Corticotropin‐Releasing Factor Acting on Corticotropin‐Releasing Factor Receptor Type 1 is Critical for Binge Alcohol Drinking in Mice
2012
The corticotropin releasing factor (CRF) system regulates many important physiological functions and includes the ligands, CRF, urocortins 1, 2 and 3 (Ucn1, Ucn2 and Ucn3) and their receptors, CRF receptor type 1 (CRFR1) and type 2 (CRFR2) (Bale and Vale, 2004; Hauger et al., 2006). CRF binds with greater affinity to CRFR1 than CRFR2 while Ucn1 binds both receptor types with equal affinity. Ucn 2 and 3 act only at CRFR2 (Hauger et al., 2006; Pioszak et al., 2008; Ryabinin et al., 2002).
The CRF system is involved in the regulation of alcohol consumption (Cowen and Lawrence, 2006; Cowen et al., 2004; Heilig and Koob, 2007). In particular, CRFR1 antagonists attenuated drinking in dependent rats but not in non-dependent controls (Funk et al., 2007; Gehlert et al., 2007; Gilpin et al., 2008; Ji et al., 2008; Sommer et al., 2008). In agreement, Chu et al. (2007) reported that a CRFR1 antagonist attenuated the increase in alcohol consumption observed after dependence and an abstinent period in C57BL/6J mice. In contrast, a CRFR2 agonist was found to decrease alcohol self-administration in dependent rats while having the opposite effect in non-dependent animals (Funk and Koob, 2007). These findings suggest that the CRF system is especially important in the transition from excessive drinking to alcohol dependence. In agreement with pharmacological studies, polymorphisms in the human gene encoding CRFR1 have been shown to be associated with excessive drinking (Treutlein et al., 2006). Similarly, a polymorphism in the gene encoding CRFR1 in rats selectively bred for alcohol preference was found to be associated with their high alcohol intake (Hansson et al., 2006).
However, studies using genetically-modified mice have provided inconclusive and contradictory evidence on the role of CRF system in alcohol drinking. For example, CRFR1-deficient mice were found to consume similar amounts of alcohol as wild-type (WT) littermates in a continuous 2-bottle choice procedure and did not increase their alcohol intake after induction of dependence. On the other hand, prolonged alcohol consumption and repeated stress resulted in higher alcohol intake in these KOs compared to WTs (Chu et al., 2007; Sillaber et al., 2002). A recent study by Pastor et al. (2011) showed that drinking in CRFR1 KO mice was sensitive to ethanol concentration and only consumption of 20% ethanol was reduced compared to the WTs, while there was no difference in the consumption of 3%, 6% and 10% ethanol. A deletion of the CRFR2 gene only slightly increased alcohol intake in the limited access procedure while having no effect when access was continuous (Sharpe et al., 2005). On the other hand, CRF knockout (KO) mice consumed more alcohol than controls in continuous and limited access experiments, and CRF overexpressing mice consumed less alcohol than WTs (Olive et al., 2003; Palmer et al., 2004).
The discrepancies between pharmacological and KO studies could be due to developmental compensations in the genetically-manipulated mice or may preclude a role for the system in moderate alcohol consumption and instead suggest a role in binge drinking. More recent pharmacological studies have suggested exactly this, i.e., that this system is involved in excessive binge-like alcohol consumption in non-dependent animals (Lowery et al., 2008; 2010; Sparta et al., 2008).
Effects of genetic manipulations of specific components of the CRF system have never been addressed in models of binge drinking. Therefore, in the studies detailed here, we investigated the roles of several components of the CRF system in binge alcohol consumption, utilizing the “drinking-in-the-dark” (DID) paradigm (Rhodes et al., 2005; 2007; Ryabinin et al., 2003; Sharpe et al., 2005). Specifically we used CRFR1, CRFR2, CRF and Ucn1 KO mice to avoid potential non-specific actions of pharmacological agents and to identify the specific ligand(s) regulating alcohol drinking in this procedure.
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