Deficits in Prefrontal Cortical and Extrastriatal Dopamine Release in Schizophrenia
Authors: Mark Slifstein, Elsmarieke van de Giessen, Jared Van Snellenberg, Judy L. Thompson, Rajesh Narendran, Roberto Gil, Elizabeth Hackett, Ragy Girgis, Najate Ojeil, Holly Moore, Deepak D’Souza, Robert T. Malison, Yiyun Huang, Keunpoong Lim, Nabeel Nabulsi, Richard E. Carson, Jeffrey A. Lieberman, Anissa Abi-Dargham
Journal: JAMA Psychiatry (2015)

<h3>Importance</h3> Multiple lines of evidence suggest a deficit in dopamine release in the prefrontal cortex (PFC) in schizophrenia. Despite the prevalence of the concept of prefrontal cortical hypodopaminergia in schizophrenia, in vivo imaging of dopamine release in the PFC has not been possible until now, when the validity of using the positron emission tomographic D2/3 radiotracer carbon 11–labeled FLB457 in combination with the amphetamine paradigm was clearly established. <h3>Objectives</h3> To (1) test amphetamine-induced dopamine release in the dorsolateral PFC (DLPFC) in drug-free or drug-naive patients with schizophrenia (SCZ) and healthy control (HC) individuals matched for age, sex, race/ethnicity, and familial socioeconomic status;(2) test blood oxygenation level–dependent (BOLD) functional magnetic resonance imaging activation during a working memory task in the same participants; and (3) examine the relationship between positron emission tomographic and functional magnetic resonance imaging outcome measures. <h3>Design, Setting and Participants</h3> Positron emission tomographic imaging with carbon 11–labeled FLB457 before and following 0.5 mg/kg of amphetamine by mouth. Blood oxygenation level–dependent functional magnetic resonance imaging during the self-ordered working memory task. Twenty patients with schizophrenia recruited from the inpatient and outpatient research facilities at New York State Psychiatric Institute and 21 healthy control individuals participated, and data were acquired between June 16, 2011, and February 25, 2014. <h3>Main Outcomes and Measure</h3> The percentage change in binding potential (∆BP<sub>ND</sub>) in the DLPFC following amphetamine, BOLD activation during the self-ordered working memory task compared with the control task, and the correlation between these 2 outcome measures. <h3>Results</h3> We observed significant differences in the effect of amphetamine on DLPFC BP<sub>ND</sub>(mean [SD], ∆BP<sub>ND</sub>in HC: −7.5% [11%]; SCZ: +1.8% [11%];<i>P</i> = .01); a generalized blunting in dopamine release in SCZ involving most extrastriatal regions and the midbrain; and a significant association between ∆BP<sub>ND</sub>and BOLD activation in the DLPFC in the overall sample including patients with SCZ and HC individuals. <h3>Conclusions and Relevance</h3> To our knowledge, these results provide the first in vivo evidence for a deficit in the capacity for dopamine release in the DLPFC in SCZ and suggest a more widespread deficit extending to many cortical and extrastriatal regions including the midbrain. This contrasts with the well-replicated excess in dopamine release in the associative striatum in SCZ and suggests a differential regulation of striatal dopamine release in associative striatum vs extrastriatal regions. Furthermore, dopamine release in the DLPFC relates to working memory–related activation of this region, suggesting that blunted release may affect frontal cortical function.