Disruption of nicotine conditioning by dopamine D3 receptor ligands

Tobacco smoking is the first cause of preventable death in modern countries. Nicotine replacement therapy or sustained release bupropion helps smoking cessation, but relapse rates are still very high. Nicotine, like other drugs of abuse, activates the dopamine mesolimbic system, which originates in the ventral tegmental area and projects notably to the nucleus accumbens. Situations or environmental stimuli previously associated with cigarette smoking, for example, smell of cigarette smoke, can elicit craving in abstinent smokers and promote relapse. Reducing the effects of nicotine-associated cues might therefore have potential therapeutic utility for smoking cessation. Such an approach has been validated for cocaine in animals, by using the dopamine D3 receptor-selective partial agonist BP 897, which inhibits cocaine cue-induced drug-seeking behavior. Here we show that rats repeatedly injected with nicotine in a particular environment develop nicotine-conditioned locomotor responses, accompanied by an increase in D3 receptor expression in the nucleus accumbens. This conditioned behavior was inhibited by BP 897 or a selective D3 receptor antagonist, suggesting that antagonizing dopamine selectively at the D3 receptor disrupts nicotine-conditioned effects and might represent a novel therapeutic approach for smoking cessation.