Stimulation of 5-HT2C Receptors Improves Cognitive Deficits Induced by Human Tryptophan Hydroxylase 2 Loss of Function Mutation
| Autor: | Adeline Etiévant, Francis Lemay, Stella Manta, Guy Escoffier, François S. Roman, François Y. Doré, Jean Levasseur-Moreau, Jean-Martin Beaulieu, Thomas Del’Guidice, Morgane Lemasson |
|---|---|
| Přispěvatelé: | Institut de pharmacologie moléculaire et cellulaire (IPMC), Université Nice Sophia Antipolis (... - 2019) (UNS), Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA)-Centre National de la Recherche Scientifique (CNRS), Institut cellule souche et cerveau / Stem Cell and Brain Research Institute (SBRI), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM), Neurobiologie des interactions cellulaires et neurophysiopathologie - NICN (NICN), Institut National de la Recherche Agronomique (INRA)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Neurobiologie intégrative et adaptative (NIA), Université de Provence - Aix-Marseille 1-Centre National de la Recherche Scientifique (CNRS), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS), Institut cellule souche et cerveau (SBRI), Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Institut cellule souche et cerveau (U846 Inserm - UCBL1) |
| Rok vydání: | 2013 |
| Předmět: |
Agonist
medicine.drug_class Perseveration Mice Transgenic Reversal Learning Motor Activity Tryptophan Hydroxylase Piperazines 5-Hydroxytryptophan Mice Cognition Serotonin Agents Dopamine Uptake Inhibitors Reward Avoidance Learning Receptor Serotonin 5-HT2C medicine Animals Humans Maze Learning Pharmacology TPH2 Methylphenidate [SCCO.NEUR]Cognitive science/Neuroscience Cognitive flexibility Tryptophan hydroxylase Olfactory Perception medicine.disease Psychiatry and Mental health Schizophrenia Pyrazines Mutation Original Article medicine.symptom Cognition Disorders Psychology Neuroscience Serotonin 5-HT2 Receptor Agonists medicine.drug |
| Zdroj: | Neuropsychopharmacology Neuropsychopharmacology, Nature Publishing Group, 2014, 39 (5), pp.1125-1134. ⟨10.1038/npp.2013.313⟩ Neuropsychopharmacology, 2014, 39 (5), pp.1125-1134. ⟨10.1038/npp.2013.313⟩ |
| ISSN: | 1740-634X 0893-133X 0007-0920 |
| DOI: | 10.1038/npp.2013.313 |
| Popis: | International audience; Polymorphisms in the gene encoding the serotonin synthesis enzyme Tph2 have been identified in mental illnesses, including bipolar disorder, major depression, autism, schizophrenia, and ADHD. Deficits in cognitive flexibility and perseverative behaviors are shared common symptoms in these disorders. However, little is known about the impact of Tph2 gene variants on cognition. Mice expressing a human TPH2 variant (Tph2-KI) were used to investigate cognitive consequences of TPH2 loss of function and pharmacological treatments. We applied a recently developed behavioral assay, the automated H-maze, to study cognitive functions in Tph2-KI mice. This assay involves the consecutive discovery of three different rules: a delayed alternation task, a non-alternation task, and a delayed reversal task. Possible contribution of locomotion, reward, and sensory perception were also investigated. The expression of loss-of-function mutant Tph2 in mice was associated with impairments in reversal learning and cognitive flexibility, accompanied by perseverative behaviors similar to those observed in human clinical studies. Pharmacological restoration of 5-HT synthesis with 5-hydroxytryptophan or treatment with the 5-HT(2C) receptor agonist CP809.101 reduced cognitive deficits in Tph2-KI mice and abolished perseveration. In contrast, treatment with the psychostimulant methylphenidate exacerbated cognitive deficits in mutant mice. Results from this study suggest a contribution of TPH2 in the regulation of cognition. Furthermore, identification of a role for a 5-HT(2) receptor agonist as a cognition-enhancing agent in mutant mice suggests a potential avenue to explore for the personalized treatment of cognitive symptoms in humans with reduced 5-HT synthesis and TPH2 polymorphisms. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|