Antidepressant treatments and function of glutamate ionotropic receptors mediating amine release in hippocampus

Neuropharmacology. 2007 Jul;53(1):27-36. doi: 10.1016/j.neuropharm.2007.04.006. Epub 2007 Apr 29.


Previous evidences showed that, besides noradrenaline (NA) and 5-hydroxytryptamine (5-HT), glutamate transmission is involved in the mechanism of action of antidepressants (ADs), although the relations between aminergic and glutamatergic systems are poorly understood. The aims of this investigation were to evaluate changes in the function of glutamate AMPA and NMDA receptors produced by acute and chronic administration of the two ADs reboxetine and fluoxetine, selective inhibitors of NA and 5-HT uptake, respectively. Rats were treated acutely (intraperitoneal injection) or chronically (osmotic minipump infusion) with reboxetine or fluoxetine. Isolated hippocampal nerve endings (synaptosomes) prepared following acute/chronic treatments were labelled with [(3)H]NA or [(3)H]5-HT and [(3)H]amine release was monitored during exposure in superfusion to NMDA/glycine, AMPA or K(+)-depolarization. Acute and chronic reboxetine reduced the release of [(3)H]NA evoked by NMDA/glycine or by AMPA. The NMDA/glycine-evoked release of [(3)H]NA was also down-regulated by chronic fluoxetine. Only acute, but not chronic, fluoxetine inhibited the AMPA-evoked release of [(3)H]5-HT. The release of [(3)H]NA and [(3)H]5-HT elicited by K(+)-depolarization was almost abolished by acute reboxetine or fluoxetine, respectively, but recovered during chronic ADs administration. ADs reduced NMDA receptor-mediated releasing effects in noradrenergic terminals after acute and chronic administration, although by different mechanisms. Chronic treatments markedly reduced the expression level of NR1 subunit in synaptic membranes. The noradrenergic and serotonergic release systems seem to be partly functionally interconnected and interact with glutamatergic transmission to down-regulate its function. The results obtained support the view that glutamate plays a major role in AD activity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amines / metabolism*
  • Animals
  • Antidepressive Agents / pharmacology*
  • Corpus Striatum / drug effects
  • Corpus Striatum / metabolism
  • Corpus Striatum / ultrastructure
  • Drug Interactions
  • Excitatory Amino Acid Agents / pharmacology
  • Fluoxetine / pharmacology
  • Gene Expression
  • Hippocampus / drug effects*
  • Hippocampus / metabolism
  • Hippocampus / ultrastructure
  • Male
  • Morpholines / pharmacology
  • N-Methylaspartate / pharmacology
  • Potassium / pharmacology
  • Rats
  • Rats, Sprague-Dawley
  • Reboxetine
  • Receptors, Glutamate / physiology*
  • Synaptosomes / drug effects
  • Synaptosomes / metabolism
  • Time Factors
  • Tritium / metabolism
  • alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / pharmacology


  • Amines
  • Antidepressive Agents
  • Excitatory Amino Acid Agents
  • Morpholines
  • Receptors, Glutamate
  • Fluoxetine
  • Tritium
  • N-Methylaspartate
  • alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid
  • Reboxetine
  • Potassium