Neural substrates of drug craving and relapse in drug addiction.

Drug addiction is characterized by motivational disturbances such as compulsive drug taking and episodes of intense drug craving. Recent advances using animal models of relapse have shown that drug-seeking behaviour can be triggered by drug-associated cues, by stress and by 'priming' injections of the drugs themselves, events also known to trigger drug craving in human drug addicts. Current evidence suggests that these stimuli all induce relapse, at least in part, by their common ability to activate the mesolimbic dopamine system. Drug-associated cues and stress can activate this system via neural circuits from the prefrontal cortex and amygdala and through activation of the hypothalamic-pituitary-adrenal axis. Our studies suggest that dopamine triggers relapse to drug-seeking behaviour by stimulating D2-dopamine receptors which inhibit the cyclic AMP second messenger pathway in the neurones of the nucleus accumbens. In contrast, compounds which activate D1 receptors prevent relapse to drug-seeking behaviour, possibly through satiation of reward pathways. Chronic neuroadaptations in dopamine receptor signalling pathways in the nucleus accumbens caused by repeated drug use are hypothesized to produce tolerance to the rewarding effects of D1-receptor stimulation, leading to increased drug intake during drug self-administration. Conversely, these same neuroadaptations are hypothesized to enhance drug craving by potentiating D2 receptor-mediated signals during abstinence. These findings identify D1 and D2-dopamine receptor mechanisms as potential targets for developing anticraving compounds to treat drug addiction.