Cannabinoid CB1 receptor antagonists as promising new medications for drug dependence.

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, Delta(9)-tetrahydrocannabinol (Delta(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 Delta(9)-THC and nicotine. Rimonabant (SR141716), a CB(1) receptor antagonist, blocks both the dopamine-releasing and discriminative and rewarding effects of Delta(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 cocaine-priming 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 Delta(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.