Serotonin induces depolarization in lateral amygdala neurons by activation of TRPC-like current and inhibition of GIRK current depending on 5-HT(2C) receptor

Neuropharmacology. 2014 Jul;82:49-58. doi: 10.1016/j.neuropharm.2014.03.007. Epub 2014 Mar 21.

Abstract

Regional differences are known in the serotonin-induced modulation of neuronal activity within the amygdala. This in vitro study in rats focuses on analyzing the ionic mechanism underlying serotonin-induced depolarization in the lateral amygdala. Serotonin depolarized membrane potential by 5 mV, which is underlain by a serotonin-induced inward current at rest with a characteristic reversal potential of -105 mV. From pharmacological experiments, the 5-HT2C subtype was singled out as the receptor subtype involved. Under blockade of K(+) channels by Ba(2+), 5-HT induced an inward current with no reversal at the range between -50 and -130 mV, which was identified as a TRPC-like current. This current was blocked by the specific phosphatidylinositol 3-kinse (PI3-kinase) inhibitor LY294002, pointing to its dependence on PI3-kinase. The Ba(2+)-sensitive component, obtained by subtraction, showed a strong outward rectification and the reversal potential of K(+), indicating that this component results from a serotonin-induced inhibition of G-protein coupled inwardly rectifying K(+) channel (GIRK) current. By wortmannin, an inhibitor of both PI3-kinase and PI4-kinase, a serotonin-induced phosphatidylinositol 4,5-bisphosphate (PIP2) depletion was revealed to underlie GIRK inhibition. Thus, the serotonin-induced current turned out to be caused by a combined occurrence of GIRK inhibition and PI3-kinase-dependent TRPC-like current. With serotonergic modulation, all these mechanisms should be recruited in lateral amygdala principal neurons and likely contribute to generation of region-specific neuronal activity patterns within the amygdala, which may at least partly implement its required role in fear and anxiety.

Keywords: GIRK; Lateral amygdala; PI3-kinase; PIP2; Serotonin; TRPC.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amygdala / drug effects
  • Amygdala / physiology*
  • Androstadienes / pharmacology
  • Animals
  • Barium / pharmacology
  • Chromones / pharmacology
  • Enzyme Inhibitors / pharmacology
  • G Protein-Coupled Inwardly-Rectifying Potassium Channels / antagonists & inhibitors
  • G Protein-Coupled Inwardly-Rectifying Potassium Channels / metabolism*
  • Membrane Potentials / drug effects
  • Membrane Potentials / physiology
  • Minor Histocompatibility Antigens
  • Morpholines / pharmacology
  • Neurons / drug effects
  • Neurons / physiology*
  • Patch-Clamp Techniques
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphoinositide-3 Kinase Inhibitors
  • Phosphotransferases (Alcohol Group Acceptor) / antagonists & inhibitors
  • Phosphotransferases (Alcohol Group Acceptor) / metabolism
  • Potassium Channel Blockers / pharmacology
  • Rats, Wistar
  • Receptor, Serotonin, 5-HT2C / metabolism*
  • Serotonin / metabolism*
  • TRPC Cation Channels / metabolism*
  • Wortmannin

Substances

  • Androstadienes
  • Chromones
  • Enzyme Inhibitors
  • G Protein-Coupled Inwardly-Rectifying Potassium Channels
  • Minor Histocompatibility Antigens
  • Morpholines
  • Phosphoinositide-3 Kinase Inhibitors
  • Potassium Channel Blockers
  • Receptor, Serotonin, 5-HT2C
  • TRPC Cation Channels
  • Barium
  • 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
  • Serotonin
  • Phosphotransferases (Alcohol Group Acceptor)
  • phosphatidylinositol phosphate 4-kinase
  • Wortmannin