Selective inhibition of cocaine-seeking behaviour by a partial dopamine D-3 receptor agonist

Environmental stimuli that are reliably associated with the effects of many abused drugs, especially stimulants such as cocaine, can produce craving a nd relapse in abstinent human substance abusers(1-4). In animals, such cues can induce and maintain drug-seeking behaviour and also reinstate drug-see king after extinction(5-7). Reducing the motivational effects of drug-relat ed cues might therefore be useful in the treatment of addiction(3). Converg ing pharmacological(8,9), human post-mortem(10) and genetic(11) studies imp licate the dopamine D-3 receptor(12) in drug addiction. Here we have design ed BP 897, the first D-3-receptor-selective agonist, as assessed in vitro w ith recombinant receptors and in vivo with mice bearing disrupted D-3-recep tor 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 b ehaviour that depends upon the presentation of drug-associated cues, withou t having any intrinsic, primary rewarding effects. Our data indicate that c ompounds like BP 897 could be used for reducing the drug craving and vulner ability to relapse that are elicited by drug-associated environmental stimu li.