Aberrant accumulation of serotonin in dopaminergic neurons

Neuroscience Letters
R MossnerI Seif

Abstract

Gene targeting approaches greatly facilitate insight into the functioning of monoamine transporters, the targets of potent antidepressants. The serotonin transporter (5-HTT) is the molecular target of a large number of antidepressants. To assess the clearance of serotonin (5-HT) in the absence of the 5-HTT, we have generated double knockout mice lacking both the 5-HTT and the catabolizing enzyme monoamine oxidase A (MAOA). We found aberrant 5-HT accumulation in the striatum of these MAOA/5-HTT double knockout mice. By additional ablation of the dopamine transporter (DAT), this aberrant 5-HT accumulation was abolished in MAOA/5-HTT/DAT triple knockout mice. Thus, aberrant uptake of 5-HT occurs in dopaminergic terminals under conditions of elevated 5-HT levels, and this aberrant uptake is mediated by the DAT. These findings have important consequences for antidepressant therapy, since during treatment of depression with selective serotonin reuptake inhibitors, clearance of 5-HT by dopaminergic neurons may reduce the desired therapeutic elevation of extracellular 5-HT levels. This provides a molecular rationale for improving antidepressant efficacy by additional pharmacological inhibition of the DAT.

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Citations

Aug 23, 2007·Psychopharmacology·Meredith A FoxDennis L Murphy
Dec 22, 2010·Journal of Psychiatry & Neuroscience : JPN·Stefano PorcelliAlessandro Serretti
Dec 21, 2010·Journal of Psychiatry & Neuroscience : JPN·Simon N Young
Apr 29, 2011·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Mads Breum LarsenSusan G Amara
Jul 21, 2009·Respiratory Physiology & Neurobiology·C RealP Escourrou
May 23, 2012·The European Journal of Neuroscience·Esmee S B van KleefAlexandre Bonnin
Sep 11, 2007·Biochemical Pharmacology·Leonard L Howell, Heather L Kimmel
Oct 29, 2013·Pharmacology, Biochemistry, and Behavior·Olivia F O'LearyJohn F Cryan
Mar 14, 2012·The World Journal of Biological Psychiatry : the Official Journal of the World Federation of Societies of Biological Psychiatry·Jens BenninghoffDan Rujescu
Mar 25, 2009·The International Journal of Neuropsychopharmacology·Ana P GuimarãesMara H Hutz

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