Selective inhibition of cocaine-seeking behaviour by a partial dopamine D3 receptor agonist

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(1-4). In animals, such cues can induce and maintain drug-seeking behaviour and also reinstate drug-seeking after extinction(5-7). Reducing the motivational effects of drug-related cues might therefore be useful in the treatment of addiction(3). Converging pharmacological(8,9), human post-mortem(10) and genetic(11) studies implicate the dopamine D-3 receptor(12) in drug addiction. Here we have designed BP 897, the first D-3-receptor-selective agonist, as assessed in vitro with recombinant receptors and in vivo with mice bearing disrupted D-3-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.