Journal Article

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

Sizer, Sarah E., Price, Michaela E., Parrish, Brian P., Raab‐Graham, Kimberly F., McCool, Brian A., Alexander, Nancy J., Egido‐Betancourt, Hailey X.

2025

Overview

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 (BLANAC and BLABNST neurons). We found that CIE/WD diminished feed‐forward GABA release from lateral paracapsular cells (LPCs) specifically onto male BLANAC 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 BLABNST 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. Rat basolateral amygdala principal neurons projecting to the nucleus accumbens (BLANAc) and bed nucleus of the stria terminalis (BLABNST) represent independent cell populations. In male BLANAc neurons only (left), CIE/WD decreases feedforward GABA release from lateral paracapsular interneurons. In BLABNST neurons (right), GABA release from ‘local’ feedback interneurons is greater in females; but CIE/WD diminishes spontaneous GABA release attributable to these ‘local’ interneurons in both sexes. Thus, CIE/WD dysregulation of BLA GABAergic neurotransmission is sex‐, synapse‐ and population‐specific.

• Publisher: John Wiley & Sons, Inc
• Subject: Amygdala / Animals / Basolateral Nuclear Complex - drug effects / Basolateral Nuclear Complex - metabolism / Central Nervous System Depressants - pharmacology / Confocal microscopy / Drug abuse / Ethanol / Ethanol - administration & dosage / Ethanol - pharmacology / feed‐back inhibition / feed‐forward inhibition / Female / gamma-Aminobutyric Acid - metabolism / Gender differences / Glutamatergic transmission / Innervation / Interneurons / Interneurons - drug effects / Interneurons - metabolism / Male / Neurons - drug effects / Neurons - metabolism / Nucleus accumbens / Nucleus Accumbens - drug effects / Nucleus Accumbens - metabolism / Opioid receptors / Parvalbumin / Parvalbumins - metabolism / Rats / Receptors, Opioid, mu - drug effects / Receptors, Opioid, mu - metabolism / Sex differences / Sex Factors / Stria terminalis / Substance Withdrawal Syndrome - metabolism / Substance Withdrawal Syndrome - physiopathology / Vesicular Inhibitory Amino Acid Transport Proteins - drug effects / Vesicular Inhibitory Amino Acid Transport Proteins - metabolism / whole‐cell voltage‐clamp electrophysiology / γ-Aminobutyric acid