Attention-deficit/hyperactivity disorder (ADHD) is a common disorder of attention, hyperactivity and excessive impulsive behavior. Although the cause of this syndrome is unknown, genetic factors contribute strongly to its etiology. Recent advances in molecular biology have revealed that such a genetic component is based partially upon the polymorphism of the dopamine D4 receptor gene (DRD4). Using juvenile rats with neonatal dopaminergic lesions, a widely utilized animal model of ADHD, we recently found motor hyperactivity in this model is dose-dependently reversed by several D4 receptor-selective antagonists and exacerbated by a D4 agonist. We also found the severity of lesion-induced hyperactivity is significantly correlated to the changes of D4 receptor binding in the basal forebrain. These findings represent rare evidence of a physiological function of D4 receptor, and provide first experimental basis for a specific role of this receptor in ADHD. Recent clinical studies suggest that DRD4 polymorphism is associated with the predominantly inattentive type ADHD as well as attention problems in general population. The importance of D4 receptor in attention is also indicated by converging evidence from biochemical and pharmacological studies in animals. Thus, increased dopamine neurotransmission in frontal cortex, a brain area critical for cognitive function, has been correlated to better performance in an attentional task in rats. Such an increase in dopamine transmission can be produced by D4 antagonists. Accordingly, we propose to study the role of D4 receptor in sustained attention using a five-choice serial reaction time task (5-CSRTT). Effects of D4 antagonists will be examined in normal rats versus rats screened for poor performance, a putative model for ADHD. Results from the proposed study shall clarify the role of D4 receptor in normal attention process, as well as under conditions that correspond to clinical ADHD. The findings may also provide a pharmacological basis for innovative treatment for ADHD to replace stimulant therapy.
| Moran-Gates, Taylor; Gan, Lu; Park, Young Shik et al. (2006) Repeated antipsychotic drug exposure in developing rats: dopamine receptor effects. Synapse 59:92-100 |
| Moran-Gates, Taylor; Zhang, Kehong; Baldessarini, Ross J et al. (2005) Atomoxetine blocks motor hyperactivity in neonatal 6-hydroxydopamine-lesioned rats: implications for treatment of attention-deficit hyperactivity disorder. Int J Neuropsychopharmacol 8:439-44 |
| Tarazi, Frank I; Zhang, Kehong; Baldessarini, Ross J (2004) Dopamine D4 receptors: beyond schizophrenia. J Recept Signal Transduct Res 24:131-47 |
