Increased Synaptic Dopamine Function in Associative Regions of the Striatum in Schizophrenia

Context: A long-standing version of the dopamine hypothesis of schizophrenia postulates that hyperactivity of dopaminergic transmission at D-2 receptors in the limbic striatum is associated with the illness and that blockade of mesolimbic D-2 receptors is responsible for the antipsychotic action of D-2 receptor antagonists. Objective: To localize dopaminergic hyperactivity within the striatum in schizophrenia. Design: Case-control study. Setting: Inpatient research unit. Participants: Eighteen untreated patients with schizophrenia and 18 healthy control subjects matched for age, sex, ethnicity, parental socioeconomic status, cigarette smoking, and weight. Main Outcome Measures: Percentage change in dopamine D-2 receptor availability in striatal subregions within each subject measured by positron emission tomography with carbon 11-labeled raclopride before and during pharmacologically induced dopamine depletion. Results: In the associative striatum, acute dopamine depletion resulted in a larger increase in D-2 receptor availability in patients with schizophrenia (mean [SD], 15% [7%]) than in control subjects (10% [7%], P = .045), suggesting higher synaptic dopamine concentration. Within the associative striatum, this effect was most pronounced in the precommissural dorsal caudate (15% [8%] in patients vs 9% [8%] in controls, P = .03). No between-group differences were observed in the limbic and sensorimotor striatum. Conclusions: These findings suggest that schizophrenia is associated with elevated dopamine function in associative regions of the striatum. Because the precommissural dorsal caudate processes information from the dorsolateral prefrontal cortex, this observation also suggests that elevated subcortical dopamine function might adversely affect performance of the dorsolateral prefrontal cortex in schizophrenia. On the other hand, the absence of a group difference in the limbic striatum brings into question the therapeutic relevance of the mesolimbic selectivity of second-generation antipsychotic drugs.