Anxiety corticotropin-releasing hormone

CRH (Corticotropin releasing hormone) is expressed in the nucleus paraventricularis of the hypothalamus and drives the stress hormone system by activating synthesis and release of corticotropin at the pituitary and in turn corticosteroid from the adrenal cortex. CRH is also expressed at many other brain locations not involved in neuroendocrine regulation, e.g. the prefrontal cortex and the amygdala. Preclinical studies have shown that CRH also coordinates the behavioral adaptation to stress (e.g. anxiety, loss of appetite, decreased sleepiness, autonomic changes, loss of libido). 

Several neuropeptides are under current investigation for their role in anxiety disorders. Important neuropeptides include neuropeptide Y (NPY), substance P, and cholecystokinin. NPY appears to have a role in reducing the effect of stress hormones and inhibiting activity of the LC. Both mechanisms may contribute to the anxiolytic properties seen experimentally. Substance P may have anxiolytic and antidepressant properties. This may be due in part to its effects on corticotropin-releasing hormone.21... 

Holsboer F (1999) The rationale for corticotropin-releasing hormone receptor (CRH-R) antagonists to treat depression and anxiety. J Psychiatr Res 33 181-214... 

Bale TL, Contarino A, Smith GW, Chan R, Gold LH, Sawchenko PE, Koob GF, Vale WW, Lee KF (2000) Mice deficient for corticotropin-releasing hormone receptor-2 display anxiety-like behaviour and are hypersensitive to stress. Nat Genet 24 410-414 Bale TL, Picetti R, Contarino A, Koob GF, Vale WW, Lee KF (2002) Mice deficient for both corticotropin-releasing factor receptor 1 (CRFRl) and CRFR2 have an impaired stress response and display dichotomous anxiety-like behavior. J Neurosci 22 193-199 Barberis C, Tribollet M (1996) Vasopressin and oxytocin receptors in the central nervous system. Grit RevNeurobiol 10 119-154... 

Muller MB, Zimmermann S, SiUaber I, Hagemeyer TP, Deussing JM, Timpl P, et al (2003) Limbic corticotropin-releasing hormone receptor 1 mediates anxiety-related behaviour and is required for hormonal adaptation to stress. Nat Neimosci 6 1100-1107 MuUer U (1999) Ten years of gene targeting targeted mouse mutants, from vector design to phenotype analysis. Mech Dev 82 3-21... 

Skutella T, Probst JC, Renner U, Holsboer F, Behl C (1998) Corticotropin-releasing hormone receptor (type 1) antisense targeting reduces anxiety. Neuroscience 85 795-805... 

Timpl P, Spanagel R, SUlaber I, Kresse A, Reul JMHM, Stalla GK, Blanquet V, Sleekier T, Holsboer F, Wimst W (1998) Impaired stress response and reduced anxiety in mice lacking a fimctional corticotropin-releasing hormone receptor 1. Nat Genet 19 162-166... 

Interactions Between Corticotropin-Releasing Hormone and Serotonin Implications for the Aetiology and Treatment of Anxiety Disorders... 

Ressler KJ, Nemeroff CB (2000) Role of serotonergic and noradrenergic systems in the pathophysiology of depression and anxiety disorders. Depress Anxiety 12 2-19 Reul JMHM, Holsboer F (2002) Corticotropin-releasing hormone receptors 1 and 2 in anxiety and depression. Curr Opin Pharmacol 2 23-33 Rex A, Marsden CA, Fink H (1993) 5-HTlA receptors and changes in extracellular 5-HT in the guinea-pigprefrontal cortex—involvementin aversive behaviour. J Psychopharmacol 7 338-345... 

Skutella T, Montkowski A, Stohr T, Probst JC, Landgraf R, Holsboer F, Jirikowski GF (1994) Corticotropin-releasing hormone oligodeoxynucleotide treatment attenuates social defeat-induced anxiety in rats. Cell Mol Neurobiol 14 579-588 Skutella T, Probst JC, Renner U, Holsboer F, Behl C (1998) Corticotropin-releasing hormone receptor (type I) antisense targeting reduces anxiety. Neuroscience 85 795-805... 

Effects of early environmental adversity on HPA mediation of neurodevelopment have also been demonstrated in non-human primates (Coplan et al., 1995). Corticotropin-releasing hormone (CRH) intracerebro-ventricular administration in rhesus monkeys that had been separated from their mothers produced behavioral inhibition and increases in ACTH and cortisol. Coplan et al (1995) presented evidence for persistently elevated cerebrospinal fluid concentrations of corticotropin-releasing factor (CRF) in grown macaques that had been reared by mothers in unpredictable environmental conditions. Further studies in adversely reared adult monkeys demonstrated an inverse relationship between mean CRF concentrations and GH response to clonidine (Coplan et al., 2000). In light of evidence that reduced GH response to clonidine has been shown in other anxiety disorders (Charney and Bremner, 1999), Coplan et al. (2000) hypothesize that GH response to clonidine may inversely reflect trait-like increases of central nervous system CRF activity. Data linking childhood anxiety to growth deficits are consistent with this view (Pine et al., 1996). Activity, of the HPA axis, as related to early environmental... 

FICURE 1-1. Intracerebral infusion of antisense oligonucleotides (AS-ODN) that were targeted to the cloned CRH, and CRH2 receptor mRNA prevent translation into the receptor protein. Only a knock-down of the CRH, receptor, but not of the CRH2 receptor, reduces anxiety-related behavior in rats that were exposed to the elevated plus-maze test after central corticotropin-releasing hormone (CRH) administration. P <. 05, P <. 01. 

Patchev VK, Shoaib M, Holsboer F, et al The neurosteroid tetrahydroprogesterone counteracts corticotropin-releasing hormone-induced anxiety and alters the release and gene expression of corticotropin-releasing hormone in the rat hypothalamus. Neuroscience 62 265-271, 1994... 

Based on a new substantial body of pharmacological and clinical evidence, it is anticipated that the modulation of the effects of corticotropin releasing hormone or factor (CRH or CRF) may eventually play a role in the treatment of depression or anxiety-related disorders. This interest in CRH as a new important target for drug discovery is clearly evident. Recently Gilligan et al. [74] have observed that the Suzuki reaction can be used to synthesize a variety of aryl-substituted heterocyclic antagonists of the CRH receptor (Eq. (43)). 

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