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Decreased Prefrontal Cortical Dopamine Transmission in Alcoholism
Rajesh Narendran, M.D.; Neale Scott Mason, Ph.D.; Jennifer Paris, M.Ed., M.S.L.; Michael L. Himes, B.S.; Antoine B. Douaihy, M.D.; W. Gordon Frankle, M.D.
Am J Psychiatry 2014;171:881-888. doi:10.1176/appi.ajp.2014.13121581
View Author and Article Information

Drs. Narendran, Mason, and Frankle have participated in contractual research work at the University of Pittsburgh for Ono Pharmaceutical Co. Mr. Himes and Dr. Frankle have served as consultants to Ono Pharmaceutical Co. All other authors report no financial relationships with commercial interests.

Supported by the National Institute on Alcohol Abuse and Alcoholism (NIAAA) Award R01AA018330. The content of this study is solely the responsibility of the authors and does not necessarily represent the official views of the NIAAA or NIH.

From the Departments of Radiology and Psychiatry, University of Pittsburgh, Pittsburgh, Pa.

Address correspondence to Dr. Narendran (narendranr@upmc.edu).

Copyright © 2014 by the American Psychiatric Association

Received December 04, 2013; Revised February 07, 2014; Accepted March 18, 2014.

Abstract

Objective  Basic studies have demonstrated that optimal levels of prefrontal cortical dopamine are critical to various executive functions such as working memory, attention, inhibitory control, and risk/reward decisions, all of which are impaired in addictive disorders such as alcoholism. Based on this and imaging studies of alcoholism that have demonstrated less dopamine in the striatum, the authors hypothesized decreased dopamine transmission in the prefrontal cortex in persons with alcohol dependence.

Method  To test this hypothesis, amphetamine and [11C]FLB 457 positron emission tomography were used to measure cortical dopamine transmission in 21 recently abstinent persons with alcohol dependence and 21 matched healthy comparison subjects. [11C]FLB 457 binding potential, specific compared to nondisplaceable uptake (BPND), was measured in subjects with kinetic analysis using the arterial input function both before and after 0.5 mg kg−1 of d-amphetamine.

Results  Amphetamine-induced displacement of [11C]FLB 457 binding potential (ΔBPND) was significantly smaller in the cortical regions in the alcohol-dependent group compared with the healthy comparison group. Cortical regions that demonstrated lower dopamine transmission in the alcohol-dependent group included the dorsolateral prefrontal cortex, medial prefrontal cortex, orbital frontal cortex, temporal cortex, and medial temporal lobe.

Conclusions  The results of this study, for the first time, unambiguously demonstrate decreased dopamine transmission in the cortex in alcoholism. Further research is necessary to understand the clinical relevance of decreased cortical dopamine as to whether it is related to impaired executive function, relapse, and outcome in alcoholism.

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FIGURE 1. Baseline [11C]FLB 457 Binding Potential (BPND) in Healthy Comparison and Alcohol-Dependent Subjectsa

a The bar graph shows the lack of difference in D2/3 receptor availability in cortical regions of interest in the alcohol-dependent group (red bars) compared with the healthy comparison group (blue bars). MTL=medial temporal lobe; DLPFC=dorsolateral prefrontal cortex; OFC=orbital frontal cortex; MPFC=medial prefrontal cortex; ACC=anterior cingulate cortex; TEMP=temporal cortex; PAR=parietal cortex; and OCC=occipital cortex.

FIGURE 2. [11C]FLB 457 Binding Potential (BPND) at Baseline and Following Amphetamine Administration in Healthy Comparison and Alcohol-Dependent Subjectsa

a The bar graphs show [11C]FLB 457 BPND under baseline (blue bars) and postamphetamine (red bars) conditions in the healthy comparison group (panel A) and the alcohol-dependent group (panel B). Amphetamine led to a significant decrease in [11C]FLB 457 BPND in healthy comparison subjects but not in the alcohol-dependent group ([*] represents p<0.05, following the false discovery rate correction for multiple comparisons). MTL=medial temporal lobe; DLPFC=dorsolateral prefrontal cortex; OFC=orbital frontal cortex; MPFC=medial prefrontal cortex; ACC=anterior cingulate cortex; TEMP=temporal cortex; PAR=parietal cortex; and OCC=occipital cortex.

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TABLE 1.Demographic and Clinical Parameters for Healthy Comparison and Alcohol-Dependent Subjects
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TABLE 2.[11C]FLB 457 Positron Emission Tomography Scan Parametersa
Table Footer Note

a Comparison between scan conditions was performed with paired t tests (statistical significance, p<0.05).

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TABLE 3.Amphetamine-Induced Displacement of [11C]FLB 457 Binding Potential
Table Footer Note

a Analysis was conducted using two-tailed, unpaired t tests.

Table Footer Note

b Values were significant following multiple corrections using false discovery rate.

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