Role of CRF1 and CRF2 receptors in fear and anxiety

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. (C) 2002 Elsevier Science Ltd. All rights reserved.