Role of CRF1 and CRF2 receptors in fear and anxiety

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Abstract

Fear and anxiety are common emotions that can be triggered by stress. This paper reviews the work examining the role played by specific corticotropin-releasing factor (CRF) receptors in mediating the expression of these emotions. Several lines of evidence taken from CRF1 transgenic knockout mice, CRF1 antisense oligonucleotide studies, and CRF1 receptor antagonist work suggest that the anxiety inducing effects of CRF are mediated by the CRF1 receptor. Of these three methodological approaches, the work using transgenic CRF1 knockout mice appears to be the most consistent. In contrast, the work using specific CRF1 antagonists has produced somewhat varied results that may be explained, in part, by the testing method. When animals are stressed prior to behavioral testing, CRF1 receptor antagonists appear to have anxiolytic-like effects. In addition, chronic dosing with CRF1 antagonists may have more potent anxiolytic-like effects, especially in animal models of spontaneous anxiety, than acute dosing procedures. Spontaneous anxiety is defined as behavior that is elicited entirely by the testing situation without current or prior aversive or explicitly induced stress. CRF1 antisense oligonucleotide work is difficult to interpret because of potential toxicological side effects produced by the antisense oligonucleotide and, in some cases, the absence of verifiable reductions in CRF1 receptor densities after treatment. Similar methods—CRF2 knockouts, CRF2 antisense oligonucleotides, and CRF2 antagonists—were used to evaluate the function of CRF2 receptors in emotionality. In comparison to the large number of CRF1 receptor studies, fewer CRF2 receptor investigations have been conducted and these studies have yielded mixed results. However, recent work demonstrating a robust reduction in CRF2 receptors using a CRF2 antisense oligonucleotide with minimal toxicity, and dose response studies using a peptide CRF2 antagonist suggest that CRF2 receptors play a role in stress-induced and spontaneous anxiety. Furthermore, inhibiting the actions of both CRF1 and CRF2 receptors produces a greater reduction in stress-induced behavior than inhibition of either receptor alone. Thus, current data suggest that CRF1 and CRF2 receptors are involved in the mediation of fear and anxiety behavior.

Introduction

Exposure to excessive or uncontrollable stress is a major factor associated with a variety of illnesses including psychopathology. Psychosocial stressors may trigger mood disorders or exacerbate the symptoms of schizophrenia as well as contributing to its relapse [1], [2], [3]. In early life, exposure to stress may increase the risk of developing behavioral problems and may sensitize the young to stressors elevating the risk for stress-induced psychopathology [4], [5]. As a result, there is an intense effort to identify and unravel the key systems responsible for mediating the body's response to stress [6].

One system that has attracted considerable attention in the last two decades involves corticotropin-releasing factor (CRF). This 41-amino acid peptide is hypothesized to play an essential role in coordinating endocrine, autonomic, immune, and behavioral responses to stress [7], [8], [9], [10], [11]. CRF and urocortin, a CRF-like peptide, are widely distributed throughout the mammalian brain [12], [13], [14], [15], [16]. These peptides exert their biological actions via two major G protein-coupled seven-transmembrane domain receptor subtypes known as CRF1[17], [18], [19] and CRF2[20], [21]. The CRF2 receptor has α- and β-splice variants. In addition, a CRF2γ receptor is found in human brain [22]. Studies demonstrate that CRF1 and CRF2 receptors have distinct pharmacological profiles and unique distribution patterns in brain and peripheral tissues [23], [24]. For example, in the rat, high densities of CRF1 receptors are found in the pituitary, brain stem, cerebellum, amygdala, and cortex whereas CRF receptors are found predominantly in the lateral septum, ventromedial hypothalamus, and olfactory bulb [25], [26]. A somewhat similar receptor distribution pattern is found in the rhesus monkey brain with the exception of increased densities of CRF2 receptors in the brain regions including the neocortex, amygdala, and hippocampal formation [27]. CRF receptors occur in nonneuronal cells of the brain such as the choroid plexis and in peripheral tissue including the heart, lung, and skeletal muscle [21], [25], [28]. In addition to CRF1 and CRF2 receptors, CRF and urocortin also bind to a CRF-binding protein [29].

The identification of CRF receptor subtypes has led to a number of studies addressing its functional properties. This paper examines the evidence for CRF1 and CRF2 mediation of fear and anxiety. Recent reviews discussing specific CRF receptor functions associated with other conditions including eating, gastrointestinal distress, substance abuse, and immunomodulation can be found elsewhere [30], [31], [32], [33], [34].

Section snippets

Animal testing methods

To evaluate alterations in fear and anxiety, various animal tests that generally involve psychological conflict are used to determine the unique contributions of CRF1 and CRF2 receptors. An important issue in interpreting the role of specific CRF receptors in emotional behavior is whether or not the animals were exposed to a form of stress prior to conflict testing. Therefore, to clarify this issue, emotional behavior elicited entirely by the testing situation without current or prior aversive

CRF1 receptor knockout studies

Three studies reported that mice lacking the CRF1 receptor exhibited behavior suggestive of reduced anxiety (Table 1). In four different tests of spontaneous anxiety—open-field, light–dark box, defensive-withdrawal, elevated plus maze—which normally inhibits behavioral activity, mutant mice consistently exhibited elevated levels of locomotion consistent with an anxiolytic-like profile [38], [39], [40]. In these studies, analyses were also conducted to determine whether there was a general

CRF2 receptor knockout studies

Unlike the reduction in anxiety behavior generally reported in CRF1 knockout animals, CRF2 deficient mice do not show a consistent change in anxiety behavior (Table 3). One study reported that CRF2 deficiency produced no significant effects on anxiety responses in the elevated plus maze or in an open field test [65]. In another study, CRF2 knockout mice showed no behavioral alterations in the light–dark test but appeared to exhibit increased anxiety in the elevated plus maze and open field test

Summary

Experiments focusing on the CRF1 receptor have produced data that generally support its role in emotional behavior. In studies using CRF1 antagonists, the bulk of the evidence suggests that various CRF1 antagonists have prominent effects in normalizing stress-induced anxiety and lesser or variable effects on spontaneous anxiety behavior. In addition, CRF1 antagonists appear effective in reversing the anxiety producing effects of exogenous CRF. Hence, CRF1 receptors may begin to have a

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