Is It Really a Matter of Simple Dualism? Corticotropin-Releasing Factor Receptors in Body and Mental Health

Abstract

Physiological responses to stress coordinated by the hypothalamo-pituitary-adrenal axis are concerned with maintaining homeostasis in the presence of real or perceived challenges. Regulators of this axis are corticotrophin releasing factor (CRF) and CRF related neuropeptides, including urocortins 1, 2, and 3. They mediate their actions by binding to CRF receptors (CRFR) 1 and 2, which are located in several stress-related brain regions. The prevailing theory has been that the initiation of and the recovery from an elicited stress response is coordinated by two elements, viz. the (mainly) opposing, but well balanced actions of CRFR1 and CRFR2. Such a dualistic view suggests that CRF/CRFR1 controls the initiation of, and urocortins/CRFR2 mediate the recovery from stress to maintain body and mental health. Consequently, failed adaptation to stress can lead to neuropathology, including anxiety and depression. Recent literature, however, challenges such dualistic and complementary actions of CRFR1 and CRFR2, and suggests that stress recruits CRF system components in a brain area and neuron specific manner to promote adaptation as conditions dictate.

The effects of neuropeptide urocortin 2 on the spontaneous discharge and glutamatergic neurotransmission of striatum neurons

“…Regulators of this axis were CRF and CRF related neuropeptides, including UCNs 1, 2, and 3. They mediated their actions by binding to CRF R1 and CRF R2, which were located in several stress-related brain regions (Janssen and Kozicz, 2013). Based on data obtained in animal studies, neuropeptides and their receptors might be targeted by new candidate neuropharmacons with the hope that they will become important and effective tools in the management of stress related mood disorders (Kormos and Gaszner, 2013).…”

Preclinical evidence implicating corticotropin‐releasing factor signaling in ethanol consumption and neuroadaptation

“…2006; Hauger et al . 2006; Janssen & Kozicz 2013). The roles of CRF 1 and CRF 2 in behavior have also been interpreted with regard to their involvement in responses to (real or perceived) escapable vs. inescapable stressors.…”

MOLECULAR EVOLUTION OF GPCRS: CRH/CRH receptors

“…Generally, CRH receptors are associated with the homoeostatic actions on cells and organisms with respect to energy metabolism and the associated diuretic requirements in response to stressful challenges (Chen et al 2003, Lovejoy 2012, Janssen & Kozicz 2013, Lovejoy & De Lannoy 2013. Fundamentally, the CRH peptide and receptor system is associated with sympathetic arousal in vertebrates.…”

“…At a clinical level, considerable evidence indicates that chronically elevated levels of CRH in the CNS play a significant role in the aetiology of a number of affective and neurological disorders, thus there has been much interest in understanding the regulatory mechanisms of the CRH receptors. This has been reviewed in detail by a number of authors (Dunn & Berridge 1990, Mitchell 1998, Hauger et al 2006, Rotzinger et al 2010, Janssen & Kozicz 2013. In clinical and mammalian model systems, both receptor systems are implicated in different elements of stress-associated pathologies.…”

“…Thus, these theories of the actions of the CRH receptors are consistent with our classical understanding of the regulation of the stress response. However, Janssen & Kozicz (2013) have recently challenged this view of the respective actions of the receptors, while respecting Selye's (1950) original hypothesis. They have argued that stressful stimuli impinge upon regions of the brain to activate particular neurotransmitter-specific regions (glutamate, GABA, dopamine and 5-HT) depending upon the specific challenge leading to an appropriate stress-associated response that may be mitigated by either CRH1 or CRH2 receptors.…”