Dopamine D3 receptor agents as potential new medications for drug addiction

Abstract

All drugs abused by humans increase dopamine in the shell of nucleus accumbens, which implicate the neurons of this structure in their hedonic and reinforcing properties. Among the various dopamine receptor subtypes, the D(1) (D(1)R) and D(3) (D(3)R) receptors co-localise in accumbal shell neurons. Synergistic D(1)R/D(3)R interactions at this level were found on gene expression and during induction and expression of behavioral sensitisation to levodopa in rats bearing unilateral lesions of dopamine neurons. Behavioral sensitisation to abused drugs is a component of their long-term effects. Converging pharmacologic, human postmortem and genetic studies suggest the involvement of the D(3)R in reinforcing effects of drugs; D(3)R agonists reduced cocaine self-administration in rats, without disrupting the maintenance of self-administration. These data suggest the use of D(3)R agonists as partial substitutes to treat cocaine dependence, by affecting its reward component. However, substitution therapies maintain dependence and may be inefficient on drug craving and relapse, which are the unsolved and critical problems in the treatment of drug addiction. Recently, a highly selective and partial D(3)R agonist was shown to reduce cocaine-associated cue-controlled behaviour in rats, without having any primary intrinsic effects. As drug-associated cues maintain drug-seeking in animals and elicit craving and relapse in humans, such D(3)R agents have potential therapeutic applications.