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      Striatal Dopamine D 2/D 3 Receptor Availability Is Associated with Executive Function in Healthy Controls but Not Methamphetamine Users

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          Abstract

          Background

          Dopamine D 2/D 3 receptor availability in the striatum has been linked with executive function in healthy individuals, and is below control levels among drug addicts, possibly contributing to diminished executive function in the latter group. This study tested for an association of striatal D 2/D 3 receptor availability with a measure of executive function among research participants who met DSM-IV criteria for methamphetamine dependence.

          Methods

          Methamphetamine users and non-user controls ( n = 18 per group) completed the Wisconsin Card Sorting Test and positron emission tomography with [ 18F]fallypride.

          Results

          The methamphetamine users displayed significantly lower striatal D 2/D 3 receptor availability on average than controls after controlling for age and education ( p = 0.008), but they did not register greater proportions of either perseverative or non-perseverative errors when controlling for education (both ps ≥ 0.622). The proportion of non-perseverative, but not perseverative, errors was negatively correlated with striatal D 2/D 3 receptor availability among controls ( r = -0.588, p = 0.010), but not methamphetamine users ( r = 0.281, p = 0.258), and the group-wise interaction was significant ( p = 0.030).

          Conclusions

          These results suggest that cognitive flexibility, as measured by perseverative errors on the Wisconsin Card Sorting Test, is not determined by signaling through striatal D 2/D 3 receptors in healthy controls, and that in stimulant abusers, who have lower D 2/D 3 receptor availability, compensation can effectively maintain other executive functions, which are associated with D 2/D 3 receptor signaling in controls.

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          Most cited references58

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          Dysfunction of the prefrontal cortex in addiction: neuroimaging findings and clinical implications.

          The loss of control over drug intake that occurs in addiction was initially believed to result from disruption of subcortical reward circuits. However, imaging studies in addictive behaviours have identified a key involvement of the prefrontal cortex (PFC) both through its regulation of limbic reward regions and its involvement in higher-order executive function (for example, self-control, salience attribution and awareness). This Review focuses on functional neuroimaging studies conducted in the past decade that have expanded our understanding of the involvement of the PFC in drug addiction. Disruption of the PFC in addiction underlies not only compulsive drug taking but also accounts for the disadvantageous behaviours that are associated with addiction and the erosion of free will.
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            Dynamic dopamine modulation in the basal ganglia: a neurocomputational account of cognitive deficits in medicated and nonmedicated Parkinsonism.

            Dopamine (DA) depletion in the basal ganglia (BG) of Parkinson's patients gives rise to both frontal-like and implicit learning impairments. Dopaminergic medication alleviates some cognitive deficits but impairs those that depend on intact areas of the BG, apparently due to DA ''overdose.'' These findings are difficult to accommodate with verbal theories of BG/DA function, owing to complexity of system dynamics: DA dynamically modulates function in the BG, which is itself a modulatory system. This article presents a neural network model that instantiates key biological properties and provides insight into the underlying role of DA in the BG during learning and execution of cognitive tasks. Specifically, the BG modulates the execution of ''actions'' (e.g., motor different parts of the frontal cortex. Phasic changes in DA, which occur during error feedback, dynamically modulate the BG threshold for facilitating/suppressing a cortical command in response to particular stimuli. Reduced dynamic range of DA explains Parkinson and DA overdose deficits with a single underlying dysfunction, despite overall differences in raw DA levels. Simulated Parkinsonism and medication effects provide a theoretical basis for behavioral data in probabilistic classification and reversal tasks. The model also provides novel testable predictions for neuropsychological and pharmacological studies, and motivates further investigation of BG/DA interactions with the prefrontal cortex in working memory.
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              Low level of brain dopamine D2 receptors in methamphetamine abusers: association with metabolism in the orbitofrontal cortex.

              The role of dopamine in the addictive process (loss of control and compulsive drug intake) is poorly understood. A consistent finding in drug-addicted subjects is a lower level of dopamine D2 receptors. In cocaine abusers, low levels of D2 receptors are associated with a lower level of metabolism in the orbitofrontal cortex. Because the orbitofrontal cortex is associated with compulsive behaviors, its disruption may contribute to compulsive drug intake in addicted subjects. This study explored whether a similar association occurs in methamphetamine abusers. Fifteen methamphetamine abusers and 20 non-drug-abusing comparison subjects were studied with positron emission tomography (PET) and [11C]raclopride to assess the availability of dopamine D2 receptors and with [18F]fluorodeoxyglucose to assess regional brain glucose metabolism, a marker of brain function. Methamphetamine abusers had a significantly lower level of D2 receptor availability than comparison subjects (a difference of 16% in the caudate and 10% in the putamen). D2 receptor availability was associated with metabolic rate in the orbitofrontal cortex in abusers and in comparison subjects. Lower levels of dopamine D2 receptor availability have been previously reported in cocaine abusers, alcoholics, and heroine abusers. This study extends this finding to methamphetamine abusers. The association between level of dopamine D2 receptors and metabolism in the orbitofrontal cortex in methamphetamine abusers, which replicates previous findings in cocaine abusers, suggests that D2 receptor-mediated dysregulation of the orbitofrontal cortex could underlie a common mechanism for loss of control and compulsive drug intake in drug-addicted subjects.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                14 December 2015
                2015
                : 10
                : 12
                : e0143510
                Affiliations
                [1 ]Department of Psychiatry and Biobehavioral Sciences, University of California Los Angeles, Los Angeles, California, United States of America
                [2 ]VA Greater Los Angeles Healthcare System, Los Angeles, California, United States of America
                [3 ]Brain Research Institute, University of California Los Angeles, Los Angeles, California, United States of America
                [4 ]Department of Physics, University of California Irvine, Irvine, California, United States of America
                [5 ]Department of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, California, United States of America
                University of Western Ontario, CANADA
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Conceived and designed the experiments: MEB ACD MAM EDL. Performed the experiments: ACD MAM. Analyzed the data: MEB MAM. Contributed reagents/materials/analysis tools: MAM EDL. Wrote the paper: MEB ACD MAM EDL.

                [¤a]

                Current address: Department of Neurology, University of California San Francisco, San Francisco, California, United States of America

                [¤b]

                Current address: VA Northern California Health Care System, Martinez, California, United States of America

                Article
                PONE-D-15-24952
                10.1371/journal.pone.0143510
                4699455
                26657223
                c229a703-10db-4563-86cd-dec4500fe406

                This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication

                History
                : 10 June 2015
                : 5 November 2015
                Page count
                Figures: 2, Tables: 2, Pages: 16
                Funding
                The research was supported by National Institutes of Health grants R01 DA020726 (EDL), P20 DA022539 (EDL), K23 DA027734 (ACD), M0I RR00865 (UCLA GCRC), by endowments from the Thomas P. and Katherine K. Pike Chair in Addiction Studies (EDL), and the Marjorie M. Greene Trust. MEB was supported by T32 DA024635. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
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