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

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.

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).

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.

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.