Update on corticotropin-releasing factor pharmacotherapy for psychiatric disorders: a revisionist view.
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ABSTRACT:
SUBMITTER: Koob GF
PROVIDER: S-EPMC3238086 | biostudies-literature | 2012 Jan
REPOSITORIES: biostudies-literature
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Update on corticotropin-releasing factor pharmacotherapy for psychiatric disorders: a revisionist view.
Koob George F GF Zorrilla Eric P EP
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 20120101 1
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Project description:This article is part of a Special Issue "SBN 2014". Stress is a potential etiology contributor to both post-traumatic stress disorders (PTSD) and major depression. One stress-related neuropeptide that is hypersecreted in these disorders is corticotropin releasing factor (CRF). Dysregulation of CRF has long been linked to the emotion and mood symptoms that characterize PTSD and depression. However, the idea that CRF also mediates the cognitive disruptions observed in patients with these disorders has received less attention. Here we review literature indicating that CRF can alter cognitive functions. Detailed are anatomical studies revealing that CRF is poised to modulate regions required for learning and memory. We also describe preclinical behavioral studies that demonstrate CRF's ability to alter fear conditioning, impair memory consolidation, and alter a number of executive functions, including attention and cognitive flexibility. The implications of these findings for the etiology and treatment of the cognitive impairments observed in stress-related psychiatric disorders are described.
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Project description:To maintain well-being, all organisms require the ability to re-establish homeostasis in the presence of adverse physiological or psychological experiences. The regulation of the hypothalamic-pituitary adrenal (HPA) axis during stress is important in preventing maladaptive responses that may increase susceptibility to affective disorders. Corticotropin-releasing hormone (CRH) is a central stress hormone in the HPA axis pathway and has been implicated in stress-induced psychiatric disorders, reproductive and cardiac function, as well as energy metabolism. In the context of psychiatric disorders, CRH dysfunction is associated with the occurrence of post-traumatic stress disorder, major depression, anorexia nervosa, and anxiety disorders. Here, we review the synthesis, molecular signaling and regulation, as well as synaptic activity of CRH. We go on to summarize studies of altered CRH signaling in mutant animal models. This assembled data demonstrate an important role for CRH in neuroendocrine, autonomic, and behavioral correlates of adaptation and maladaptation. Next, we present findings regarding human genetic polymorphisms in CRH pathway genes that are associated with stress and psychiatric disorders. Finally, we discuss a role for regulators of CRH activity as potential sites for therapeutic intervention aimed at treating maladaptive behaviors associated with stress.
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Project description:Drug addiction is a complex disorder that is characterized by compulsivity to seek and take the drug, loss of control in limiting intake of the drug, and emergence of a withdrawal syndrome in the absence of the drug. The transition from casual drug use to dependence is mediated by changes in reward and brain stress functions and has been linked to a shift from positive reinforcement to negative reinforcement. The recruitment of brain stress systems mediates the negative emotional state produced by dependence that drives drug seeking through negative reinforcement mechanisms, defined as the "dark side" of addiction. In this chapter we focus on behavioral and cellular neuropharmacological studies that have implicated brain stress systems (i.e., corticotropin-releasing factor [CRF]) in the transition to addiction and the predominant brain regions involved. We also discuss the implication of CRF recruitment in compulsive eating disorders.
| S-EPMC6155477 | biostudies-literature
Project description:Recent technical advances have greatly facilitated G-protein coupled receptors crystallography as evidenced by the number of successful x-ray structures that have been reported recently. These technical advances include novel detergents, specialised crystallography techniques as well as protein engineering solutions such as fusions and conformational thermostabilisation. Using conformational thermostabilisation, it is possible to generate variants of GPCRs that exhibit significantly increased stability in detergent micelles whilst preferentially occupying a single conformation. In this paper we describe for the first time the application of this technique to a member of a class B GPCR, the corticotropin releasing factor receptor 1 (CRF1R). Mutational screening in the presence of the inverse agonist, CP-376395, resulted in the identification of a construct with twelve point mutations that exhibited significantly increased thermal stability in a range of detergents. We further describe the subsequent construct engineering steps that eventually yielded a crystallisation-ready construct which recently led to the solution of the first x-ray structure of a class B receptor. Finally, we have used molecular dynamic simulation to provide structural insight into CRF1R instability as well as the stabilising effects of the mutants, which may be extended to other class B receptors considering the high degree of structural conservation.
| S-EPMC4498186 | biostudies-literature
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| S-EPMC2386996 | biostudies-literature
Project description:Corticotropin releasing factor (CRF) receptor antagonists have been sought since the stress-secreted peptide was isolated in 1981. Although evidence is mixed concerning the efficacy of CRF(1) antagonists as antidepressants, CRF(1) antagonists might be novel pharmacotherapies for anxiety and addiction. Progress in understanding the two-domain model of ligand-receptor interactions for CRF family receptors might yield chemically novel CRF(1) receptor antagonists, including peptide CRF(1) antagonists, antagonists with signal transduction selectivity and nonpeptide CRF(1) antagonists that act via the extracellular (rather than transmembrane) domains. Novel ligands that conform to the prevalent pharmacophore and exhibit drug-like pharmacokinetic properties have been identified. The therapeutic utility of CRF(1) antagonists should soon be clearer: several small molecules are currently in Phase II/III clinical trials for depression, anxiety and irritable bowel syndrome.
