期刊
MOLECULAR PSYCHIATRY
卷 17, 期 9, 页码 926-939出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/mp.2011.87
关键词
aminergic neurotransmission; antidepressant response; depression; mood; organic cation transporter
资金
- French Ministry for Research
- Societe Francaise de Pharmacologie et Therapeutique
- Fondation pour la Recherche Medicale
- EGIDE foundation
- Institut National pour la Sante et la Recherche Scientifique (INSERM)
- Fondation de France
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. Molecular Psychiatry (2012) 17, 926-939; doi: 10.1038/mp.2011.87; published online 19 July 2011
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