The Corticotropin Releasing Factor Receptor 1 in Alcohol Use Disorder: Still a Valid Drug Target?

Pomrenze, Matthew B.; Fetterly, Tracy L.; Winder, Danny G.; Messing, Robert O.

doi:10.1111/acer.13507

Cited by 38 publications

(33 citation statements)

References 194 publications

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“…There are several recent reviews from 2016-2018 providing the details of other important stress responsive systems (like Corticotrophin Releasing Factor, Neuropeptide Y, and glucocorticoid receptor, etc.) from preclinical evidence to the recent clinical trials [Koob and Mason, 2016;Mantsch et al, 2016;Blaine and Sinha, 2017;Mason, 2017;Robinson and Thiele, 2017;Spierling and Zorrilla, 2017;Tunstall et al, 2017;Pomrenze et al, 2017]. The main focus in this mini-review is several other important stress responsive systems, which recently has not been reviewed, like arginine vasopressin/V1b receptors (Part I), and proopiomelanocortin/β-endorphin (Part II).…”

Section: Introductionmentioning

confidence: 99%

Involvement of Activated Brain Stress Responsive Systems in Excessive and “Relapse” Alcohol Drinking in Rodent Models: Implications for Therapeutics

Zhou

Kreek

2018

J Pharmacol Exp Ther

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Addiction to specific drugs (such as alcohol, psychostimulants and opioids) shares some common direct or downstream effects on the brain stress-responsive systems, including arginine vasopressin and its V1b receptors, dynorphin and the kappa opioid receptors, proopiomelanocortin/β-endorphin and the mu opioid receptors, and the endocannabinoids. Further study of these systems, through laboratory-based and translational research, could lead to the discovery of novel treatment targets and the early optimization of interventions (for example, combination) for the pharmacological therapy of alcoholism.

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Section: Introductionmentioning

confidence: 99%

Involvement of Activated Brain Stress Responsive Systems in Excessive and “Relapse” Alcohol Drinking in Rodent Models: Implications for Therapeutics

Zhou

Kreek

2018

J Pharmacol Exp Ther

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“…Despite this single, well-validated target, no drug nor therapeutic options have been developed as treatments. One example of this for AUD is the corticotrophin releasing factor (CRF) system, which has tremendous research support for its involvement in AUD pathology, yet CRF inhibitors have produced disappointing results in double-blind, placebo controlled trials (Kwako et al 2015; Pomrenze et al 2017; Schwandt et al 2016). …”

Section: Traditional Approachmentioning

confidence: 99%

“…There are a number of possible reasons for this, including genetically heterogeneous human populations and the complexities of alcohol’s many targets (Most et al 2014; Pomrenze et al 2017). The brain is highly complex, and psychiatric diseases are characterized by numerous symptoms.…”

Section: Traditional Approachmentioning

confidence: 99%

From gene networks to drugs: systems pharmacology approaches for AUD

2018

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The alcohol research field has amassed an impressive number of gene expression datasets spanning key brain areas for addiction, species (humans as well as multiple animal models), and stages in the addiction cycle (binge/intoxication, withdrawal/negative effect, and preoccupation/anticipation). These data have improved our understanding of the molecular adaptations that eventually lead to dysregulation of brain function and the chronic, relapsing disorder of addiction. Identification of new medications to treat alcohol use disorder (AUD) will likely benefit from the integration of genetic, genomic, and behavioral information included in these important datasets. Systems pharmacology considers drug effects as the outcome of the complex network of interactions a drug has rather than a single drug-molecule interaction. Computational strategies based on this principle that integrate gene expression signatures of pharmaceuticals and disease states have shown promise for identifying treatments that ameliorate disease symptoms (called in silico gene mapping or connectivity mapping). In this review, we suggest that gene expression profiling for in silico mapping is critical to improve drug repurposing and discovery for AUD and other psychiatric illnesses. We highlight studies that successfully apply gene mapping computational approaches to identify or repurpose pharmaceutical treatments for psychiatric illnesses. Furthermore, we address important challenges that must be overcome to maximize the potential of these strategies to translate to the clinic and improve healthcare outcomes.

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“…Results from both clinic and preclinical studies have showed profound alterations of stress responsive systems after chronic alcohol abuse. Specifically, alcohol has direct or downstream effects on several hypothalamic stress‐responsive systems, including arginine vasopressin (AVP), oxytocin, corticotrophin releasing hormone (CRH) and their receptors, dynorphin and the kappa opioid receptors (KOP‐r) . The studies in both humans and rodents also provide clear support for the importance of these stress responsive systems in the process of alcohol consumption with strong interactions with hypothalamic‐pituitary‐adrenal (HPA) hormones and their receptors (eg, glucocorticoid receptors), especially after stress .…”

Section: Introductionmentioning

confidence: 99%

Nuclear transcriptional changes in hypothalamus of Pomc enhancer knockout mice after excessive alcohol drinking

Zhou

Liang

Low

et al. 2019

Genes Brain and Behavior

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Persistent alterations of proopiomelanocortin (Pomc) and mu‐opioid receptor (Oprm1) activity and stress responses after alcohol are critically involved in vulnerability to alcohol dependency. Gene transcriptional regulation altered by alcohol may play important roles. Mice with genome‐wide deletion of neuronal Pomc enhancer1 (nPE1−/−), had hypothalamic‐specific partial reductions of beta‐endorphin and displayed lower alcohol consumption, compared to wildtype littermates (nPE1+/+). We used RNA‐Seq to measure steady‐state nuclear mRNA transcripts of opioid and stress genes in hypothalamus of nPE1+/+ and nPE1−/− mice after 1‐day acute withdrawal from chronic excessive alcohol drinking or after water. nPE1−/− had lower basal Pomc and Pdyn (prodynorphin) levels compared to nPE1+/+, coupled with increased basal Oprm1 and Oprk1 (kappa‐opioid receptor) levels, and low alcohol drinking increased Pomc and Pdyn to the basal levels of nPE1+/+ in the water group, without significant effects on Oprm1 and Oprk1. In nPE1+/+, excessive alcohol intake increased Pomc and Oprm1, with no effect on Pdyn or Oprk1. For stress genes, nPE1−/− had lowered basal Oxt (oxytocin) and Avp (arginine vasopressin) that were restored by low alcohol intake to basal levels of nPE1+/+. In nPE1+/+, excessive alcohol intake decreased Oxt and Avpi1 (AVP‐induced protein1). Functionally examining the effect of pharmacological blockade of mu‐opioid receptor, we found that naltrexone reduced excessive alcohol intake in nPE1+/+, but not nPE1−/−. Our results provide evidence relevant to the transcriptional profiling of the critical genes in mouse hypothalamus: enhanced opioid and reduced stress gene transcripts after acute withdrawal from excessive alcohol may contribute to altered reward and stress responses.

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The Corticotropin Releasing Factor Receptor 1 in Alcohol Use Disorder: Still a Valid Drug Target?

Cited by 38 publications

References 194 publications

Involvement of Activated Brain Stress Responsive Systems in Excessive and “Relapse” Alcohol Drinking in Rodent Models: Implications for Therapeutics

Involvement of Activated Brain Stress Responsive Systems in Excessive and “Relapse” Alcohol Drinking in Rodent Models: Implications for Therapeutics

From gene networks to drugs: systems pharmacology approaches for AUD

Nuclear transcriptional changes in hypothalamus of Pomc enhancer knockout mice after excessive alcohol drinking

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