Defining the role of corticotropin releasing factor binding protein in alcohol consumption

Abstract

The corticotropin releasing factor (CRF) exerts its effects by acting on its receptors and on the binding protein (CRFBP), and has been implicated in alcohol use disorder (AUD). Therefore, identification of the exact contribution of each protein that mediates CRF effects is necessary to design effective therapeutic strategies for AUD. A series of in vitro/in vivo experiments across different species were performed to define the biological discrete role of CRFBP in AUD. First, to establish the CRFBP role in receptor signaling, we developed a novel chimeric cell-based assay and showed that CFRBP full length can stably be expressed on the plasma membrane. We discovered that only CRFBP(10 kD) fragment is able to potentiate CRF-intracellular Ca2+ release. We provide evidence that CRHBP gene loss increased ethanol consumption in mice. Then, we demonstrate that selective reduction of CRHBP expression in the center nucleus of the amygdala (CeA) decreases ethanol consumption in ethanol-dependent rats. CRFBP amygdalar downregulation, however, does not attenuate yohimbine-induced ethanol self-administration. This effect was associated with decreased hemodynamic brain activity in the CRFBP-downregulated CeA and increased hemodynamic activity in the caudate putamen during yohimbine administration. Finally, in alcohol-dependent patients, genetic variants related to the CRFBP(10 kD) fragment were associated with greater risk for alcoholism and anxiety, while other genetic variants were associated with reduced risk for anxiety. Taken together, our data provide evidence that CRFBP may possess both inhibitory and excitatory roles and may represent a novel pharmacological target for the treatment of AUD.

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).…”

“…SNPs in the CRHBP (10kD) fragment, rs10055255, rs10062367 , and rs7728378 were each shown to be associated with increased risk of alcohol drinking and/or anxiety in patients with alcohol use disorder (Haass-Koffler et al 2016). …”

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).…”

“…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). SNPs in the CRHBP (10kD) fragment, rs10055255, rs10062367 , and rs7728378 were each associated with increased risk of alcohol drinking and/or anxiety in patients with alcohol use disorder (Haass-Koffler et al, 2016). …”

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

“…Indeed, compared to rodents, where there is limited CRFR2 expression in the CeA (Van Pett et al 2000), primates express high density of CRFR2 in the CeA (Sanchez et al 1999), although the functional relevance of this has not yet been determined. CRFBP in rodents was recently shown to interact with CRFR2 in the VTA to influence binge-like alcohol drinking (Haass-Koffler et al 2016). Therefore, a deeper understanding of the relationship between alcohol and brain CRF system plasticity and signaling, especially CRFR2 signaling and CRF-BP, may be necessary to effectively leverage the brain CRF system as a therapeutic target for reducing excessive alcohol drinking and negative affect in at least a subset of humans living with AUD.…”