Brain Dopamine D ₁ Receptors in Twins Discordant for Schizophrenia

Objective: It has been suggested that deficits in higher-order cognitive functions serve as intermediate phenotypic indicators of genetic vulnerability to schizophrenia. The dopamine hypothesis of schizophrenia postulates that insufficiency of dopamine transmission in the prefrontal cortex contributes to the cognitive deficits observed in patients with the disease, and there is robust empirical evidence for a central role of prefrontal cortex dopamine D ₁ receptors in working memory functions. Method: The authors examined the genetic and nongenetic effects on D ₁ receptor binding in schizophrenia by studying monozygotic and dizygotic twin pairs discordant for schizophrenia as well as healthy comparison twins using positron emission tomography (PET) and the D ₁ receptor antagonist ligand [ ¹¹ C]SCH 23390. Performance on neuropsychological tests sensitive to frontal lobe functioning was evaluated. Results: High D ₁ receptor density in the medial prefrontal cortex, superior temporal gyrus, and heteromodal association cortex (angular gyrus) was associated with increasing genetic risk for schizophrenia (comparison twins < unaffected dizygotic co-twins < unaffected monozygotic co-twins). Medicated schizophrenia patients demonstrated a widespread reduction in D ₁ receptor binding when compared with the unaffected co-twin, and higher doses of antipsychotics were associated with lower D ₁ receptor binding in the frontotemporal regions. Conclusions: This study demonstrated an association between genetic risk for schizophrenia and alterations in cortical D ₁ receptor binding, an observation that has implications for future studies of the molecular genetics of schizophrenia. In addition, the data indicate a widespread reduction of D ₁ receptor binding in medicated schizophrenia patients, supporting a link between antipsychotic drug action and dopamine D ₁ receptor down-regulation.