Increased left striatal dopamine transmission in unaffected siblings of schizophrenia patients in response to acute metabolic stress

A genetic alteration in sensitivity to stress, mediated by mesolimbic hyperdopaminergia, is thought to play a role in the onset, exacerbation and relapse of schizophrenia. Dopamine sensitivity to stress was tested in individuals at higher than average genetic risk for schizophrenia (siblings of patients). Using a PET paradigm of [(11)C]raclopride in a bolus plus constant infusion tracer injection, the central DA response to acute metabolic stress (bolus of 2-Deoxy-D-Glucose, 40mg/kg) in unaffected siblings of patients with schizophrenia (n=8) and healthy controls (n=10) was measured by BPND of [(11)C]raclopride before and after the 2DG challenge. After metabolic stress, controls but not siblings displayed a significant decrease in BPND of [(11)C]raclopride in the striatum; no such differences were apparent in the ventral striatum. Siblings but not controls displayed significant asymmetry (L>R) in the stress-induced DA release, especially in ventral striatum, which correlated strongly with psychometric measures of psychosis liability. The results suggest that asymmetry in the mesolimbic DA response to stress is associated with genetic risk for schizophrenia, possibly reflecting the functional consequences of structural disconnectivity underlying psychotic symptoms.