Central amygdala corticotropin-releasing factor neurons promote hyponeophagia but do not control alcohol drinking in mice

Mol Psychiatry. 2022 May;27(5):2502-2513. doi: 10.1038/s41380-022-01496-9. Epub 2022 Mar 9.


Corticotropin-releasing factor (CRF) signaling in the central nucleus of the amygdala (CeA) plays a critical role in rodent models of excessive alcohol drinking. However, the source of CRF acting in the CeA during alcohol withdrawal remains to be identified. In the present study, we hypothesized that CeA CRF interneurons may represent a behaviorally relevant source of CRF to the CeA increasing motivation for alcohol via negative reinforcement. We first observed that Crh mRNA expression in the anterior part of the mouse CeA correlates positively with alcohol intake in C57BL/6J males with a history of chronic binge drinking followed by abstinence and increases upon exposure to chronic intermittent ethanol (CIE) vapor inhalation. We then found that chemogenetic activation of CeA CRF neurons in Crh-IRES-Cre mouse brain slices increases gamma-aminobutyric acid (GABA) release in the medial CeA, in part via CRF1 receptor activation. While chemogenetic stimulation exacerbated novelty-induced feeding suppression (NSF) in alcohol-naïve mice, thereby mimicking the effect of withdrawal from CIE, it had no effect on voluntary alcohol consumption, following either acute or chronic manipulation. Furthermore, chemogenetic inhibition of CeA CRF neurons did not affect alcohol consumption or NSF in chronic alcohol drinkers exposed to air or CIE. Altogether, these findings indicate that CeA CRF neurons produce local release of GABA and CRF and promote hyponeophagia in naïve mice, but do not drive alcohol intake escalation or negative affect in CIE-withdrawn mice. The latter result contrasts with previous findings in rats and demonstrates species specificity of CRF circuit engagement in alcohol dependence.

Publication types

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

MeSH terms

  • Alcohol Drinking / metabolism
  • Alcoholism* / metabolism
  • Animals
  • Central Amygdaloid Nucleus* / metabolism
  • Corticotropin-Releasing Hormone / metabolism
  • Ethanol / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Neurons / metabolism
  • Rats
  • Receptors, Corticotropin-Releasing Hormone / genetics
  • Substance Withdrawal Syndrome* / metabolism
  • gamma-Aminobutyric Acid / metabolism


  • Receptors, Corticotropin-Releasing Hormone
  • Ethanol
  • gamma-Aminobutyric Acid
  • Corticotropin-Releasing Hormone