Enhanced CRF Signaling in the VTA Following Binge Drinking

点击翻译按钮获取中文摘要

DESCRIPTION (provided by applicant): Binge and/or excessive drinking is a problematic component of alcoholism which has been correlated with enhanced alcohol use disorder in adolescents (Hingson et al., 2005; 2007; Miller et al. 2007). However, the neural mechanisms that mediate this behavior remain unclear. Here, we utilize a mouse model of binge and/or excessive drinking known as drinking in the dark (DID) to examine corticotropin releasing factor (CRF) signaling in the ventral tegmental area (VTA), a structure involved in the etiology of drug and alcohol abuse. In the DID model, C57BL/6J mice drink approximately 10 g/kg and achieve blood ethanol concentrations of approximately 100 mg/dL or 0.1%, which is equivalent to 4-6 drinks over a 2 hour period in a normal sized human male (Rhodes et al., 2005; 2007). CRF is a widely expressed neuropeptide that has been shown to modulate neurobiological responses to ethanol (for review see Koob, 2003). Preliminary data suggest that binge ethanol drinking in mice results in a greater CRF-induced potentiation of NMDA current in VTA dopamine (DA) neurons. However, the CRF receptor subtypes involved in this increased potentiation remain unknown. Therefore, Specific Aim I will examine which CRF receptor subtype mediates this increased NMDA potentiation. For this aim, I will employ patch-clamp electrophysiology. Specific Aim II will complement the first aim by examining whether intra-VTA administration of selective antagonists (CRFi receptor, CRF2 receptor, CRF-binding protein) reduces the high ethanol consumption associated with DID procedures. 1 hypothesize that binge drinking of ethanol becomes modulated by increased CRFi receptor signaling in the VTA and that blockade of the CRFi receptor in the VTA will reduce high ethanol consumption associated with excessive binge-like drinking. By utilizing both in vitro and in vivo techniques, I feel that I will fully be able to address the questions presented in this proposal. Results from this proposal will identify a possible pharmacological target (CRF signaling in the VTA) that may be useful in targeting specific alcoholic patient populations.