Review
Corticotropin-releasing factor receptors 1 and 2 in anxiety and depression

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Abstract

Corticotropin-releasing factor (CRF) and its related family members are implicated in stress-related disorders such as anxiety and depression. Recently, two new members of this neuropeptide family have been discovered in the brain: urocortin II (also known as stresscopin-related peptide) and urocortin III (also known as stresscopin). These urocortins are selective agonists for the CRF2 receptor, show a distinct neuroanatomical localization and are involved in stress-coping responses such as anxiolysis. Thus, CRF, the urocortins and their receptors form an intricate network in the brain involved in the acute phase as well as the recovery phase of the stress response.

Introduction

Anxiety and major depressive disorders are the most prominent stress-related psychiatric disorders and they impair the lives of approximately 10–15% of the population. For decades, the success of pharmacological treatment of these disorders has been dampened by various factors, including long latency of clinical effect, treatment resistance, adverse side effects, and, in the case of the anxiolytic benzodiazepines, tolerance and addictive potential. Although the themes of stress, anxiety and other stress-related disorders have been a topic of investigation continuously since the 1940s, anti-depressant and anxiolytic drugs that are currently prescribed stem from the 1950s and are based on pharma-cological interaction with the classic neurotransmitters.

In 1981 a new era began: corticotropin-releasing factor (CRF) was discovered as the principal mediator of the effects of stress on the hypothalamic-pituitary-adrenocortical axis (HPA axis) and behavior [1]. Not surprisingly, clinical studies soon demonstrated that this neuropeptide is implicated in depression and anxiety disorders 2., 3., 4., 5.. Basic research studies also presented evidence that elevated central CRF levels are involved in the etiology of stress-related physiological and behavioral disorders [6]. For the pharmacology field, the discovery of two CRF receptors and a non-receptor CRF-binding protein (CRFBP) was an immense breakthrough. With the recent discovery of more (endogenous) ligands beside CRF, the concept is dawning that CRF, its congeners and their receptors form an intricate network in the brain that potentially provides a variety of targets for drug intervention. In this review, we describe recent findings on the properties of CRF1 and CRF2 receptors and their ligands in the brain. Based on these exciting developments, we depict a new concept of the role of CRF1 and CRF2 receptors and their ligands in both the acute and recovery phase of the stress response. This concept is also presented as a framework for the pathophysiology of anxiety and major depressive disorders.

Section snippets

CRF and its receptors: a growing family

The CRF family of neuropeptides has undergone considerable expansion during recent times. Until recently, together with CRF, the family comprised structurally-related peptides including urocortin (Ucn) [7], fish urotensin I [8] and amphibian sauvagine [9]. The biological actions of CRF and Ucn are mediated via two types of G-protein-coupled receptors, CRF1 and CRF2, which have different expression patterns and physiological functions 10., 11., 12.. Two different splice variants of CRF2 have

Receptor distribution

As revealed by in situ hybridization histochemistry studies, CRF1 and CRF2 mRNA show a distinct but overlapping distribution in the brain (Fig. 1a; 12., 18., 19•., 20•.). CRF1 is widely distributed in central nervous system regions involved in sensory information processing and motor control, whereas CRF2 is virtually restricted to subcortical structures (Fig. 1a). Moderate levels of both receptors are expressed in the dorsal and median raphe nuclei, whereas only low levels are found in the

The role of CRF1 and CRF2 receptors in stress processes

During the past few years, many studies have been conducted to discern the roles of CRF1 and CRF2 receptors in stress-related physiological and behavioral processes to gain insight into anxiety and major depressive disorders. Various strategies have been employed, including pharmacological approaches, mutant mice with functional deletions in the receptors and antisense oligodeoxynucleotide technology. These investigations have provided insight into the complex roles of CRF1 and CRF2 in the

Conclusions and perspectives

Overall, the blueprint of an intricate network controlling the acute and the recovery phase of the stress coping response is being drawn up. Recent advances—for example, the identification of new members of the CRF neuropeptide family, elucidating the dual function of CRF1 and CRF2 receptors in anxiety and HPA regulation and the CRF–MR regulatory shunt in HPA axis control— have provided the cornerstones enabling a significant leap in our understanding of the wiring and timing of the stress

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

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