Aberrant accumulation of serotonin in dopaminergic neurons

Neurosci Lett. 2006 Jun 19;401(1-2):49-54. doi: 10.1016/j.neulet.2006.02.081. Epub 2006 Apr 25.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain / drug effects
  • Brain / metabolism*
  • Brain Chemistry / genetics
  • Depressive Disorder / drug therapy
  • Depressive Disorder / metabolism
  • Depressive Disorder / physiopathology
  • Dopamine / metabolism*
  • Dopamine Plasma Membrane Transport Proteins / genetics
  • Female
  • Male
  • Mice
  • Mice, Knockout
  • Monoamine Oxidase / genetics*
  • Neurons / drug effects
  • Neurons / metabolism*
  • Presynaptic Terminals / metabolism
  • Presynaptic Terminals / ultrastructure
  • Serotonin / metabolism*
  • Serotonin Plasma Membrane Transport Proteins / genetics*
  • Serotonin Uptake Inhibitors / pharmacology
  • Up-Regulation / drug effects
  • Up-Regulation / genetics

Substances

  • Dopamine Plasma Membrane Transport Proteins
  • Serotonin Plasma Membrane Transport Proteins
  • Serotonin Uptake Inhibitors
  • Serotonin
  • Monoamine Oxidase
  • Dopamine