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      Dopamine D 1, D 2, D 3 Receptors, Vesicular Monoamine Transporter Type-2 (VMAT2) and Dopamine Transporter (DAT) Densities in Aged Human Brain

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          Abstract

          The dopamine D 1, D 2, D 3 receptors, vesicular monoamine transporter type-2 (VMAT2), and dopamine transporter (DAT) densities were measured in 11 aged human brains (aged 77–107.8, mean: 91 years) by quantitative autoradiography. The density of D 1 receptors, VMAT2, and DAT was measured using [ 3H]SCH23390, [ 3H]dihydrotetrabenazine, and [ 3H]WIN35428, respectively. The density of D 2 and D 3 receptors was calculated using the D 3-preferring radioligand, [ 3H] WC-10 and the D 2-preferring radioligand [ 3H]raclopride using a mathematical model developed previously by our group. Dopamine D 1, D 2, and D 3 receptors are extensively distributed throughout striatum; the highest density of D 3 receptors occurred in the nucleus accumbens (NAc). The density of the DAT is 10–20-fold lower than that of VMAT2 in striatal regions. Dopamine D 3 receptor density exceeded D 2 receptor densities in extrastriatal regions, and thalamus contained a high level of D 3 receptors with negligible D 2 receptors. The density of dopamine D 1 linearly correlated with D 3 receptor density in the thalamus. The density of the DAT was negligible in the extrastriatal regions whereas the VMAT2 was expressed in moderate density. D 3 receptor and VMAT2 densities were in similar level between the aged human and aged rhesus brain samples, whereas aged human brain samples had lower range of densities of D 1 and D 2 receptors and DAT compared with the aged rhesus monkey brain. The differential density of D 3 and D 2 receptors in human brain will be useful in the interpretation of PET imaging studies in human subjects with existing radiotracers, and assist in the validation of newer PET radiotracers having a higher selectivity for dopamine D 2 or D 3 receptors.

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          Most cited references76

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          Modulation of striatal projection systems by dopamine.

          The basal ganglia are a chain of subcortical nuclei that facilitate action selection. Two striatal projection systems--so-called direct and indirect pathways--form the functional backbone of the basal ganglia circuit. Twenty years ago, investigators proposed that the striatum's ability to use dopamine (DA) rise and fall to control action selection was due to the segregation of D(1) and D(2) DA receptors in direct- and indirect-pathway spiny projection neurons. Although this hypothesis sparked a debate, the evidence that has accumulated since then clearly supports this model. Recent advances in the means of marking neural circuits with optical or molecular reporters have revealed a clear-cut dichotomy between these two cell types at the molecular, anatomical, and physiological levels. The contrast provided by these studies has provided new insights into how the striatum responds to fluctuations in DA signaling and how diseases that alter this signaling change striatal function.
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            BDNF controls dopamine D3 receptor expression and triggers behavioural sensitization.

            Brain-derived neurotrophic factor (BDNF), like other neurotrophins, is a polypeptidic factor initially regarded to be responsible for neuron proliferation, differentiation and survival, through its uptake at nerve terminals and retrograde transport to the cell body. A more diverse role for BDNF has emerged progressively from observations showing that it is also transported anterogradely, is released on neuron depolarization, and triggers rapid intracellular signals and action potentials in central neurons. Here we report that BDNF elicits long-term neuronal adaptations by controlling the responsiveness of its target neurons to the important neurotransmitter, dopamine. Using lesions and gene-targeted mice lacking BDNF, we show that BDNF from dopamine neurons is responsible for inducing normal expression of the dopamine D3 receptor in nucleus accumbens both during development and in adulthood. BDNF from corticostriatal neurons also induces behavioural sensitization, by triggering overexpression of the D3 receptor in striatum of hemiparkinsonian rats. Our results suggest that BDNF may be an important determinant of pathophysiological conditions such as drug addiction, schizophrenia or Parkinson's disease, in which D3 receptor expression is abnormal.
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              Coordinated expression of dopamine receptors in neostriatal medium spiny neurons.

