Effects of lithium and aripiprazole on brain stimulation reward and neuroplasticity markers in the limbic forebrain |
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| Institution: | 1. Laboratory of Behavioral Neuroscience, Department of Psychology, School of Social Sciences, University of Crete, 74100 Rethymno, Crete, Greece;2. Translational Neuropharmacology, Department of Clinical Neuroscience, Center for Molecular Medicine, Karolinska Institute, 171 76 Stockholm, Sweden;3. Astellas Pharma Global Development, Inc., Northbrook, IL 60062, USA;1. Division of Electrophysiology, Department of Cardiovascular Medicine, University of Münster, Münster, Germany;2. Märkische Kliniken GmbH, Department of Cardiology and Angiology, Klinikum Lüdenscheid, University of Witten-Herdecke, Germany;3. Laboratory for Alzheimer''s Disease, RIKEN Brain Science Institute, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan;4. Department of Pharmacology, Faculty of Medicine, Saitama Medical University, 38 Moro-hongo, Moroyama-machi, Iruma-gun, Saitama 350-0495, Japan;5. Department of Aging Neurobiology, Center for Development of Advanced Medicine for Dementia, National Center for Geriatrics and Gerontology, 35 Gengo, Morioka, Obu-shi, Aichi 474-8522, Japan;1. Centro de Biología Molecular “Severo Ochoa” (CBM“SO”), CSIC/UAM, 28049 Madrid, Spain;2. Department of Neurochemistry and Neuropharmacology, IIBB – Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), CSIC, Barcelona, Spain;3. Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain;4. Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Instituto de Salud Carlos III, Madrid, Spain;1. Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Maastricht University, Maastricht, The Netherlands. European Graduate School of Neuroscience (EURON);2. Division of Molecular Psychiatry, Department of Psychiatry and Psychotherapy, Laboratory of Translational Neuroscience, University of Würzburg, Würzburg, Germany;1. Imperial College London, United Kingdom;2. GJK Pharma Limited, United Kingdom;3. The Ann Hayes Consultancy, United Kingdom |
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| Abstract: | Bipolar disorder (BD) is a severe pathological condition with impaired reward-related processing. The present study was designed to assess the effects of two commonly used BD medications, the mood stabilizer lithium chloride (LiCl) and the atypical antipsychotic and antimanic agent aripiprazole, in an animal model of reward and motivation and on markers of neuroplasticity in the limbic forebrain in rats. We utilized intracranial self-simulation (ICSS) to assess the effects of acute and chronic administration of LiCl and aripiprazole on brain stimulation reward, and phosphorylation studies to determine their effects on specific cellular neuroplasticity markers, i.e., the phosphorylation of CREB and crucial phosphorylation sites on the GluA1 subunit of AMPA receptors and the NA1 and NA2B subunits of NMDA receptors, in the limbic forebrain. Chronic LiCl induced tolerance to the anhedonic effect of the drug observed after acute administration, while chronic aripiprazole induced a sustained anhedonic effect. These distinct behavioral responses might be related to differences in molecular markers of neuroplasticity. Accordingly, we demonstrated that chronic LiCl, but not aripiprazole, decreased phosphorylation of CREB at the Ser133 site and NA1 at the Ser896 site in the prefrontal cortex and GluA1 at the Ser831 site and NA2B at the Ser1303 site in the ventral striatum. The present study provides evidence for BD medication-evoked changes in reward and motivation processes and in specific markers of neuronal plasticity in the limbic forebrain, promoting the notion that these drugs may blunt dysregulated reward processes in BD by counteracting neuronal plasticity deficits. |
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| Keywords: | Aripiprazole Brain reward Intracellular signaling Lithium Self-stimulation |
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