Examining the role of ASIC1A in mouse models of addiction and CO2-evoked panic-like behaviors

Abstract

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 previously 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 NAc increased cocaine-conditioned place preference, suggesting an unexpected role for ASIC1A in addiction-related behavior. Investigating the underlying mechanisms, we identified a novel postsynaptic current during neurotransmission 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 cocaineevoked plasticity in AMPA-to-NMDA ratio, all resembling changes previously associated with cocaine-induced behavior. Together, these data suggest ASIC1A inhibits plasticity underlying addiction-related behavior, and raise the possibility of therapies for drug addiction by targeting ASIC-dependent neurotransmission. The amygdala plays critical roles in the learning and expression of fear-related behavior. Previous studies have implicated the amygdala in CO2-evoked fear-like behavior in mice; however, a more recent study demonstrated that humans lacking the amygdala bilaterally experience fear and panic with CO2-inhalation. Because all subjects lacking the amygdala had panic attacks after inhaling CO2 compared to only 25% of controls, this data suggests the amygdala may play an inhibitory role in CO2-evoked panic. To assess the role of the amygdala in CO2-evoked behaviors in mice, we lesioned the amygdala and optogenetically stimulated different amygdalar nuclei. We found that large unilateral and