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Journal of Neuroscience


Chronic alcohol exposure leads to a neuroinflammatory response involving activation of the nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) inflammasome and pro-inflammatory cytokine production. Acute ethanol (EtOH) exposure activates GABAergic synapses in the central and basolateral amygdala (BLA) ex vivo, but whether this rapid modulation of synaptic inhibition is due to an acute inflammatory response and alters anxiety-like behavior in male and female animals is not known. Here, we tested the hypotheses that acute EtOH facilitates inhibitory synaptic transmission in the BLA by activating the NLRP3 inflammasome-dependent acute inflammatory response, that the alcohol-induced increase in inhibition is cell type- and sex-dependent, and that acute EtOH in the BLA reduces anxiety-like behavior. Acute EtOH application at a binge-like concentration (22-44 mM) stimulated synaptic GABA release from putative parvalbumin interneurons onto BLA principal neurons in ex vivo brain slices from male, but not female, rats. The EtOH facilitation of synaptic inhibition was blocked by antagonists of the toll-like receptor 4 (TLR4), the NLRP3 inflammasome, and interleukin-1 receptors, suggesting it was mediated by a rapid local neuroinflammatory response in the BLA. In vivo, bilateral injection of EtOH directly into the BLA produced an acute concentration-dependent reduction in anxiety-like behavior in male but not female rats. These findings demonstrate that acute EtOH in the BLA regulates anxiety-like behavior in a sex-dependent manner and suggest that this effect is associated with presynaptic facilitation of parvalbumin-expressing interneuron inputs to BLA principal neurons via a local NLRP3 inflammasome-dependent neuroimmune response.

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Creative Commons Attribution 4.0 International License
This work is licensed under a Creative Commons Attribution 4.0 International License.