Acute alcohol and chronic drinking bidirectionally regulate the excitability of prefrontal cortex vasoactive intestinal peptide interneurons

Neuropharmacology. 2023 Nov 1:238:109638. doi: 10.1016/j.neuropharm.2023.109638. Epub 2023 Jul 22.


The prefrontal cortex (PFC) regulates drinking behaviors and affective changes following chronic alcohol use. PFC activity is dynamically modulated by local inhibitory interneurons (INs), which can be divided into non-overlapping groups with distinct functional roles. Within deeper layers of neocortex, INs that express either parvalbumin or somatostatin directly inhibit pyramidal cells. By contrast, the plurality of all remaining INs express vasoactive intestinal peptide (VIP), reside within superficial layers, and preferentially target other types of INs. While recent studies have described adaptations to PFC parvalbumin-INs and somatostatin-INs in alcohol use models, whether ethanol or drinking affect the physiology of PFC VIP-INs has not been reported. To address this gap, we used genetically engineered female and male mice to target VIP-INs in layers 1-3 of prelimbic PFC for whole-cell patch-clamp electrophysiology. We found that ethanol (20 mM, ∼0.09 BEC/90 mg/dL) application to PFC brain slices enhances VIP-IN excitability. We next examined effects following chronic drinking by providing mice with 4 weeks of intermittent access (IA) ethanol two-bottle choice in the home cage. In these studies, VIP-INs from female and male IA ethanol mice displayed reduced excitability relative to cells from water-only controls. Finally, we assessed whether these effects continue into abstinence. After 7-13 days without ethanol, the hypo-excitability of VIP-INs from male IA ethanol mice persisted, whereas cells from female IA ethanol mice were not different from their controls. Together, these findings illustrate that acute ethanol enhances VIP-IN excitability and suggest these cells undergo pronounced homeostatic changes following long-term drinking.

Keywords: Addiction; Alcohol use disorder; Intrinsic properties; Preclinical model; Sex differences; Synaptic physiology.

Publication types

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

MeSH terms

  • Action Potentials
  • Animals
  • Ethanol / pharmacology
  • Female
  • Interneurons / physiology
  • Male
  • Mice
  • Neocortex* / metabolism
  • Parvalbumins
  • Prefrontal Cortex
  • Somatostatin / metabolism
  • Somatostatin / pharmacology
  • Vasoactive Intestinal Peptide* / metabolism
  • Vasoactive Intestinal Peptide* / pharmacology


  • Vasoactive Intestinal Peptide
  • Parvalbumins
  • Ethanol
  • Somatostatin