Acid sensing ion channel (ASIC) inhibitors exhibit anxiolytic-like activity in preclinical pharmacological models

Psychopharmacology (Berl). 2009 Mar;203(1):41-52. doi: 10.1007/s00213-008-1373-7. Epub 2008 Oct 24.

Abstract

Rationale: Acid sensing ion channels (ASICs) are proton-gated ion channels located in the central and peripheral nervous systems. Of particular interest is ASIC1a, which is located in areas associated with fear and anxiety behaviors. Recent reports suggest a role for ASIC1a in preclinical models of fear conditioning and anxiety.

Objectives: The present experiments evaluated various ASIC inhibitors in preclinical models of autonomic and behavioral parameters of anxiety. In addition, neurochemical studies evaluated the effects of an ASIC inhibitor (A-317567) on neurotransmitter levels in the amygdala.

Results: In electrophysiological studies using hippocampal primary neuronal cultures, three ASIC inhibitors (PcTX-1, A-317567, and amiloride) produced concentration-dependent inhibition of acid-evoked currents. In the stress-induced hyperthermia model, acute administration of psalmotoxin 1 (PcTX-1; 10-56 ng, i.c.v.), A-317567 (0.1-1.0 mg/kg, i.p.), and amiloride (10-100 mg/kg, i.p.) prevented stress-induced elevations in core body temperature. In the four-plate test, acute treatment with PcTX-1 (10-56 ng, i.c.v.) and A-317567 (0.01-0.1 mg/kg, i.p.), but not amiloride (3-100 mg/kg, i.p.), produced dose-dependent and significant increases in the number of punished crossings relative to vehicle-treated animals. Additionally, PcTX-1 (56-178 ng, i.c.v.), A-317567 (0.1-10 mg/kg, i.p.), and amiloride (10-100 mg/kg, i.p.) lacked significant anxiolytic-like activity in the elevated zero maze. In neurochemical studies, an infusion of A-317567 (100 microM) into the amygdala significantly elevated the extracellular levels of GABA, but not glutamate, in this brain region.

Conclusions: These findings demonstrate that ASIC inhibition produces anxiolytic-like effects in some behavioral models and indicate a potential role for GABAergic mechanisms to underlie these anxiolytic-like effects.

MeSH terms

  • Acid Sensing Ion Channels
  • Amiloride / pharmacology
  • Amygdala / drug effects
  • Amygdala / metabolism
  • Animals
  • Anti-Anxiety Agents / pharmacology*
  • Anxiety / drug therapy*
  • Anxiety / metabolism
  • Anxiety / psychology
  • Behavior, Animal / drug effects
  • Cells, Cultured
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Drug Evaluation, Preclinical* / methods
  • Exploratory Behavior / drug effects
  • Fever / metabolism
  • Fever / prevention & control
  • Fever / psychology
  • Glutamic Acid / metabolism
  • Hippocampus / drug effects
  • Hippocampus / embryology
  • Hippocampus / metabolism
  • Isoquinolines / pharmacology
  • Male
  • Membrane Potentials
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Microdialysis
  • Naphthalenes / pharmacology
  • Nerve Tissue Proteins / antagonists & inhibitors*
  • Nerve Tissue Proteins / metabolism
  • Neurons / drug effects
  • Neurons / metabolism
  • Peptides
  • Rats
  • Rats, Sprague-Dawley
  • Sodium Channel Blockers / pharmacology*
  • Sodium Channels / metabolism
  • Spider Venoms / pharmacology
  • Stress, Psychological / complications
  • Stress, Psychological / metabolism
  • gamma-Aminobutyric Acid / metabolism

Substances

  • A-317567
  • ASIC1 protein, mouse
  • Acid Sensing Ion Channels
  • Anti-Anxiety Agents
  • Isoquinolines
  • Naphthalenes
  • Nerve Tissue Proteins
  • PcTX1 protein, Psalmopoeus cambridgei
  • Peptides
  • Sodium Channel Blockers
  • Sodium Channels
  • Spider Venoms
  • Glutamic Acid
  • gamma-Aminobutyric Acid
  • Amiloride