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CRF-BP in Alcohol Dependence PDF Print E-mail
Investigating the Role of CRF-BP in the Development of Alcohol Dependence
Collaboration with Bonci Lab
Military women and men are subject to a wide range of additional stressors as part of their military duties.  Exposure to traumatic stressors has been strongly implicated in the elevated rates of substance abuse and dependence among veterans and substance abuse has been found to be highly comorbid with post-traumatic stress disorder (McFall et al., 1992).  There is also accumulating scientific evidence showing stressors enhance addictive behaviors and are a common cause of relapse drinking (for reviews see Sarnyai et al., 2001; Shalev et al., 2002).  One of the most difficult aspects in treating alcohol dependence is the relapse to uncontrolled drinking that frequently occurs after a period of abstinence.  Factors such as stress and exposure to situations previously associated with alcohol drinking (referred to as "cues") are found to contribute to relapse drinking.  Corticotrophin releasing factor (CRF) is a 41-amino acid peptide that has been shown to induce various behavioral changes related to adaptation to stress.  CRF has also been shown to play a key role in stress-induced reinstatement of alcohol and cocaine seeking.  The CRF system including the CRF-binding protein (CRF-BP) and the CRF receptors, CRF-R1 and CRF-R2, are thought to contribute in different ways, to the physiological adaptations that result from stress.  The main goal of this project is to determine the role of CRF-BP, a protein that binds CRF, in the development of alcohol dependence and relapse using rodent models of drinking.

What is CRF and how might it modulate ethanol-mediated behaviors?
CRF was initially identified as a hypothalamic factor responsible for stimulating adrenocorticotropic hormone (ACTH) secretion from the anterior pituitary (Vale et al., 1981), where it induces various behavioral changes related to adaptation to stress (for a review see Sarnyai et al., 2001).  The multiple actions of CRF are mediated by two classes of specific CRF receptors, CRF-R1 (Chang et al., 1993; Chen et al., 1993; Perrin et al., 1993) and CRF-R2 (Lovenberg et al., 1995; Liaw et al., 1996).  CRF-R2 exists as two splice variants, the neuronal CRF-R2a and the peripheral CRF-R2b (for review, see Dautzenberg and Hauger, 2002).  The CRF-BP binds CRF with high affinity and it was principally believed to inhibit its physiological actions in the periphery (Kemp et al., 1998).  CRF-BP is also present in the central nervous system and in contrast to the periphery, where CRF-BP is circulating, it is membrane-bound and this may be important for its activity (Behan et al., 1995).  Thus the role of CRF-BP in the brain may be more complex than originally thought (Chan et al., 2000).  In fact, preliminary data from the Bonci Laboratory at the Gallo Center suggest that CRF interaction with CRF-BP may positively modulate the CRF-R2 function (Figure 1).  It was shown that the interaction of CRF-R2s and CRF-BP by CRF is necessary to potentiate NMDA receptor currents in the ventral tegmental area (VTA) (Ungless et al., 2001, Fig. 1).  NMDAR's play a central role in modulating burst firing activity of DA neurons, which in turn increases the efficiency of DA release.  Thus, by counteracting the activation of CRF-R2, it may be possible to modulate ethanol-mediated behaviors.  Wang and colleagues have recently shown that intra-VTA injections of alpha helical CRF (9-41), a peptide that inhibits CRF, blocks footshock stress-induced reinstatement of cocaine-seeking behavior (Wang et al., 2005).  In addition, the CRF antagonist d-Phe CRF (12-41) (Menzaghi et al., 1994) injected into the median raphe nucleus (MRN) inhibits intermittent footshock stress-induced reinstatement to alcohol under extinction conditions (Le et al., 2002).  This study also suggests that CRF signaling plays a significant role in stress-induced relapse to drug seeking.


CRF.jpg
Figure 1. Illustration of the interaction of the CRF system and NMDARs in dopamine neurons in the VTA. Preliminary data suggest that the CRF-BP is important for the ability of CRF (or CRF-like ligands) to potentiate NMDAR function.  We hypothesize that when CRF is not bound to the CRF-BP it does not activate CRF-R2 (left panel). However, when CRF is bound to the CRF-BP, it can activate CRF-R2 to potentiate NMDAR-mediated EPSCs in VTA neurons (right panel).

Purpose of Project
Inhibition of CRF interaction with the CRF-BP in the VTA prevents stress-induced relapse following abstinence in alcohol-experienced animals.  The main goal of this project is to determine the role of the CRF, CRF-BP and CRF-R2 interaction in the VTA in alcohol consumption, self-administration and stress-induced reinstatement.