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Lawrence S. Kegeles, MD, PhD; Anissa Abi-Dargham, MD; W. Gordon Frankle, MD; Roberto Gil, MD; Thomas B. Cooper, MA; Mark Slifstein, PhD; Dah-Ren Hwang, PhD; Yiyun Huang, PhD; Suzanne N. Haber, PhD; Marc Laruelle, MD

Arch Gen Psychiatry. 2010;67(3):231-239.

Context  A long-standing version of the dopamine hypothesis of schizophrenia postulates that hyperactivity of dopaminergic transmission at D₂ receptors in the limbic striatum is associated with the illness and that blockade of mesolimbic D₂ receptors is responsible for the antipsychotic action of D₂ 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 D₂ 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 D₂ 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.

Author Affiliations: Departments of Psychiatry (Drs Kegeles, Abi-Dargham, Frankle, Gil, Slifstein, Hwang, Huang, and Laruelle and Mr Cooper) and Radiology (Drs Kegeles, Abi-Dargham, Hwang, and Huang), Columbia University College of Physicians and Surgeons, New York, New York; Division of Translational Imaging, New York State Psychiatric Institute, New York (Drs Kegeles, Abi-Dargham, Frankle, Gil, Slifstein, Hwang, Huang, and Laruelle and Mr Cooper); Departments of Neurobiology and Anatomy, University of Rochester School of Medicine, Rochester, New York (Dr Haber); Schizophrenia and Cognitive Disorder Discovery Performance Unit, Neurosciences Center of Excellence in Drug Discovery, GlaxoSmithKline, Harlow, England (Dr Laruelle); and Department of Neurosciences, Imperial College, London, England (Dr Laruelle).

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