The ASIC1a antagonist PcTX‐1 reduces fear‐related behavior

Abstract

Anxiety disorders are the most common psychiatric disorder. Current medications often fail to achieve remission. Identifying novel pharmacological targets in animal models of fear may lead to new therapies. We found that the acid sensing ion channel (ASIC1a) plays an important role in fear-related behavior. ASIC1a is located at synapses, where it may be activated by extracellular protons, and modulates synaptic plasticity. In mice, deletion of the ASIC1a gene significantly reduces the fear response to predator odor, open spaces, and Pavlovian fear conditioning. We hypothesized that ASIC1a antagonists might act similarly. To test this hypothesis, we used the recently identified ASIC1a antagonist PcTX-1. When we found that PcTX-1 blocks ASIC1a-mediated currents in transfected CHO cells, we tested its effect on fear-related behavior. We administered PcTX-1 or artificial cerebrospinal fluid into mice by intracerebroventricular cannula and assessed the fear-response to the predator odor trimethylthiazoline (TMT) and in the open field test. Consistent with an anxiolytic effect, in wild type mice PcTX-1 greatly diminished TMT-evoked freezing and increased center time in the open field. PcTX-1 had little or no effect on fear-related behavior in the ASIC1a null mice. Thus, inhibition of ASIC1a with PcTX-1 attenuates fear response in mice. These data suggest that pharmacological inhibition of ASIC1a may provide a novel way to reduce anxiety in patients.