Inactivation of a CRF-dependent Amygdalofugal Pathway Reverses Addiction-Like Behaviors in Alcohol-Dependent Rats

Nat Commun. 2019 Mar 18;10(1):1238. doi: 10.1038/s41467-019-09183-0.

Abstract

The activation of a neuronal ensemble in the central nucleus of the amygdala (CeA) during alcohol withdrawal has been hypothesized to induce high levels of alcohol drinking in dependent rats. In the present study we describe that the CeA neuronal ensemble that is activated by withdrawal from chronic alcohol exposure contains ~80% corticotropin-releasing factor (CRF) neurons and that the optogenetic inactivation of these CeA CRF+ neurons prevents recruitment of the neuronal ensemble, decreases the escalation of alcohol drinking, and decreases the intensity of somatic signs of withdrawal. Optogenetic dissection of the downstream neuronal pathways demonstrates that the reversal of addiction-like behaviors is observed after the inhibition of CeA CRF projections to the bed nucleus of the stria terminalis (BNST) and that inhibition of the CRFCeA-BNST pathway is mediated by inhibition of the CRF-CRF1 system and inhibition of BNST cell firing. These results suggest that the CRFCeA-BNST pathway could be targeted for the treatment of excessive drinking in alcohol use disorder.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Alcoholism / pathology
  • Alcoholism / physiopathology*
  • Animals
  • Behavior, Addictive / physiopathology*
  • Behavior, Animal
  • Central Amygdaloid Nucleus / cytology
  • Central Amygdaloid Nucleus / metabolism
  • Central Amygdaloid Nucleus / pathology
  • Central Amygdaloid Nucleus / physiopathology*
  • Corticotropin-Releasing Hormone / genetics
  • Corticotropin-Releasing Hormone / metabolism*
  • Disease Models, Animal
  • Humans
  • Male
  • Neural Pathways / metabolism
  • Neural Pathways / physiopathology
  • Neurons / metabolism
  • Optogenetics
  • Rats
  • Septal Nuclei / cytology
  • Septal Nuclei / metabolism
  • Septal Nuclei / pathology
  • Septal Nuclei / physiopathology*
  • Substance Withdrawal Syndrome / metabolism
  • Substance Withdrawal Syndrome / pathology
  • Substance Withdrawal Syndrome / physiopathology
  • Substance Withdrawal Syndrome / psychology

Substances

  • Corticotropin-Releasing Hormone