title: Effects of lithium and aripiprazole on brain stimulation reward and neuroplasticity markers in the limbic forebrain.
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.
authors.affiliation: Laboratory of Behavioral Neuroscience, Department of Psychology, School of Social Sciences, University of Crete, 74100 Rethymno, Crete, Greece; Translational Neuropharmacology, Department of Clinical Neuroscience, Center for Molecular Medicine, Karolinska Institute, 171 76 Stockholm, Sweden.
authors.forename: Maria
authors.initials: M
authors.lastname: Mavrikaki
authors.affiliation: Translational Neuropharmacology, Department of Clinical Neuroscience, Center for Molecular Medicine, Karolinska Institute, 171 76 Stockholm, Sweden.
authors.forename: Nicoletta
authors.initials: N
authors.lastname: Schintu
authors.affiliation: Laboratory of Behavioral Neuroscience, Department of Psychology, School of Social Sciences, University of Crete, 74100 Rethymno, Crete, Greece.
authors.forename: Andreas
authors.initials: A
authors.lastname: Kastellakis
authors.affiliation: Astellas Pharma Global Development, Inc., Northbrook, IL 60062, USA.
authors.forename: George G
authors.initials: GG
authors.lastname: Nomikos
authors.affiliation: Translational Neuropharmacology, Department of Clinical Neuroscience, Center for Molecular Medicine, Karolinska Institute, 171 76 Stockholm, Sweden.
authors.forename: Per
authors.initials: P
authors.lastname: Svenningsson
authors.affiliation: Laboratory of Behavioral Neuroscience, Department of Psychology, School of Social Sciences, University of Crete, 74100 Rethymno, Crete, Greece. Electronic address: panagis@uoc.gr.
authors.forename: George
authors.initials: G
authors.lastname: Panagis
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D000068180:Aripiprazole / Q000008:administration & dosage / Q000494:pharmacology*; D015415:Biomarkers / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D004361:Drug Tolerance; D004558:Electric Stimulation; D008032:Limbic System / Q000187:drug effects* / Q000378:metabolism; D018021:Lithium Chloride / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009473:Neuronal Plasticity / Q000187:drug effects; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D016548:Prosencephalon / Q000187:drug effects* / Q000378:metabolism; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D021122:Protein Subunits / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D012201:Reward
chemical_list: D014150:Antipsychotic Agents; D000068180:Aripiprazole; D015415:Biomarkers; D017362:Cyclic AMP Response Element-Binding Protein; D018021:Lithium Chloride; D009419:Nerve Tissue Proteins; D021122:Protein Subunits; D018091:Receptors, AMPA; D016194:Receptors, N-Methyl-D-Aspartate; C508137:Creb1 protein, rat
keywords: Aripiprazole; Brain reward; Intracellular signaling; Lithium; Self-stimulation