The D3 Dopamine Receptor and Substance Dependence

Abstract

Behavioral sensitization, the progressive and enduring enhancement of certain stimulant-induced behaviors following repetitive drug use, is mediated in part by dopaminergic pathways known to play a role in drug dependence. It has been theorized that sensitization underlies the development of drug craving and initiates addictive behaviors of drug dependence. We propose that down-regulation of D3 dopamine receptor function contributes to sensitization. Rodent locomotion is regulated by the opposing influence of dopamine receptor subtypes, with D3 stimulation inhibiting and concurrent D1/D2 receptor activation stimulating locomotion. The D3 receptor has greater occupancy than D1 or D2 receptors following stimulant drug administration. Sensitization may therefore result in part from greater accommodation of the inhibitory D3 receptor “brake” on locomotion, leading to progressive locomotion increase following repeated stimulant exposure. Further study is needed to test this proposed model, and to clarify the role of individual dopamine receptor subtypes in sensitization and drug dependence.