The dopamine D3 receptor and drug addiction

Hedonic and reinforcing properties of drugs of abuse are closely related to brain dopamine neuron activity. All these drugs increase dopamine release in the shell of nucleus accumbens, a brain region in which neurons co-express the D₁ (D₁R) and D₃ (D₃R) dopamine receptor subtypes, that converging pharmacological, human post-mortem and genetic studies suggest to be implicated in drug addiction. The D₃R, through a cross-talk with the D₁R, is involved in induction and expression of behavioral sensitization to levodopa in rats bearing unilateral lesions of dopamine neurons. Behavioral sensitization, a cardinal feature of addiction arises from repeated administration of drugs of abuse is thought to play a role in intensification of reinforcing efficacy of these drugs observed under certain conditions. Stimulation of the D₃R also appears to enhance the reinforcing effect of cocaine in rats. By interacting with these processes, D₃R agents have potential therapeutic applications for treating drug addiction. BP 897 (N-[4-(4-(2-methoxyphenyl) piperazin-1-yl) butyl] naphtalen 2-carboxamide dichlorhydrate), a partial and highly selective D₃R agonistin vitro, behaves as an agonist or an antagonistin vivo depending on the response considered. BP 897 has the unprecedented property to reduce cocaine-seeking behavior induced by presentation of a cocaine-associated cue, without having any intrinsic reinforcing effect. As drug-associated cues maintain drug-seeking in animals and elicit craving and relapse in humans, D₃R agents like BP 897 may represent new medications for drug addiction, with minimal liability to maintaining dependence.