Binge Drinking Decreases Corticotropin‐Releasing Factor‐Binding Protein Expression in the Medial Prefrontal Cortex of Mice

Abstract

Background Dysregulation of the corticotropin releasing factor (CRF) system has been observed in rodent models of binge drinking, with a large focus on CRF-Receptor 1 (CRF-R1). The role of CRF-Binding Protein (CRF-BP), a key regulator of CRF activity, in binge drinking is less well understood. In humans, single nucleotide polymorphisms in CRHBP are associated with alcohol use disorder and stress-induced alcohol craving, suggesting a role for CRF-BP in vulnerability to alcohol addiction. Methods The role and regulation of CRF-BP in binge drinking were examined in mice exposed to the drinking in the dark (DID) paradigm. Using in situ hybridization, the regulation of CRF-BP, CRF-R1, and CRF mRNA expression was determined in the stress and reward systems of C57BL/6J mice after repeated cycles of DID. To determine the functional role of CRF-BP in binge drinking, CRF-BP knockout (CRF-BP KO) mice were exposed to 6 cycles of DID, during which alcohol consumption was measured and compared to wild-type mice. Results CRF-BP mRNA expression was significantly decreased in the prelimbic (PL) and infralimbic (IL) medial prefrontal cortex (mPFC) of C57BL/6J mice after 3 cycles and in the PL mPFC after 6 cycles of DID. No significant changes in CRF or CRF-R1 mRNA levels were observed in mPFC, ventral tegmental area (VTA), bed nucleus of the stria terminalis (BNST), or amygdala after 3 cycles of DID. CRF-BP KO mice do not show significant alterations in drinking compared to wild-type mice across 6 cycles of DID. Conclusions These results reveal that repeated cycles of binge drinking alter CRF-BP mRNA expression in the mPFC, a region responsible for executive function and regulation of emotion and behavior, including responses to stress. We observed a persistent decrease in CRF-BP mRNA expression in the mPFC after 3 and 6 DID cycles, which may allow for increased CRF signaling at CRF-R1 and contribute to excessive binge-like ethanol consumption.

Don’t stress about CRF: assessing the translational failures of CRF1antagonists

“…Indeed, the CRF-BP has recently received attention as a potential target for its role in alcohol use disorder (Haass-Koffler et al 2016, Ketchesin et al 2016); and, particularly, its role in the escalation of alcohol drinking may involve interaction with CRF 2 receptors (Albrechet-Souza et al 2015, Quadros et al 2016). Receptor activity modifying proteins (RAMPs) are other molecules that interact directly with the CRF system, as RAMP2 binds CRF 1 and increases its surface expression and signaling sensitivity (Wootten et al 2013).…”

Corticotropin-Releasing Factor (CRF) and Addictive Behaviors

“…Wang, You, Rice, & Wise, 2007). The CRF-BP has recently received attention as a potential target for its role in alcohol use disorder (Haass-Koffler et al, 2016; Ketchesin, Stinnett, & Seasholtz, 2016), and its role in the escalation of alcohol drinking may involve its interaction with CRF 2 (Albrechet-Souza et al, 2015; Quadros, Macedo, Domingues, & Favoretto, 2016). Intriguingly, recent gene variant studies in humans have shown that the CRHBP rs1875999 locus was associated with risk for both cocaine and heroin addiction in African Americans in a study of heroin addicts ( n = 314), cocaine addicts ( n = 281), and healthy controls ( n = 208) (Levran, Peles, et al, 2014; Levran, Randesi, et al, 2014).…”

Corticotropin-Releasing Factor (CRF) Neurocircuitry and Neuropharmacology in Alcohol Drinking

“…This suggests a unique functional neuroadaptation in the CeA following repeated binge cycles that may contribute to escalated alcohol use and maintenance of excessive binge-like alcohol intake. Similar to adolescents, repeated cycles of DID do not alter CRF-ir or CRF mRNA outside the CeA (i.e., in the BNST, BLA, MeA, NAc core and shell, lateral hypothalamus, or lateral septum; Ketchesin et al 2016; Lowery-Gionta et al 2012). Interestingly, the VTA exhibits transient increases in CRF and decreases in CRF-BP levels following acute binge cycles that normalize after repeated binge exposures (Ketchesin et al 2016; Lowery-Gionta et al 2012; Rinker et al 2017).…”

“…Similar to adolescents, repeated cycles of DID do not alter CRF-ir or CRF mRNA outside the CeA (i.e., in the BNST, BLA, MeA, NAc core and shell, lateral hypothalamus, or lateral septum; Ketchesin et al 2016; Lowery-Gionta et al 2012). Interestingly, the VTA exhibits transient increases in CRF and decreases in CRF-BP levels following acute binge cycles that normalize after repeated binge exposures (Ketchesin et al 2016; Lowery-Gionta et al 2012; Rinker et al 2017). More specifically, CRF mRNA and CRF-ir in VTA are increased following 1 cycle of DID, but CRF-ir normalizes after 6 cycles of DID (CRF mRNA was not measured after 6 cycles; Lowery-Gionta et al 2012; Rinker et al 2017).…”

“…This increase in CeA CRF-ir persists 18-24 hours post-binge, well after alcohol has been cleared from blood and brain (Lowery-Gionta et al 2012). This increase in CRF immunoreactivity may not be due to higher local CRF synthesis, as CRF mRNA was unchanged in the CeA 24 hours after the last of 3 DID cycles (Ketchesin et al 2016). Additionally, repeated bouts of binge-like alcohol drinking result in a reduction in the ability of CRF to enhance GABAergic transmission in the CeA (Lowery-Gionta et al 2012), which differs from alcohol dependence effects on CRF modulation of CeA GABAergic transmission (see below).…”