Role of CRF1 and CRF2 receptors in fear and anxiety
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 CRF2α 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]. CRF2β 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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