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      Adenosine A 2A Receptors in Striatal Glutamatergic Terminals and GABAergic Neurons Oppositely Modulate Psychostimulant Action and DARPP-32 Phosphorylation

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          Abstract

          Adenosine A 2A receptors (A 2AR) are located postsynaptically in striatopallidal GABAergic neurons, antagonizing dopamine D 2 receptor functions, and are also located presynaptically at corticostriatal terminals, facilitating glutamate release. To address the hypothesis that these two A 2AR populations differently control the action of psychostimulants, we characterized A 2AR modulation of cocaine-induced effects at the level of DARPP-32 phosphorylation at Thr-34 and Thr-75, c-Fos expression, and psychomotor activity using two lines of cell-type selective A 2AR knockout (KO) mice with selective A 2AR deletion in GABAergic neurons (striatum-A 2AR-KO mice), or with A 2AR deletion in both striatal GABAergic neurons and projecting cortical glutamatergic neurons (forebrain-A 2AR-KO mice). We demonstrated that striatum-A 2AR KO mice lacked A 2ARs exclusively in striatal GABAergic terminals whereas forebrain-A 2AR KO mice lacked A 2ARs in both striatal GABAergic and glutamatergic terminals leading to a blunted A 2AR-mediated facilitation of synaptosomal glutamate release. The inactivation of A 2ARs in GABAergic neurons reduced striatal DARPP-32 phosphorylation at Thr-34 and increased its phosphorylation at Thr-75. Conversely, the additional deletion of corticostriatal glutamatergic A 2ARs produced opposite effects on DARPP-32 phosphorylation at Thr-34 and Thr-75. This distinct modulation of DARPP-32 phosphorylation was associated with opposite responses to cocaine-induced striatal c-Fos expression and psychomotor activity in striatum-A 2AR KO (enhanced) and forebrain-A 2AR KO mice (reduced). Thus, A 2ARs in glutamatergic corticostriatal terminals and in GABAergic striatal neurons modulate the action of psychostimulants and DARPP-32 phosphorylation in opposite ways. We conclude that A 2ARs in glutamatergic terminals prominently control the action of psychostimulants and define a novel mechanism by which A 2ARs fine-tune striatal activity by integrating GABAergic, dopaminergic and glutamatergic signaling.

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          Cell type-specific loss of BDNF signaling mimics optogenetic control of cocaine reward.

          The nucleus accumbens is a key mediator of cocaine reward, but the distinct roles of the two subpopulations of nucleus accumbens projection neurons, those expressing dopamine D1 versus D2 receptors, are poorly understood. We show that deletion of TrkB, the brain-derived neurotrophic factor (BDNF) receptor, selectively from D1+ or D2+ neurons oppositely affects cocaine reward. Because loss of TrkB in D2+ neurons increases their neuronal excitability, we next used optogenetic tools to control selectively the firing rate of D1+ and D2+ nucleus accumbens neurons and studied consequent effects on cocaine reward. Activation of D2+ neurons, mimicking the loss of TrkB, suppresses cocaine reward, with opposite effects induced by activation of D1+ neurons. These results provide insight into the molecular control of D1+ and D2+ neuronal activity as well as the circuit-level contribution of these cell types to cocaine reward.
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            Distinct roles of synaptic transmission in direct and indirect striatal pathways to reward and aversive behavior.

            In the basal ganglia, convergent input and dopaminergic modulation of the direct striatonigral and the indirect striatopallidal pathways are critical in rewarding and aversive learning and drug addiction. To explore how the basal ganglia information is processed and integrated through these two pathways, we developed a reversible neurotransmission blocking technique, in which transmission of each pathway was selectively blocked by specific expression of transmission-blocking tetanus toxin in a doxycycline-dependent manner. The results indicated that the coordinated modulation of these two pathways was necessary for dopamine-mediated acute psychostimulant actions. This modulation, however, shifted to the predominant roles of the direct pathway in reward learning and cocaine sensitization and the indirect pathway in aversive behavior. These two pathways thus have distinct roles: the direct pathway critical for distinguishing associative rewarding stimuli from nonassociative ones and the indirect pathway for rapid memory formation to avoid aversive stimuli.
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              Presynaptic control of striatal glutamatergic neurotransmission by adenosine A1-A2A receptor heteromers.

              The functional role of heteromers of G-protein-coupled receptors is a matter of debate. In the present study, we demonstrate that heteromerization of adenosine A1 receptors (A1Rs) and A2A receptors (A2ARs) allows adenosine to exert a fine-tuning modulation of glutamatergic neurotransmission. By means of coimmunoprecipitation, bioluminescence and time-resolved fluorescence resonance energy transfer techniques, we showed the existence of A1R-A2AR heteromers in the cell surface of cotransfected cells. Immunogold detection and coimmunoprecipitation experiments indicated that A1R and A2AR are colocalized in the same striatal glutamatergic nerve terminals. Radioligand-binding experiments in cotransfected cells and rat striatum showed that a main biochemical characteristic of the A1R-A2AR heteromer is the ability of A2AR activation to reduce the affinity of the A1R for agonists. This provides a switch mechanism by which low and high concentrations of adenosine inhibit and stimulate, respectively, glutamate release. Furthermore, it is also shown that A1R-A2AR heteromers constitute a unique target for caffeine and that chronic caffeine treatment leads to modifications in the function of the A1R-A2AR heteromer that could underlie the strong tolerance to the psychomotor effects of caffeine.
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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
                2013
                28 November 2013
                : 8
                : 11
                : e80902
                Affiliations
                [1 ]Molecular Neuropharmacology Lab, Department of Neurology, Boston University School of Medicine, Boston, Massachusetts, United States of America
                [2 ]Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal
                [3 ]Instituto Cajal, Consejo Superior de Investigaciones Científicas, and Centros de Investigación Biomédica en Red, Instituto de Salud Carlos III, Madrid, Spain
                [4 ]Robert Stone Dow Neurobiology Laboratories, Legacy Research Institute, Portland, Oregon, United States of America
                [5 ]Faculty of Medicine, University of Coimbra, Coimbra, Portugal
                INSERM/CNRS, France
                Author notes

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

                Conceived and designed the experiments: JFC RAC RM. Performed the experiments: HYS PC PG JQL. Analyzed the data: HYS PC PG. Contributed reagents/materials/analysis tools: JFC RAC RM DB. Wrote the paper: HYS JFC RAC DB.

                Article
                PONE-D-12-12075
                10.1371/journal.pone.0080902
                3842921
                24312250
                891bad24-880c-4f4b-b18a-dabc652466a0
                Copyright @ 2013

                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
                : 27 April 2012
                : 17 October 2013
                Page count
                Pages: 11
                Funding
                This study was supported by the National Institutes of Health (NIH) grants NS048995, NS41083-05 and NS41083-07, and United States Department of Defense grant W81XWH-07-1-0012 to JFC, grants of PTDC/SAU-NEU/108668/2008 and DARPA-BAA-09-68 to RAC; grants from the Spanish Ministries de Ciencia e Innovación and Sanidad y Política Social, ISCIII: BFU2010-20664, PNSD, RedRTA (RD06/0001/1011) and CIBERNED to RM; National Institute of Mental Health (NIMH) grant R01MH083973 to DB, and a NIH grant R01NS073947. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
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