Cannabinoid CB₁ Receptor Antagonists as Promising New Medications for Drug Dependence

Abstract

This review examines the development of cannabinoid CB 1 receptor antagonists as a new class of therapeutic agents for drug addiction. Abused drugs [alcohol, opiates, ⌬ 9 -tetrahydrocannabinol (⌬ 9 -THC), and psychostimulants, including nicotine] elicit a variety of chronically relapsing disorders by interacting with endogenous neural pathways in the brain. In particular, they share the common property of activating mesolimbic dopamine brain reward systems, and virtually all abused drugs elevate dopamine levels in the nucleus accumbens. Cannabinoid CB 1 receptors are expressed in this brain reward circuit and modulate the dopamine-releasing effects of ⌬ 9 -THC and nicotine. Rimonabant (SR141716), a CB 1 receptor antagonist, blocks both the dopamine-releasing and discriminative and rewarding effects of ⌬ 9 -THC in animals. Blockade of CB 1 receptor activity by genetic invalidation also decreases rewarding effects of opiates and alcohol in animals. Although CB 1 receptor blockade is generally ineffective in reducing the self-administration of cocaine in rodents and primates, it reduces the reinstatement of extinguished cocaine-seeking behavior produced by cocaine-associated conditioned stimuli and cocainepriming injections. Likewise, CB 1 receptor blockade is effective in reducing nicotine-seeking behavior induced by re-exposure to nicotine-associated stimuli. Some of these findings have been recently validated in humans. In clinical trials, Rimonabant blocks the subjective effects of ⌬ 9 -THC in humans and prevents relapse to smoking in exsmokers. Findings from both clinical and preclinical studies suggest that ligands blocking CB 1 receptors offer a novel approach for patients suffering from drug dependence that may be efficacious across different classes of abused drugs.

The selective dopamine D3 receptor antagonists SB-277011A and NGB 2904 and the putative partial D3 receptor agonist BP-897 attenuate methamphetamine-enhanced brain stimulation reward in rats

“…Growing evidence demonstrates that blockade of D 3 receptors by the selective D 3 receptor antagonists SB-277011A or NGB 2904 or by the putative partial D 3 receptor agonist BP-897 significantly inhibits reinstatement of drug-seeking behaviors triggered by addictive drugs, such as cocaine, nicotine, or alcohol, drug-associated cues or foot-shock stress (Vorel et al 2002;Andreoli et al 2003;Xi et al 2004Xi et al , 2006Cervo et al 2007), and also inhibits cocaine or nicotine self-administration under progressive-ratio (PR), second-order, or high-effort/low-payoff reinforcement schedules (Di Ciano et al 2003;Xi et al 2005Xi et al , 2006Ross et al 2007). These data support the potential use of selective D 3 receptor antagonists or partial agonists in the clinical treatment of drug craving and relapse to drug-taking or drug-seeking behavior (see reviews by Le Foll and Goldberg 2005;Heidbreder et al 2005;Xi and Gardner 2007). In contrast, the D 3 receptor antagonists SB-277011A and NGB 2904 or the partial D 3 agonist BP-897 have no significant effect on intravenous cocaine or nicotine self-administration under fixed-ratio reinforcement (Pilla et al 1999;Vorel et al 2002;Xi et al 2005Xi et al , 2006Ross et al 2007), but low doses attenuate cocaine-or nicotine-enhanced electrical brain stimulation reward (BSR; Pak et al 2006;Xi et al 2006;Xi and Gardner 2007).…”

“…Among the five DA receptor subtypes identified in the brain, the DA D 3 receptor has attracted much attention for development of anti-addiction medications in preclinical animal studies (Le Foll and Goldberg 2005;Heidbreder et al 2005;Xi and Gardner 2007). This is based on the following facts: First, DA D 3 receptors have a unique anatomical distribution in that they are preferentially localized in the mesolimbic DA system, with the greatest densities of D 3 receptors in the NAc, islands of Calleja, and olfactory tubercle (Diaz et al 2000;Stanwood et al 2000;Sokoloff et al 2006).…”

“…This is based on the following facts: First, DA D 3 receptors have a unique anatomical distribution in that they are preferentially localized in the mesolimbic DA system, with the greatest densities of D 3 receptors in the NAc, islands of Calleja, and olfactory tubercle (Diaz et al 2000;Stanwood et al 2000;Sokoloff et al 2006). Because the DA projections from the ventral tegmental area to the NAc-olfactory tubercle complex, which includes the islands of Calleja, have an important role in brain reward function (see review by Ikemoto 2007), this restricted neuroanatomic localization may underlie D 3 receptor involvement in drug reward and addiction (Le Foll and Goldberg 2005;Heidbreder et al 2005). Second, D 3 receptors have the highest affinity for endogenous DA of all known receptors (Levant 1997;Sokoloff et al 2001), suggesting a predominant role for D 3 receptors in the normal functioning of the mesolimbic DA system.…”

The PET Radioligand [11C]MePPEP Binds Reversibly and with High Specific Signal to Cannabinoid CB1 Receptors in Nonhuman Primate Brain

“…CB 1 receptors are especially abundant in cerebellum, substantia nigra, globus pallidus, hippocampus, and lateral striatum (Herkenham et al, 1990). The CB 1 receptor mediates several pharmacological effects and is an active target for therapeutic drug development (Howlett et al, 2002;Le Foll and Goldberg, 2005). Cannabinoid receptor ligands may be useful for the treatment of pain (Walker et al, 1999), nausea (Simoneau et al, 2001), appetite control (Gelfand and Cannon, 2006;Kirkham and Tucci, 2006), and smoking cessation (Gelfand and Cannon, 2006).…”

Cannabis and endocannabinoid modulators: Therapeutic promises and challenges

“…While the development of a rodent model of delta-9-THC self-administration has so far been unsuccessful [128], it is clear that the endocannabinoid system, acting through CB1, is actively involved in the dopaminergic mesolimbic brain reward circuit [128,129]. Cannabinoids enhance the release of dopamine in the nucleus accumbens, an effect due to an enhanced firing of mesolimbic dopaminergic neurons [130].…”