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Levodopa effects on [ 11C]raclopride binding in the resting human brain

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      Abstract

      Rationale: Synaptic dopamine (DA) release induced by amphetamine or other experimental manipulations can displace [ 11C]raclopride (RAC*) from dopamine D2-like receptors. We hypothesized that exogenous levodopa might increase dopamine release at striatal synapses under some conditions but not others, allowing a more naturalistic assessment of presynaptic dopaminergic function. Presynaptic dopaminergic abnormalities have been reported in Tourette syndrome (TS). Objective: Test whether levodopa induces measurable synaptic DA release in healthy people at rest, and gather pilot data in TS. Methods: This double-blind crossover study used RAC* and positron emission tomography (PET) to measure synaptic dopamine release 4 times in each of 10 carbidopa-pretreated, neuroleptic-naïve adults: before and during an infusion of levodopa on one day and placebo on another (in random order). Five subjects had TS and 5 were matched controls. RAC* binding potential (BP ND) was quantified in predefined anatomical volumes of interest (VOIs). A separate analysis compared BP ND voxel by voxel over the entire brain. Results: DA release declined between the first and second scan of each day (p=0.012), including on the placebo day. Levodopa did not significantly reduce striatal RAC* binding and striatal binding did not differ significantly between TS and control groups. However, levodopa’s effect on DA release differed significantly in a right midbrain region (p=0.002, corrected), where levodopa displaced RAC* by 59% in control subjects but increased BP ND by 74% in TS subjects. Discussion: Decreased DA release on the second scan of the day is consistent with the few previous studies with a similar design, and may indicate habituation to study procedures. We hypothesize that mesostriatal DA neurons fire relatively little while subjects rest, possibly explaining the non-significant effect of levodopa on striatal RAC* binding. The modest sample size argues for caution in interpreting the group difference in midbrain DA release with levodopa.

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          Despite the overt nature of most motor and phonic tic phenomena, the development of valid and reliable scales to rate tic severity has been an elusive goal. The Yale Global Tic Severity Scale (YGTSS) is a new clinical rating instrument that was designed for use in studies of Tourette's syndrome and other tic disorders. The YGTSS provides an evaluation of the number, frequency, intensity, complexity, and interference of motor and phonic symptoms. Data from 105 subjects, aged 5 to 51 years, support the construct, convergent, and discriminant validity of the instrument. These results indicate that the YGTSS is a promising instrument for the assessment of tic severity in children, adolescents and adults.
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            Author and article information

            Affiliations
            [1 ]Departments of Psychiatry, Neurology, Radiology, and Anatomy & Neurobiology, Washington University School of Medicine, St. Louis, MO, 63110, USA
            [2 ]School of Arts and Sciences, Washington University, St. Louis, MO, 63130, USA
            [3 ]Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, 63110, USA
            [4 ]Departments of Psychiatry & Behavioral Sciences, and Radiology, Northwestern University Feinberg School of Medicine, Chicago, IL, 60611, USA
            [5 ]Departments of Radiology, Psychiatry, Bioengineering, and Anatomy & Neurobiology, Washington University, St. Louis, MO, 63130, USA
            [6 ]Temple University, Philadelphia, PA, USA
            [7 ]Department of Ophthalmology, University of Cincinnati, Cincinnati, OH, USA
            [8 ]Avid Radiopharmaceuticals, Philadelphia, PA, USA
            [1 ]Umeå Center for Functional Brain Imaging, Umeå, Sweden
            Department of Psychiatry, Washington University in St. Louis, USA
            [1 ]Division of Neurology, University of Alberta, Edmonton, AB, Canada
            [1 ]Department of Research of Technology and Development, Hôpital Pitié Salpêtrière, Paris, France
            Author notes

            Designed study: KJB

            Authorized User, i.e. responsible for appropriate human administration of radiopharmaceuticals: MAM

            Analyzed data: KJB, MLP, JMK, TH, LW, MAM

            Contributed research tools: JMK, LW, MAM

            Searched and summarized relevant literature: MLP

            Wrote the manuscript: KJB

            Reviewed drafts and approved the final draft: KJB, MLP, JMK, TH, LW, MAM

            Competing interests: Author KJB received honoraria for educational presentations from a grant from the US CDC to the Tourette Syndrome Association. There are no other potential conflicts of interest.

            Journal
            F1000Res
            F1000Res
            F1000Research
            F1000Research
            F1000Research (London, UK )
            2046-1402
            23 January 2015
            2015
            : 4
            4490799
            10.12688/f1000research.5672.1
            Copyright: © 2015 Black KJ et al.

            This is an open access article distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

            Data associated with the article are available under the terms of the Creative Commons Zero "No rights reserved" data waiver (CC0 1.0 Public domain dedication).

            Product
            Funding
            Funded by: Tourette Syndrome Association
            Funded by: National Institute of Health
            Award ID: K24 MH087913
            Award ID: R21 MH098670
            Data collection was supported by the Tourette Syndrome Association and manuscript preparation was supported in part by NIH grants K24 MH087913 and R21 MH098670.
            I confirm that the funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
            Categories
            Research Article
            Articles
            Motor Systems
            Movement Disorders
            Neurobiology of Disease & Regeneration
            Neuroimaging

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