Ethanol and Corticotropin-Releasing Factor

Converging evidence from numerous investigations suggests that the role of corticotropin-releasing factor (CRF) in modulating the neurobiological effects of ethanol is dependent on the duration of exposure. Generally, initial or acute exposures to ethanol activate CRF in the hypothalamus, which activates the HPA axis stress response. Acute ethanol administration is accompanied by increases in levels of CRF, CRF-like immunoreactivity (CRF-IR), CRF heteronuclear RNA (hnRNA) and CRF messenger RNA (mRNA), as well as increased CRF1R mRNA expression in the hypothalamus. Notably, no alterations in extrahypothalamic brain regions have been reported during the early stages of ethanol exposure.

With chronic administration and withdrawal, ethanol induces further alterations in the CRF system, most of which are observed in limbic regions. Upregulation of CRF markers, including extracellular CRF, pre-pro CRF mRNA, and CRF mRNA have been reported in the amygdala, and more specifically, within the central nucleus of the amygdala (CeA) in dependent, ethanol-withdrawn rats relative to non-dependent controls. Likewise, increased levels of extracellular CRF have been observed in the bed nucleus of the stria terminalis (BNST) and enhanced CRF mRNA expression has been noted in the paraventricular nucleus of the hypothalamus (PVN) after chronic ethanol exposure. Additionally, increased CRF1R expression has been observed in the basolateral amygdala (BLA) and the medial nucleus of the amygdala (MeA), as well as the hypothalamus in dependent, ethanol-withdrawn rats. Decreases in CRF2R expression were observed in the BLA of ethanol dependent rats, while increases have been observed in the dorsal raphe of mice, and the hypothalamus of rats with a history of ethanol exposure.

Such alterations appear to be functional, as marked changes in CRF-induced excitability in the BNST and CRF-induced inhibition in the CeA have been observed following prolonged exposure to ethanol. Indeed, long-term investigations show that some of these neurobiological changes in CRFR signaling persist months into abstinence, which may contribute to the enhanced anxiety-like behaviors and stress responsiveness that are observed long after ethanol administration has ceased, and follow-up investigations show that some of these changes can be normalized through reinstatement of ethanol self-administration. Thus, the literature suggests that chronic ethanol exposure and withdrawal promote alterations in CRF signaling in extrahypothalamic regions of the amygdala, the lateral septum, and the dorsal raphe, as well as the hypothalamus. These observations are consistent with the hypothesis that a dysregulation of CRFR signaling emerges over the course of ethanol dependence, and that this dysregulation may contribute to the excessive and uncontrolled ethanol intake associated with ethanol dependence. The effects of ethanol on CRF activity lead to the prediction that CRFR antagonists may protect against excessive ethanol drinking, including binge-like drinking, in non-dependent animals because initial ethanol exposure augments CRF signaling.

The current body of preclinical literature suggests that the role of CRF signaling in low or moderate ethanol intake in the early stages of ethanol drinking is limited. For example, central administration of non-selective CRFR antagonists, such as [D-Phe,Nle,CαMeLeu]-rCRF(12-41) (D-Phe-CRF) and α-helical CRF(9-41) (ahCRF), does not significantly alter ethanol consumption or self-administration in non-dependent rats or mice with a history of ethanol exposure akin to social drinking in humans. Similar results have been obtained using peripheral administration of antagonists selective for the CRF1R, including (N,N-bis(2-methoxyethyl)-3-(4-methoxy-2-methylpheenyl)-2,5-dimethyl-pyrazolo[1,5-a]pyrimidin-7-amine (MPZP), 3-(4-Chloro-2-morpholin-4-yl-thiazol-5-yl)-8-(1-ethylpropyl)-2,6-dimethylimidazo[1,2-b]pyridazine (MTIP), (4-ethyl-[2,5,6-trimethyl-7-(2,4,6-trimethylphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amino-1-butanol (LWH-63), 2,5-dimethyl-3-(6-dimethyl-4-methylpyridin-3-yl)-7-dipropylaminopyrazolo[1,5-a]pyrimidine (R121919, also called NBI 30775), and [8-(4-bromo-2-chlorophenyl)-2,7-dimethyl-pyrazolo[1,5-a][1,3,5]triazin-4-yl]-bis-(2-methyoxyethyl)amine (MJL-1-109-2). Though there are reports of a role for CRF in stress-induced ethanol consumption by non-dependent animals, converging evidence indicates that CRFR signaling does not modulate low or moderate levels of ethanol consumption in non-dependent animals under non-stressed conditions.



Lowery-Gionta, Emily Geyer. The role of corticotropin-releasing factor in binge-like ethanol consumption. The University of North Carolina at Chapel Hill, 2011.