1. Organic cation transporter 2 controls brain norepinephrine and serotonin clearance and antidepressant response: Role of OCT2 in monoamine clearance and antidepressant response
- Author
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A H Schinkel, Caroline Chevarin, Marie-Pascale Martres, Vincent Vialou, G. Biala, A. Bacq, Alain M. Gardier, Bruno Giros, Sophie Gautron, Bruno P. Guiard, F. Louis, L. Balasse, Michel Hamon, PMSNC, Physiopathologie des Maladies du Système Nerveux Central, Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Department of Pharmacology and Pharmacodynamics [Lublin, Poland], Medical University of Lublin [Poland], Sérotonine et neuropharmacologie, Université Paris-Sud - Paris 11 ( UP11 ) -IFR141, Division of Molecular Biology [Amsterdam, The Netherlands], The Netherlands Cancer Institute [Amsterdam, The Netherlands], Neuropsychopharmacologie, Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), AB, LB and VV were recipients of fellowships from the French Ministry for Research, the Société Française de Pharmacologie et Thérapeutique and the Fondation pour la Recherche Médicale. GB was a recipient of a grant from the EGIDE foundation. Financial support was provided by the Institut National pour la Santé et la Recherche Scientifique (INSERM) and the Fondation de France., Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Paris-Sud - Paris 11 (UP11)-IFR141, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Peer, Hal, CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), and Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)
- Subjects
Male ,Venlafaxine Hydrochloride ,Action Potentials ,Anxiety ,Hippocampus ,chemistry.chemical_compound ,Plasma membrane monoamine transporter ,Mice ,Norepinephrine ,Radioligand Assay ,0302 clinical medicine ,Postsynaptic potential ,Limbic System ,antidepressant response ,Neurotransmitter ,Mice, Knockout ,0303 health sciences ,Organic cation transport proteins ,biology ,Brain ,Organic Cation Transporter 2 ,3. Good health ,Molecular Imaging ,Psychiatry and Mental health ,depression ,Antidepressant ,Monoamine transport ,Antidepressive Agents, Second-Generation ,Female ,[SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC] ,medicine.medical_specialty ,Serotonin ,Organic Cation Transport Proteins ,mood ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,Internal medicine ,medicine ,Animals ,[SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC] ,aminergic neurotransmission ,Molecular Biology ,030304 developmental biology ,organic cation transporter ,Cyclohexanols ,Mice, Inbred C57BL ,Disease Models, Animal ,Endocrinology ,chemistry ,[ SDV.NEU ] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC] ,biology.protein ,Corticosterone ,030217 neurology & neurosurgery - Abstract
International audience; High-affinity transporters for norepinephrine (NE) and serotonin (5-HT), which ensure neurotransmitter clearance at the synapse, are the principal targets of widely used antidepressant drugs. Antidepressants targeting these high-affinity transporters, however, do not provide positive treatment outcomes for all patients. Other monoamine transport systems, with lower affinity, have been detected in the brain, but their role is largely unknown. Here we report that OCT2, a member of the polyspecific organic cation transporter (OCT) family, is expressed notably in the limbic system and implicated in anxiety and depression-related behaviors in the mouse. Genetic deletion of OCT2 in mice produced a significant reduction in brain tissue concentrations of NE and 5-HT and in ex vivo uptake of both these neurotransmitters in the presence of the dual 5-HT-NE transport blocker, venlafaxine. In vivo clearance of NE and 5-HT evaluated using microiontophoretic electrophysiology was diminished in the hippocampus of OCT2(-/-) mice in the presence of venlafaxine, thereby affecting postsynaptic neuronal activity. OCT2(-/-) mice displayed an altered sensitivity to acute treatments with NE- and/or 5-HT-selective transport blockers in the forced-swim test. Moreover, the mutant mice were insensitive to long-term venlafaxine treatment in a more realistic, corticosterone-induced, chronic depression model. Our findings identify OCT2 as an important postsynaptic determinant of aminergic tonus and mood-related behaviors and a potential pharmacological target for mood disorders therapy.
- Published
- 2012
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