Plasticity of Dopamine D4 Receptors in Rat Forebrain: Temporal Association with Motor Hyperactivity Following Neonatal 6-Hydroxydopamine Lesioning

Genetic studies suggest that dopamine D4 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 D4 receptor-selective antagonists. In this study, effects of such lesions on D4 as well as other dopamine receptors (D1 and D2) 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, D4 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 D1 and D2 receptor binding in various forebrain regions. However, the time-course of lesion-induced motor hyperactivity correlated only with changes in D4, but not D1 and D2 receptors. These results further support the hypothesis that D4 receptors may play a pivotal role in lesion-induced hyperactivity, and possibly in clinical ADHD.