              In recent years, the distribution of dopamine receptor subtypes among the principal neurons of the neostriatum has been the subject of debate. Conventional anatomical and physiological approaches have yielded starkly different estimates of the extent to which D1 and D2 class dopamine receptors are colocalized. One plausible explanation for the discrepancy is that some dopamine receptors are present in physiologically significant numbers, but the mRNA for these receptors is not detectable with conventional techniques. To test this hypothesis, we examined the expression of DA receptors in individual neostriatal neurons by patch-clamp and RT-PCR techniques. Because of the strong correlation between peptide expression and projection site, medium spiny neurons were divided into three groups on the basis of expression of mRNA for enkephalin (ENK) and substance P (SP). Neurons expressing detectable levels of SP but not ENK had abundant mRNA for the D1a receptor. A subset of these cells (approximately 50%) coexpressed D3 or D4 receptor mRNA. Neurons expressing detectable levels of ENK but not SP had abundant mRNA for D2 receptor isoforms (short and long). A subset (10-25%) of these neurons coexpressed D1a or D1b mRNAs. Neurons coexpressing ENK and SP mRNAs consistently coexpressed D1a and D2 mRNAs in relatively high abundance. Functional analysis of neurons expressing lower abundance mRNAs revealed clear physiological consequences that could be attributed to these receptors. These results suggest that, although colocalization of D1a and D2 receptors is limited, functional D1 and D2 class receptors are colocalized in nearly one-half of all medium spiny projection neurons.
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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, USA )
                1932-6203
                2012
                21 November 2012
                : 7
                : 11
                : e49483
                Affiliations
                [1 ]Department of Radiology, Washington University School of Medicine, St. Louis, Missouri, United States of America
                [2 ]Department of Neurology, Washington University School of Medicine, St. Louis, Missouri, United States of America
                [3 ]Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, United States of America
                [4 ]Department of Neurobiology, Washington University School of Medicine, St. Louis, Missouri, United States of America
                [5 ]Department of Occupational Therapy, Washington University School of Medicine, St. Louis, Missouri, United States of America
                [6 ]Department of Physical Therapy, Washington University School of Medicine, St. Louis, Missouri, United States of America
                [7 ]Department of Cell Biology amd Physiology, Washington University School of Medicine, St. Louis, Missouri, United States of America
                [8 ]Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, Missouri, United States of America
                Centre for Addiction and Mental Health, Canada
                Author notes

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

                Conceived and designed the experiments: JX RHM. Performed the experiments: JS. Analyzed the data: JS JX JSP. Contributed reagents/materials/analysis tools: NJC. Wrote the paper: JS RHM.

                [¤]

                Current address: Neurosurgery Department, The Second Affiliated Hospital of Medical College, Xi'an Jiaotong University, Xi'an, Shaanxi, 710004, PR China

                Article
                PONE-D-12-23292
                10.1371/journal.pone.0049483
                3504049
                23185343
                07cc82a1-80f1-432a-a831-15f3e8249e62
                Copyright @ 2012

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 3 August 2012
                : 11 October 2012
                Page count
                Pages: 13
                Funding
                This study was supported by NIH grants MH081281, DA29840, NS075321 and P50 AG05681, the American Parkinson Disease Association (APDA), the Greater St. Louis Chapter of the APDA, the Barnes-Jewish Hospital Foundation (Elliot Stein Family Fund and Parkinson Disease Research Fund) and the Charles and Joanne Knight Alzheimer's Research Initiative of the Washington University Alzheimer's Disease Research Center.The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Biology
                Anatomy and Physiology
                Neuroscience
                Chemistry
                Medicinal Chemistry
                Radiochemistry
                Synthetic Chemistry
                Medicine
                Anatomy and Physiology
                Physiological Processes
                Aging
                Mental Health
                Neurology
                Radiology
                Science Policy
                Technology Development
                Social and Behavioral Sciences
                Psychology

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