Increased caudate dopamine D2 receptor availability as a genetic marker for schizophrenia

Context: Schizophrenia has a heritability of about 80%, but the detailed molecular genetic basis of the disorder has remained elusive. Relative hyperfunction of the subcortical dopamine system has been previously suggested to be one of the key pathophysiologic mechanisms in schizophrenic psychosis. Objective: To examine the contributions of genetic vulnerability for schizophrenia to the dopamine system in the human brain. Design: Population-based twin cohort study. Setting: Finland. Participants: Six monozygotic and 5 dizygotic unaffected co-twins of patients with schizophrenia were ascertained, along with 4 monozygotic and 3 dizygotic healthy control twins with no family history of psychotic disorders. Main Outcome Measures: Striatal dopamine D-2 receptor availability estimated with positron emission tomographic imaging and carbon 11 (C-11)-labeled raclo-pride, and performance on neuropsychological tests sensitive to frontal lobe functioning and to schizophrenia vulnerability. Results: Unaffected monozygotic co-twins had increased caudate D-2 density compared with unaffected dizygotic co-twins and healthy control twins. Higher D-2 receptor binding in caudate was associated with a poor performance on cognitive tasks related to schizophrenia vulnerability in the whole sample. Conclusions: The caudate dopamine D-2 receptor upregulation is related to genetic risk for schizophrenia. Higher dopamine D-2 receptor density in caudate is also associated with poorer performance on cognitive tasks involving corticostriatal pathways. This finding suggests that caudate dopamine dysregulation is also a trait phenomenon related to psychosis vulnerability. This pattern of results provides a theoretical rationale for early pharmacologic intervention approaches using dopamine D-2 receptor blocking drugs.