Plasticity of dopamine D4 receptors in rat forebrain: temporal association with motor hyperactivity following neonatal 6-hydroxydopamine lesioning.

Genetic studies suggest that dopamine D(4) receptor polymorphism is associated with attention deficit hyperactivity disorder (ADHD). We recently reported that motor hyperactivity in juvenile male rats with neonatal 6-hydroxydopamine lesions of the central dopamine system can be reversed by dopamine D(4) receptor-selective antagonists. In this study, effects of such lesions on D(4) as well as other dopamine receptors (D(1) and D(2)) were autoradiographically quantified at selected developmental stages. Neonatal lesions resulted in motor hyperactivity at postnatal day (PD) 25, but not at PD 37 or 60. Correspondingly, D(4) receptor levels in lesioned rats were substantially increased in caudate-putamen and decreased in nucleus accumbens at PD 25, but not at PD 37 or 60. Neonatal lesions also led to relatively minor changes in D(1) and D(2) receptor binding in various forebrain regions. However, the time-course of lesion-induced motor hyperactivity correlated only with changes in D(4), but not D(1) and D(2) receptors. These results further support the hypothesis that D(4) receptors may play a pivotal role in lesion-induced hyperactivity, and possibly in clinical ADHD.