Examining the role of ASIC1A in mouse models of addiction and CO2-evoked panic-like behaviors
Author(s)Kreple, Collin John
Contributor(s)Wemmie, John A
Full recordShow full item record
AbstractAcid-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 cocaine-evoked 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 bilateral amygdala lesions caused the emergence of escape-like jumping behavior in mice exposed to CO2 and a relative deficit in CO2-evoked freezing. This jumping behavior depended on the dorsal periaqueductal gray, a brain area previously associated with panic attacks. Additionally, the putative CO2 chemosensor ASIC1A and ASIC2 are not necessary for CO2-evoked jumping, and may even play an inhibitory role in this behavior. Optogenetic manipulation of the amygdala revealed that stimulation of the basolateral amygdala enhanced jumping behavior and inhibited freezing behavior. This may be due to the basolateral amygdala's ability to inhibit the main output center of the amygdala, the central nucleus. Together, these results suggest that different amygdalar nuclei differentially modulate CO2-evoked behavior by regulating the switch between mobile and immobile defense responses. Additionally, they provide additional evidence that amygdalar dysfunction may contribute to panic disorder.