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.
References
May 19, 1978·Brain Research·B Berger, J Glowinski
May 7, 1990·Brain Research·J A StamfordJ Millar
Jun 1, 1988·Neuroscience·P VoornH J Groenewegen
Mar 13, 1995·Brain Research·B P Jackson, R M Wightman
Jun 23, 1995·Science·O CasesJ C Shih
Oct 22, 1993·Science·H G BrunnerB A van Oost
Feb 15, 1996·Nature·B GirosM G Caron
Apr 16, 1998·European Journal of Pharmacology·M TatsumiE Richelson
Feb 15, 2001·Brain Research. Developmental Brain Research·Y PanR Simantov
Apr 12, 2001·The European Journal of Neuroscience·A RavaryP Gaspar
Jan 17, 2002·The Journal of Comparative Neurology·Tania VitalisOlivier Cases
Mar 22, 2002·The European Journal of Neuroscience·A EvrardJ Adrien
Nov 18, 2003·Nature Reviews. Neuroscience·Patricia GasparLuc Maroteaux
Jul 1, 2004·Neuropsychopharmacology : Official Publication of the American College of Neuropsychopharmacology·Hao-Wei ShenIchiro Sora
Apr 12, 2005·Neuron·Fu-Ming ZhouJohn A Dani
Citations
Aug 23, 2007·Psychopharmacology·Meredith A FoxDennis L Murphy
Aug 21, 2008·Psychopharmacology·Meredith A FoxDennis L Murphy
Nov 9, 2006·The Journal of Biological Chemistry·Kevin ChenJean Chen Shih
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
Oct 23, 2012·Genetics·Audrey ChenDavid E Krantz
Jul 21, 2009·Respiratory Physiology & Neurobiology·C RealP Escourrou
Mar 10, 2016·Neurotoxicology and Teratology·Mari S Golub, Casey E Hogrefe
Nov 6, 2007·European Journal of Pharmacology·Jie ShiLin Lu
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
Feb 20, 2021·Journal of Affective Disorders·Kateryna MurlanovaAlbert Pinhasov