Glutamate-induced post-activation inhibition of locus coeruleus neurons is mediated by AMPA/kainate receptors and sodium-dependent potassium currents

Br J Pharmacol. 2009 Feb;156(4):649-61. doi: 10.1111/j.1476-5381.2008.00004.x.

Abstract

Background and purpose: Locus coeruleus (LC) neurons respond to sensory stimuli with a glutamate-triggered burst of spikes followed by an inhibition. The aim of our work was to characterize the inhibitory effect of glutamate in the LC.

Experimental approach: Single-unit extracellular and patch-clamp recordings were performed to examine glutamate responses in rat brain slices containing the LC.

Key results: Glutamate caused an initial activation followed by a late post-activation inhibition (PAI). Both effects were blocked by an AMPA/kainate receptor antagonist but not by NMDA or metabotropic glutamate receptor antagonists. All glutamate receptor agonists were able to activate neurons, but only AMPA and quisqualate caused inhibition. In neurons clamped at -60 mV, glutamate and AMPA induced inward, followed by outward, currents, with the latter reversing polarity at -110 mV. Glutamate-induced PAI was not modified by alpha(2)-adrenoceptor, micro opioid, A(1) adenosine and GABA(A/B) receptor antagonists or Ca(2+)-dependent release blockade, but it was reduced by raising the extracellular K(+) concentration. Glutamate-induced PAI was not affected by several potassium channel, Na(+)/K(+) pump, PKC and neuronal NO synthase inhibitors or lowering the extracellular Ca(2+) concentration. The Na(+)-activated K channel opener bithionol concentration-dependently potentiated glutamate-induced PAI, whereas partial (80%) Na(+) replacement reduced glutamate- and AMPA-induced PAI. Finally, reverse transcription polymerase chain reaction assays showed the presence of mRNA for the Ca(2+)-impermeable GluR2 subunit in the LC.

Conclusions and implications: Glutamate induces a late PAI in the LC, which may be mediated by a novel postsynaptic Na(+)-dependent K(+) current triggered by AMPA/kainate receptors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Dose-Response Relationship, Drug
  • Electrodes
  • Excitatory Amino Acid Agonists / pharmacology
  • Glutamic Acid / pharmacology*
  • Locus Coeruleus / cytology
  • Locus Coeruleus / drug effects*
  • Locus Coeruleus / metabolism
  • Male
  • Neurons / drug effects*
  • Neurons / metabolism
  • Patch-Clamp Techniques
  • Potassium Channels / metabolism
  • Potassium Channels / physiology*
  • Rats
  • Rats, Sprague-Dawley
  • Rats, Wistar
  • Receptors, AMPA / antagonists & inhibitors
  • Receptors, AMPA / physiology*
  • Receptors, Glutamate / metabolism
  • Receptors, Kainic Acid / antagonists & inhibitors
  • Receptors, Kainic Acid / physiology*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Sodium / metabolism*
  • Synaptic Potentials / drug effects*

Substances

  • Excitatory Amino Acid Agonists
  • Potassium Channels
  • Receptors, AMPA
  • Receptors, Glutamate
  • Receptors, Kainic Acid
  • Glutamic Acid
  • Sodium