| S-EPMC2864802 | biostudies-literature
Project description:The central amygdala (CeA) is a critical regulator of emotional behavior that has been implicated in psychiatric illnesses, including anxiety disorders and addiction. The CeA corticotropin releasing factor receptor 1 (CRF1) system has been implicated in alcohol use disorder (AUD) and mood disorders, and has been shown to regulate anxiety-like behavior and alcohol consumption in rodents. However, the effects of CRF signaling within the CRF receptor 1-containing (CRF1+) population of the CeA remain unclear, and the effects of ethanol and CRF1 manipulations in female rodents have not been assessed. Here, we characterized inhibitory control and CRF1 signaling in male and female CRF1-GFP reporter mice. Male and female CRF1+ CeA neurons exhibited similar baseline GABAergic signaling and excitability and were comparably sensitive to CRF-induced increases in presynaptic GABA release. CRF1 antagonism reduced GABA release onto CRF1-containing neurons comparably in both males and females. Acute ethanol application reduced GABA release onto CRF1+ neurons from males, but female CRF1+ neurons were insensitive to ethanol. Exogenous CRF increased the firing rate of CRF1-containing neurons to a greater extent in male cells versus female cells, and CRF1 antagonism reduced firing in females but not males. Together, these findings indicate a critical sex-specific role for the CRF system in regulating inhibitory control and excitability of CRF1-containing neurons in the central amygdala. Sex differences in sensitivity of CRF/CRF1 signaling provide useful context for the sex differences in psychiatric illness reported in human patients, particularly AUD.
| S-EPMC8207535 | biostudies-literature
Project description:Disease-specific fluid biomarkers are in demand for parkinsonian syndromes (PS). Corticotropin-releasing hormone (CRH) was proposed as a biomarker for Lewy body disease. As such, this project aimed to confirm CRH as a potential biomarker for different PS. CRH and misfolded α-synuclein (αSyn) were measured in CSF. The primary cohort included Lewy body disease patients (i.e. Parkinson's disease or dementia with Lewy bodies, n = 77), atypical PS (n = 37) and non-parkinsonian neurodegenerative diseases (n = 164), as well as controls (n = 354). A replication cohort included Lewy body disease (n = 27), atypical PS (n = 58) and controls (n = 58). CRH was downregulated in αSyn positive Lewy body disease, αSyn positive controls and in all atypical PS compared with αSyn negative controls (P = 3.3e-05, P = 3.1e-10, P = 2.9e-03). CRH was also decreased in αSyn positive Lewy body disease compared with αSyn negative non-PS (P = 2e-03) and correlated with cognitive impairment and inflammation in αSyn positive Lewy body disease. We show that CRH is a promising biomarker for Lewy body disease and atypical PS and its association with inflammation and cognitive decline. Reductions in CRH in Lewy body disease and other PS suggest this decrease may relate to dopaminergic degeneration instead of αSyn pathology.
| S-EPMC11601160 | biostudies-literature
Project description:Background and aimsLoss of the endotoxin tolerance of intestinal epithelium contributes to a number of intestinal diseases. The etiology is not clear. Psychological stress is proposed to compromise the intestinal barrier function. The present study aims to elucidate the role of the stress-derived corticotropin releasing factor (CRF) in breaching the established intestinal epithelial endotoxin tolerance.MethodsEpithelial cells of HT-29, T84 and MDCK were exposed to lipopolysaccharide to induce the endotoxin tolerance; the cells were then stimulated with CRF. The epithelial barrier function was determined using as indicators of the endotoxin tolerant status. A water-avoid stress mouse model was employed to test the role of CRF in breaching the established endotoxin tolerance in the intestine.ResultsThe established endotoxin tolerance in the epithelial cell monolayers was broken down by a sequent exposure to CRF and LPS manifesting a marked drop of the transepithelial resistance (TER) and an increase in the permeability to a macromolecular tracer, horseradish peroxidase (HRP). The exposure to CRF also increased the expression of Cldn2 in the epithelial cells, which could be mimicked by over expression of TLR4 in epithelial cells. Over expression of Cldn2 resulted in low TER in epithelial monolayers and high permeability to HRP. After treating mice with the 10-day chronic stress, the intestinal epithelial barrier function was markedly compromised, which could be prevented by blocking either CRF, or TLR4, or Cldn2.ConclusionsPsychological stress-derived CRF can breach the established endotoxin tolerance in the intestinal mucosa.
| S-EPMC3686760 | biostudies-literature