title: Corticotropin Releasing Factor Binding Protein and CRF2 Receptors in the Ventral Tegmental Area: Modulation of Ethanol Binge Drinking in C57BL/6J Mice.
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.
authors.affiliation: Department of Psychology, Tufts University, Medford, Massachusetts.
authors.forename: Lucas
authors.initials: L
authors.lastname: Albrechet-Souza
authors.affiliation: Department of Psychology, Tufts University, Medford, Massachusetts.
authors.forename: Lara S
authors.initials: LS
authors.lastname: Hwa
authors.affiliation: Department of Psychology, Tufts University, Medford, Massachusetts.
authors.forename: Xiao
authors.initials: X
authors.lastname: Han
authors.affiliation: Department of Psychology, Tufts University, Medford, Massachusetts.
authors.forename: Eric Y
authors.initials: EY
authors.lastname: Zhang
authors.affiliation: Department of Psychology, Tufts University, Medford, Massachusetts.
authors.forename: Joseph F
authors.initials: JF
authors.lastname: DeBold
authors.affiliation: Department of Psychology, Tufts University, Medford, Massachusetts.|Department of Psychiatry, Pharmacology, and Neuroscience, Tufts University School of Medicine, Boston, Massachusetts.
authors.forename: Klaus A
authors.initials: KA
authors.lastname: Miczek
mesh_terms: D000818:Animals; D063425:Binge Drinking / Q000378:metabolism*; D002352:Carrier Proteins / Q000378:metabolism*; D000431:Ethanol / Q000008:administration & dosage*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018019:Receptors, Corticotropin-Releasing Hormone / Q000378:metabolism*; D017557:Ventral Tegmental Area / Q000187:drug effects / Q000378:metabolism*
chemical_list: C101531:CRF receptor type 2; D002352:Carrier Proteins; D018019:Receptors, Corticotropin-Releasing Hormone; C067133:corticotropin releasing factor-binding protein; D000431:Ethanol
keywords: Alcohol; CRF2 Receptor; Corticotropin Releasing Factor Binding Protein; Drinking in the Dark; Ventral Tegmental Area