Environmental stimuli that are reliably associated with the effects of many abused drugs, especially stimulants such as cocaine, can produce craving and relapse in abstinent human substance abusers. In animals, such cues can induce and maintain drug-seeking behaviour and also reinstate drug-seeking after extinction. Reducing the motivational effects of drug-related cues might therefore be useful in the treatment of addiction. Converging pharmacological, human post-mortem and genetic studies implicate the dopamine D3 receptor in drug addiction. Here we have designed BP 897, the first D3-receptor-selective agonist, as assessed in vitro with recombinant receptors and in vivo with mice bearing disrupted D3-receptor genes. BP 897 is a partial agonist in vitro and acts in vivo as either an agonist or an antagonist. We show that BP 897 inhibits cocaine-seeking behaviour that depends upon the presentation of drug-associated cues, without having any intrinsic, primary rewarding effects. Our data indicate that compounds like BP 897 could be used for reducing the drug craving and vulnerability to relapse that are elicited by drug-associated environmental stimuli.

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Anatomical, pharmacological and human post-mortem studies suggest the dopamine D 3 receptor (DRD3) gene as a candidate for drug dependence. We thus performed an association study of the Bal I polymorphism at the DRD3 gene, including 54 opiate addicts and 70 controls. Opiate addicts had a higher sensation-seeking score (on the Zü ckerman scale) than controls (P = 0.001), particularly a subgroup (70%) who had a distinctly higher score, exceeding 24. There were no marked differences in genotypes between patients as a whole and controls. However, patients with a sensation-seeking score above 24 were more frequently homozygotes for both alleles than patients with a sensation-seeking score under 24 (P = 0.038) or controls (P = 0.034). Although obtained in a sample of limited size, these results suggest that the DRD3 gene may have a role in drug dependence susceptibility in individuals with high sensation-seeking scores. This hypothesis is consistent with the role of DRD3 in mediating responses to drugs of abuse in animals and the association of homozygosity at the Bal I polymorphism with drug abuse in schizophrenic patients (see companion article by Krebs et al).Addiction to substances, including drugs and alcohol, probably arises from a combination of environmental and genetic factors. 1-3 Alcohol, opiates and psychostimulants share the ability in animals to enhance the activity of mesolimbic-mesocortical dopaminergic neurons, thought to be involved in drug reward and reinforcement. 4 The dopamine D 3 receptor (DRD3) is selectively expressed in the projection field of dopaminergic mesolimbic-mesocortical neurons. 5 Stimulation of DRD3 enhances the reinforcing properties of cocaine in rats 6 and monkeys; 7,8 behavioral sensitization occurring after repeated administration of an indirect dopamine agonist, a process also observed after repeated administration of opiates and psychostimulants, is accompanied by a selective induction of DRD3 gene expression. 9 Furthermore, DRD3 binding 10 and gene transcripts 11 are elevated in the ventral striatum of cocaine fatalities. These experimental and clinical observations suggest the DRD3 gene as a candidate for susceptibility to drug dependence.We recruited 54 patients with opiate dependence and without schizophrenia, both according to DSM-III-R criteria (mean age ± s.d. 32.3 ± 6.1 yrs), and 70 controls without drug use or any psychiatric disease (mean age 42.2 ± 7 yrs), all white males of French ancestry. The older age of controls minimises the risk of including not yet revealed addicts. Twenty-nine patients had less than three life-time comorbid substance dependences, and 25 more than three comorbid dependences. The age of first opiate use was 18.6 ± 2.9 yrs.The sensation-seeking score, as assessed using the Zü ckerman scale, was significantly higher in patients (26 ± 5) than in controls (17 ± 6, P = 0.001). The sensation-seeking score in patients was found inversely correlated with age (r = −0.37, P = 0.005), as it is in the general population. 12 However, testing for normali...