Acid-sensing ion channels contribute to synaptic transmission and inhibit cocaine-evoked plasticity

Nat Neurosci. 2014 Aug;17(8):1083-91. doi: 10.1038/nn.3750. Epub 2014 Jun 22.


Acid-sensing ion channel 1A (ASIC1A) is abundant in the nucleus accumbens (NAc), a region known for its role in addiction. Because ASIC1A has been suggested to promote associative learning, we hypothesized that disrupting ASIC1A in the NAc would reduce drug-associated learning and memory. However, contrary to this hypothesis, we found that disrupting ASIC1A in the mouse NAc increased cocaine-conditioned place preference, suggesting an unexpected role for ASIC1A in addiction-related behavior. Moreover, overexpressing ASIC1A in rat NAc reduced cocaine self-administration. Investigating the underlying mechanisms, we identified a previously unknown postsynaptic current during neurotransmission that was mediated by ASIC1A and ASIC2 and thus well positioned to regulate synapse structure and function. Consistent with this possibility, disrupting ASIC1A altered dendritic spine density and glutamate receptor function, and increased cocaine-evoked plasticity, which resemble changes previously associated with cocaine-induced behavior. Together, these data suggest that ASIC1A inhibits the plasticity underlying addiction-related behavior and raise the possibility of developing therapies for drug addiction by targeting ASIC-dependent neurotransmission.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Acid Sensing Ion Channels / deficiency
  • Acid Sensing Ion Channels / physiology*
  • Animals
  • Behavior, Animal
  • Cocaine / antagonists & inhibitors*
  • Cocaine-Related Disorders / metabolism
  • Disease Models, Animal
  • Excitatory Postsynaptic Potentials / drug effects
  • Excitatory Postsynaptic Potentials / genetics
  • Female
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Neural Inhibition / drug effects
  • Neural Inhibition / genetics*
  • Neuronal Plasticity / drug effects
  • Neuronal Plasticity / genetics*
  • Nucleus Accumbens / drug effects
  • Nucleus Accumbens / pathology
  • Nucleus Accumbens / physiology*
  • Rats
  • Synaptic Transmission / drug effects
  • Synaptic Transmission / genetics*
  • Up-Regulation / genetics


  • ASIC1 protein, mouse
  • ASIC2 protein, mouse
  • Acid Sensing Ion Channels
  • Cocaine