Trends in Pharmacological Sciences
ReviewThe CRF System as a Therapeutic Target for Neuropsychiatric Disorders
Section snippets
The CRF System as a Novel Target for Treating Neuropsychiatric Disorders
Several neuropsychiatric disorders are severe and chronic conditions that are challenging to treat [1]. Most of the medications used to treat these conditions act on monoamine systems, a paradigm of drug action that has not changed in half a century. The less-than-optimal efficacy of these medications suggests the need for innovative new approaches that depart from the conventional drug development approaches [2]. Advances in basic neurobiology indicate CRF signaling as a target for
The CRF System
In 1981 Wylie Vale and colleagues at the Salk Institute in La Jolla, CA first reported the biochemical characterization of CRF [13]. Subsequent studies found CRF mRNA and CRF to be broadly distributed in the central nervous system (CNS) and enriched in the paraventricular nucleus of the hypothalamus (PVN), brain stem, amygdala, hippocampus and, neocortex [4]. On being released from neurons, CRF binds mainly to two seven-transmembrane G protein-coupled receptors with high sequence homology (∼70%
CRF in Psychopathology: From Bench to Bedside
Abnormalities in the CRF system are implicated in a gamut of psychiatric disorders 5, 6, 31, 32. Here we discuss data from patients affected by major categories of mental illness as classified in the most recent version of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) [33]. In parallel, we also examine preclinical studies seeking to dissect the significance of these CRF abnormalities in brain function. We further review the results of clinical trials that have tested CRF1
Concluding Remarks and Future Perspectives
In conclusion, these data strongly support the hypothesis of altered CRF signaling in the etiology of mood disorders, trauma- and stress-related disorders, and substance-related and addictive disorders 34, 51, 52, 57. These data reveal a more complex association between CRF and anxiety disorders, where interactions with other neuromodulatory systems are likely to mediate its role 71, 72.
In agreement with early clinical studies 5, 12, preclinical research suggests that excessive CRF receptor
Acknowledgments
This work was primarily supported by the National Institute of Mental Health (K08 MH 105754-01).
Glossary
- Antagonist
- a compound that blocks a drug from binding to a receptor.
- Basolateral amygdala (BLA)
- a division of the amygdala that is commonly involved in the expression of fear and anxiety.
- Bed nucleus of stria terminalis (BNST)
- a brain structure that is involved in anxiety and reward. It is commonly involved in drug-seeking behavior in rodents.
- Behavioral despair
- immobile responses that animals make when they are forced to swim in a container from which they cannot escape.
- Post-traumatic stress disorder
References (80)
Behavioral, biological, and chemical perspectives on targeting CRF1 receptor antagonists to treat alcoholism
Drug Alcohol Depend.
(2013)Control of stress-induced persistent anxiety by an extra-amygdala septohypothalamic circuit
Cell
(2014)Corticotropin-releasing factor in posttraumatic stress disorder (PTSD) with secondary psychotic symptoms, nonpsychotic PTSD, and healthy control subjects
Biol. Psychiatry
(2003)Structural domains determining signalling characteristics of the CRH-receptor type 1 variant R1β and response to PKC phosphorylation
Cell. Signal.
(2008)Stress-induced redistribution of corticotropin-releasing factor receptor subtypes in the dorsal raphe nucleus
Biol. Psychiatry
(2009)Tonic modulation of anxiety-like behavior by corticotropin-releasing factor (CRF) type 1 receptor (CRF1) within the medial prefrontal cortex (mPFC) in male mice: role of protein kinase A (PKA)
Horm. Behav.
(2014)Overexpression of corticotropin-releasing factor receptor type 2 in the bed nucleus of stria terminalis improves posttraumatic stress disorder-like symptoms in a model of incubation of fear
Biol. Psychiatry
(2013)Prereproductive stress to female rats alters corticotropin releasing factor type 1 expression in ova and behavior and brain corticotropin releasing factor type 1 expression in offspring
Biol. Psychiatry
(2013)Desensitization of human CRF2(a) receptor signaling governed by agonist potency and βarrestin2 recruitment
Regul. Pept.
(2013)Role of cystic fibrosis transmembrane conductance regulator-associated ligand (CAL) in regulating the trafficking and signaling of corticotropin-releasing factor receptor 1
Cell. Signal.
(2015)