Chronic Intermittent Ethanol and Withdrawal Suppress Evoked and Spontaneous GABA Release Onto Distinct Populations of Basolateral Amygdala Principal Neurons

Abstract

Unique populations of basolateral amygdala (BLA) neurons regulate anxiety and reward through projections targeting downstream regions like the bed nucleus of the stria terminalis (BNST) and nucleus accumbens (NAC). We showed previously that withdrawal from chronic ethanol exposure (CIE/WD) produced population- and sex-specific alterations to distinct glutamatergic inputs. The current study examined GABAergic function in these distinct populations (BLA^NAC and BLA^BNST neurons). We found that CIE/WD diminished feed-forward GABA release from lateral paracapsular cells (LPCs) specifically onto male BLA^NAC neurons. Pharmacological manipulations showed this dysregulation was caused by the enhanced activity of μ-opioid receptors. CIE/WD did not alter evoked GABA release from local interneurons onto either population. However, females expressed greater GABA release from these local interneurons compared to males. Immunostaining and confocal microscopy revealed lower colocalization between the GABA vesicular transporter, vGAT and parvalbumin in females, indicating that greater GABA releases from local interneurons in this sex may be a compensatory response to lower levels of perisomatic innervation by PV⁺ interneurons. Consistent with this, there were no sex differences related to spontaneous GABAergic synaptic events although CIE/WD decreased their frequency specifically in BLA^BNST neurons from both sexes. Altogether, these findings demonstrate that CIE/WD dynamically alters GABAergic function in an input-, sex- and population-specific fashion. Moreover, there are basal sex differences in both the anatomy of BLA GABAergic synapses and their function.