs in doubt.…”

“…From a clinical perspective, rimonabant has also been shown to have beneficial effects in the management of obesity and smoking cessation, presumably as a result of its antagonist actions (Pacher et al, 2006;Padwal and Majumdar, 2007;Le Foll et al, 2008;Rigotti et al, 2009). Unfortunately, numerous reports describing gastrointestinal side effects such as nausea and emesis as well as mooddepressant actions followed the introduction of rimonabant, hampering its utility and eventually resulting in its removal from clinical practice (Després et al, 2005;Van Gaal et al, 2005;Traynor, 2007).…”

Diacylglycerol lipase disinhibits VTA dopamine neurons during chronic nicotine exposure

“…Nicotine-induced increases in VTA 2-AG formation (14) likely contribute to the well-documented CB 1 receptor influence on behavioral and physiological response to nicotine (25). In the VTA, CB 1 receptors are thought to dynamically regulate GABA release at DAergic synapses (4), allowing the possibility that 2-AG formation dampens GABAergic constraint of DA cell excitation.…”

“…The resultant decrease in DA cell excitability likely underlies the ability of CB 1 antagonists to block nicotine-induced increases in nucleus accumbens DA release and to suppress nicotine self-administration (25,(29)(30)(31)(32)(33)(34).…”

Measurement of affective state during chronic nicotine treatment and withdrawal by affective taste reactivity in mice: The role of endocannabinoids

“…Recent evidence suggests that at least some actions of nicotine are mediated indirectly through the action of endocannabinoids [17]. For instance, endocannabinoid levels are increased in the limbic forebrain of rats chronically treated with nicotine [18].…”