Extended Amygdala to Ventral Tegmental Area Corticotropin-Releasing Factor Circuit Controls Binge Ethanol Intake

Biol Psychiatry. 2017 Jun 1;81(11):930-940. doi: 10.1016/j.biopsych.2016.02.029. Epub 2016 Mar 3.


Background: Corticotropin-releasing factor (CRF) signaling at the CRF1 receptor (CRF1R) in the ventral tegmental area (VTA) can modulate ethanol consumption in rodents. However, the effects of binge-like ethanol drinking on this system have not been thoroughly characterized, and little is known about the role of CRF2R or the CRF neurocircuitry involved.

Methods: The effects of binge-like ethanol consumption on the VTA CRF system were assessed following drinking-in-the-dark procedures. Intra-VTA infusions of selective CRF1R and/or CRF2R compounds were employed to assess the contributions of these receptors in modulating binge-like ethanol consumption (n = 89). To determine the potential role of CRF projections from the bed nucleus of the stria terminalis (BNST) to the VTA, CRF neurons in this circuit were chemogenetically inhibited (n = 32). Binge-induced changes in VTA CRF system protein and messenger RNA were also assessed (n = 58).

Results: Intra-VTA antagonism of CRF1R and activation of CRF2R resulted in decreased ethanol intake, which was eliminated by simultaneous blockade of both receptors. Chemogenetic inhibition of local CRF neurons in the VTA did not alter binge-like ethanol drinking, but inhibition of VTA-projecting CRF neurons from the BNST significantly reduced intake.

Conclusions: We provide novel evidence that 1) blunted binge-like ethanol consumption stemming from CRF1R blockade requires intact CRF2R signaling, and CRF2R activation reduces binge-like drinking; 2) inhibiting VTA-projecting BNST CRF neurons attenuates binge-like drinking; and 3) binge-like ethanol drinking alters protein and messenger RNA associated with the VTA-CRF system. These data suggest that ethanol-induced activation of BNST-to-VTA CRF projections is critical in driving binge-like ethanol intake.

Keywords: Binge drinking; Corticotropin-releasing factor; Drinking in the dark; Ethanol; Extended amygdala; Ventral tegmental area.

MeSH terms

  • Acenaphthenes / pharmacology
  • Animals
  • Binge Drinking / physiopathology*
  • Clozapine / analogs & derivatives
  • Clozapine / pharmacology
  • Corticotropin-Releasing Hormone / genetics
  • Corticotropin-Releasing Hormone / physiology*
  • Designer Drugs
  • Male
  • Mice
  • Mice, Transgenic
  • Neural Pathways / physiopathology*
  • Pyrimidines / pharmacology
  • Pyrroles / pharmacology
  • Receptors, Corticotropin-Releasing Hormone / agonists
  • Receptors, Corticotropin-Releasing Hormone / antagonists & inhibitors
  • Receptors, Corticotropin-Releasing Hormone / physiology*
  • Septal Nuclei / drug effects
  • Septal Nuclei / physiopathology
  • Urocortins / pharmacology
  • Ventral Tegmental Area / drug effects
  • Ventral Tegmental Area / physiopathology*


  • 6-cyclopropylmethyl-2-(2,4-dichlorophenyl)-7-ethyl-4-methyl-7,8-dihydro-6H-1,3,6,8a-tetraazaacenaphthylene
  • Acenaphthenes
  • CRF receptor type 2
  • Designer Drugs
  • Pyrimidines
  • Pyrroles
  • Receptors, Corticotropin-Releasing Hormone
  • Urocortins
  • antalarmin
  • CRF receptor type 1
  • Corticotropin-Releasing Hormone
  • Clozapine
  • clozapine N-oxide