Corticotropin Releasing Factor Binding Protein and CRF2 Receptors in the Ventral Tegmental Area: Modulation of Ethanol Binge Drinking in C57BL/6J Mice

Alcohol Clin Exp Res. 2015 Sep;39(9):1609-18. doi: 10.1111/acer.12825. Epub 2015 Aug 6.

Abstract

Background: Most studies with corticotropin releasing factor (CRF) and ethanol (EtOH) consumption have focused on CRF type 1 (CRF1 ) receptors; less is known about other components of the CRF system, such as the CRF type 2 (CRF2 ) receptors and the CRF binding protein (CRFBP). In humans, several nucleotide polymorphisms in the CRFBP gene have been associated with EtOH abuse.

Methods: The role of the CRFBP within the ventral tegmental area (VTA) and the central nucleus of the amygdala (CeA) was investigated in C57BL/6J mice exposed to an EtOH binge drinking paradigm (drinking in the dark [DID]), or to a dependence-producing drinking protocol (2-bottle choice, intermittent access to alcohol [IAA]) for 4 weeks. Potential interactions between VTA CRFBP and CRF2 receptors on EtOH binge drinking were also assessed. Mice were microinjected with the CRFBP antagonist CRF fragment 6-33 (CRF6-33 ) into the VTA or CeA, or with the CRF2 antagonist astressin-2B (A2B) alone or in combination with CRF6-33 into the VTA, and had access to 20% (w/v) EtOH for 4 hours (DID). Separate cohorts of mice received vehicle and doses of CRF6-33 into the VTA or CeA and had access to EtOH/water for 24 hours (IAA). Blood EtOH concentrations (BECs) were measured, and signs of withdrawal by handling-induced convulsions were determined.

Results: Intra-VTA CRF6-33 and A2B reduced EtOH intake dose dependently in mice during DID. Furthermore, a combination of a subeffective dose of CRF6-33 and a lower dose of A2B promoted additive effects in attenuating EtOH binge drinking. Intra-VTA CRF6-33 did not affect EtOH consumption in mice given IAA, and intra-CeA CRF6-33 did not change alcohol consumption in both models of drinking. DID and IAA promoted pharmacologically relevant BECs; however, only mice given IAA exhibited convulsive events during withdrawal.

Conclusions: These findings suggest that VTA CRFBP is involved in the initial stages of escalated EtOH drinking by mechanisms that may involve CRF2 receptors.

Keywords: Alcohol; CRF2 Receptor; Corticotropin Releasing Factor Binding Protein; Drinking in the Dark; Ventral Tegmental Area.

Publication types

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

MeSH terms

  • Animals
  • Binge Drinking / metabolism*
  • Carrier Proteins / metabolism*
  • Ethanol / administration & dosage*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Receptors, Corticotropin-Releasing Hormone / metabolism*
  • Ventral Tegmental Area / drug effects
  • Ventral Tegmental Area / metabolism*

Substances

  • CRF receptor type 2
  • Carrier Proteins
  • Receptors, Corticotropin-Releasing Hormone
  • corticotropin releasing factor-binding protein
  • Ethanol