Stimulant side effects: Prefrontal/basal ganglia circuit control at dopamine D1/D2 receptors

Background: While side effects of stimulant medication used to treat children for attention deficit hyperactivity disorder have been clinically described as mild but variable, there is little or no research or understanding of biological mechanisms involved. Method: The present short review extends the 'tonic-phasic' dopamine hypothesis in terms of prefrontal and subcortical dopamine receptor (D1/D2) imbalance. Results: The minor allele of the dopamine D1 receptor predicts the 'zombie-like' motor side effect clinically described in some children treated with stimulant medications. Conclusion: Stimulant side effects may be best understood as reflecting imbalance in parallel cortico-thalamicstriatal circuits, and motor side effects as a result of prefrontal D1/D2 imbalance allowing greater motor inhibitory effects at subcortical D2 receptors. This is a variation of the 'tonic-phasic' hypothesis, which takes D1 allelic variation into account.