The identification of CRF receptor subtypes
The identification of CRF FLAG Peptide 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 , , , , .
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 or explicitly induced stress will be called spontaneous anxiety. Examples of spontaneous anxiety tests include the elevated plus maze, the defensive-withdrawal test, the open field, and light–dark test. Behavioral responses exhibited in tests involving unambiguous exposure to a stressor or its effects will be called stress-induced anxiety. For example, protocols involving electric foot shock, social defeat, or swim stress are typically used to induce an anxiogenic state prior to behavioral testing. In addition to these two general types of test procedures, some investigators have examined whether CRF receptor manipulations are effective in reversing the putative anxiety-stimulating effects of exogenous CRF. In reviewing the literature, it is apparent that three major methodological approaches are used to evaluate the behavioral effects induced by targeted receptor alterations. These methods include knockout procedures, antisense oligonucleotide strategies, and administration of specific CRF receptor antagonists. Advantages and limitations associated with these methods have been discussed previously (e.g. , , ).
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 predominant role under conditions involving pronounced stress when CRF neuropeptides are likely to be released. Although the consistent anxiolytic-like profile of knockout mice tested in models of spontaneous anxiety suggests otherwise, it is possible that the CRF1 knockout mouse has an emotional demeanor not altogether different from rats dosed chronically with a CRF1 antagonist or the low anxiety bred rat. It is also possible that mice are more sensitive to the stimulating anxiogenic effects of endogenous CRF as indicated by reports of anxiolytic-like responsiveness in the light–dark box and free-exploration test after acute CRF1 antagonist treatment. To date, CRF1 antisense oligonucleotide studies provide a mix of behavioral results suggesting that CRF1 knockdown is associated with spontaneous and stress-induced anxiety. In addition, CRF1 antisense treatments appear to reverse the anxiety provoking effects of exogenous CRF administration. A measurable reduction in CRF1 mRNA using the antisense oligonucleotide approach in conjunction with a consistent reduction in anxiety behavior would strengthen the hypothesis that stress-induced states are mediated by the CRF1 receptor. At present, it is unclear whether the behavioral inconsistencies noted among studies using anti-Svg-30, the CRF2 antagonist, represent a species effect, a dose effect, a delivery effect, or even a laboratory testing effect . However, it is notable that on the basis of limited work in rats using potent CRF2 antisense oligonucleotides and dose–response studies using anti-Svg-30, CRF2 receptors appear to be involved in the expression of both stress-induced and spontaneous anxiety behavior. This reported involvement of CRF2 receptors in emotional expression raises questions concerning the specificity of the CRF1 receptor in playing a unique role in anxiety and stress-induced behavior. Studies using specific CRF2 agonists , , in combination with specific CRF2 antagonists may provide further insights into the role of CRF2 systems and anxiety behavior.