Interneuronal δ-GABAA receptors regulate binge drinking and are necessary for the behavioral effects of early withdrawal

Neuropsychopharmacology. 2019 Jan;44(2):425-434. doi: 10.1038/s41386-018-0164-z. Epub 2018 Jul 28.

Abstract

Extensive evidence points to a role for GABAergic signaling in the amygdala in mediating the effects of alcohol, including presynaptic changes in GABA release, suggesting effects on GABAergic neurons. However, the majority of studies focus solely on the effects of alcohol on principal neurons. Here we demonstrate that δ-GABAARs, which have been suggested to confer ethanol sensitivity, are expressed at a high density on parvalbumin (PV) interneurons in the basolateral amygdala (BLA). Thus, we hypothesized that δ-GABAARs on PV interneurons may represent both an initial pharmacological target for alcohol and a site for plasticity associated with the expression of various behavioral maladaptations during withdrawal from binge drinking. To investigate this, we used a mouse model of voluntary alcohol intake (Drinking-in-the-Dark-Multiple Scheduled Access) to induce escalating heavy binge drinking and anxiety-like behavior in mice. This pattern of intake was associated with increased δ protein expression on parvalbumin positive interneurons in both the BLA and hippocampus. Loss of δ-GABAARs specifically in PV interneurons (PV:δ-/-) increased binge drinking behavior, reduced sensitivity to alcohol-induced motor incoordination, enhanced sensitivity to alcohol-induced hyperlocomotion and blocked the expression of withdrawal from binge drinking. This study is the first to demonstrate a role for δGABAARs specifically in PV-expressing interneurons in modulating binge alcohol intake and withdrawal-induced anxiety.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alcohol Drinking / metabolism*
  • Animals
  • Behavior, Animal / drug effects
  • Behavior, Animal / physiology
  • Binge Drinking / metabolism*
  • Ethanol / pharmacology
  • Female
  • Hippocampus / drug effects
  • Hippocampus / metabolism*
  • Interneurons / drug effects
  • Interneurons / metabolism*
  • Male
  • Mice
  • Motor Activity / drug effects
  • Motor Activity / physiology
  • Neurons / drug effects
  • Neurons / metabolism
  • Parvalbumins / metabolism
  • Receptors, GABA-A / metabolism*
  • Substance Withdrawal Syndrome / metabolism*

Substances

  • Parvalbumins
  • Receptors, GABA-A
  • Ethanol