The dopamine D3 receptor antagonist nafadotride inhibits development of locomotor sensitization to amphetamine

Behavioral sensitization is a well-studied model of behavioral plasticity m ediated at least in part by dopaminergic systems believed to play an import ant role in several psychiatric conditions. In the rodent, locomotion is re gulated by the opposing balance of D3 and D2 receptors, with D2 activation increasing and D3 stimulation inhibiting locomotion. However, receptor occu pancy of D3 dopamine receptors is far greater than D2 or D1 occupancy at ty pical post-stimulant dopamine concentrations. We therefore hypothesized tha t tolerance of D3 receptor inhibition of locomotion contributes to the deve lopment of sensitization. To test this hypothesis, we examined the effect o f the D3 receptor antagonist nafadotride on sensitization. As predicted, na fadotride inhibits augmentation of the locomotion response to repetitive am phetamine. This finding is consistent with the proposed model of adaptive d own-regulation of D3 dopamine receptor function contributing to the develop ment of behavioral sensitization. (C) 2000 Elsevier Science B.V. All rights reserved.