Corticotropin‐Releasing Factor Acting on Corticotropin‐Releasing Factor Receptor Type 1 is Critical for Binge Alcohol Drinking in Mice

Abstract

Background The corticotropin releasing factor (CRF) system has been implicated in the regulation of alcohol consumption. However, previous mouse knockout (KO) studies using continuous ethanol access have failed to conclusively confirm this. Recent studies have shown that CRF receptor 1 (CRFR1) antagonists attenuate alcohol intake in the limited access “drinking in the dark” (DID) model of binge drinking. To avoid the potential non-specific effects of antagonists, in the present study we tested alcohol drinking in CRFR1, CRFR2, CRF and Ucn1 KO and corresponding wild-type (WT) littermates using the DID paradigm. Methods On days 1–3, the CRFR1, CRFR2, Ucn1 and CRF KO mice and their respective wildtype (WT) littermates were provided with 20% ethanol or 10% sucrose for 2 hours with water available at all other times. On day 4, access to ethanol or sucrose was increased to 4 hours. At the end of each drinking session, the volume of ethanol consumed was recorded and at the conclusion of the last session, blood was also collected for blood ethanol concentration (BEC) analysis. Results CRFR1 KO mice had lower alcohol intakes and BECs and higher intakes of sucrose compared to WTs. In contrast, CRFR2 KO mice, while having reduced intakes initially, had similar alcohol intakes on days 2–4 and similar BECs as the WTs. In order to determine the ligand responsible, Ucn1 and CRF KO and WT mice were tested next. While Ucn1 KOs had similar alcohol intakes and BECs to their WTs, CRF KO mice showed reduced alcohol consumption and lower BECs compared to WTs. Conclusions Our results confirm that CRFR1 plays a key role in binge drinking and identify CRF as the ligand critically involved in excessive alcohol consumption.

Role of Corticotropin-Releasing Factor and Corticosterone in Behavioral Sensitization to Ethanol

“…In the case of EtOH drinking, studies using CRF 1 manipulations have found that these receptors are involved in EtOH effects, especially when tested in postdependent animals, in lines of rodents bred for elevated EtOH consumption or under the effects of stress (Heilig and Koob, 2007;Pastor et al, 2011). Recent data also suggest that CRF 1 can play a role in EtOH drinking even in nondependent or nonstressed animals if they are tested under conditions that facilitate elevated or binge-like drinking (Lowery and Thiele, 2010;Pastor et al, 2011;Kaur et al, 2012). Thus, as proposed previously (Breese et al, 2004;Heilig and Koob, 2007;Lowery and Thiele, 2010;Kaur et al, 2012), CRF 1 manipulations might be excellent candidates for the development of pharmaceutical interventions for excessive EtOH drinking or EtOH abuse in dependent, genetically susceptible, or stress-prone individuals.…”

“…Current research shows that other neuroadaptive changes associated with alcoholism are also related to CRF and CRF 1 . CRF 1 antagonists can block excessive alcohol drinking and the increases in anxiety-like symptoms after a history of EtOH dependence (Breese et al, 2004;Heilig and Koob, 2007;Lowery and Thiele, 2010;Kaur et al, 2012). In addition, they can prevent stress-induced reinstatement of EtOH-seeking in postdependent rodents (Heilig and Koob, 2007;Lowery and Thiele, 2010).…”

Corticotropin releasing factor: A key role in the neurobiology of addiction

“…Moreover, both CRF and CRF 1 knockout mice show reduced ethanol intake and blood ethanol concentrations in a murine model of scheduled, limited access to ethanol (“drinking-in-the-dark”) that can produce binge-like intake (Kaur et al, 2012), suggesting an early role for CRF in neuroadaptations associated with the binge/intoxication stage of the addiction cycle. Perhaps accordingly, systemic administration of small-molecule CRF 1 antagonists can reduce binge-like but not non-binge-like ethanol intake in C57BL/6J mice and outbred rats (Lowery et al, 2010;Cippitelli et al, 2012;Simms et al, 2013) (but see (Giardino and Ryabinin, 2013) for additional findings suggesting that these effects may not be specific for ethanol).…”

Frameworks of Alcohol Addiction

“…Similarly, both global (Chu et al, 2007) and conditional brain-specific Crhr1 knockout (Crhr1[NestinCre]) mice (Molander et al, 2012) show reduced ethanol intake during withdrawal in the postdependent state compared with their wildtype littermates. CRF 1 -receptor knockout mice also drink less 20% v/v ethanol under basal conditions (Pastor et al, 2011), and both CRF and CRF 1 knockout mice show reduced ethanol intake and blood ethanol concentrations in the bingelike drinking-in-the-dark paradigm of limited ethanol access (Kaur, Li, Stenzel-Poore, & Ryabinin, 2012), suggesting an early role in neuroadaptations associated with the binge/intoxication stage. Consistent with this hypothesis, systemic administration of small-molecule CRF 1 antagonists can reduce binge-like, but not nonbinge-like, ethanol intake in C57BL/6 J mice and outbred rats (Cippitelli et al, 2012;Lowery et al, 2010;Simms, Nielsen, Li, & Bartlett, 2013; but see Giardino & Ryabinin, 2013, for a suggestion that these effects may not be specific for ethanol).…”