D3 dopamine receptor, behavioral sensitization, and psychosis

Behavioral sensitization is a progressive, enduring enhancement of behavior s that develops following repeated stimulant administration. It is mediated in part by dopaminergic pathways that also modulate a number of psychiatri c conditions including the development of psychosis. We propose that down-r egulation of D3 dopamine receptor function in critical brain regions contri butes to sensitization. Rodent locomotion, a sensitizable behavior, is regu lated by the opposing influence of dopamine receptor subtypes, with D3 stim ulation opposing concurrent D1 and D2 receptor activation. The D3 dopamine receptor has a 70-fold greater affinity for dopamine than D1 or D2 dopamine receptors. This imbalance in ligand affinity dictates greater occupancy fo r D3 than D1 or D2 receptors at typical dopamine concentrations following s timulant drug administration, resulting in differences in the relative tole rance at D3 vs D1 and D2 receptors. Sensitization may therefore result in p art from accommodation of the inhibitory D3 receptor 'brake' on D1/D2 media ted behaviors, leading to a progressive locomotion increase following repea ted stimulant exposure. The requirement for differential tolerance at D3 vs D1 and D2 receptors may explain the observed development of sensitization following application of cocaine, but not amphetamine, directly into nucleu s accumbens. If correct, the 'D3 Dopamine Receptor Hypothesis' suggests D3 antagonists could prevent sensitization, and may interrupt the development of psychosis when administered during the prodromal phase of psychotic illn ess. Additional study is needed to clarify the role of the D3 dopamine rece ptor in sensitization and psychosis. Published by Elsevier Science Ltd.