Takahashi L K
Department of Psychology, University of Hawaii, 2430 Campus Road, Honolulu, HI 96822-2216, USA.
Neurosci Biobehav Rev. 2001 Dec;25(7-8):627-36. doi: 10.1016/s0149-7634(01)00046-x.
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 CRF(1) transgenic knockout mice, CRF(1) antisense oligonucleotide studies, and CRF(1) receptor antagonist work suggest that the anxiety inducing effects of CRF are mediated by the CRF(1) receptor. Of these three methodological approaches, the work using transgenic CRF(1) knockout mice appears to be the most consistent. In contrast, the work using specific CRF(1) antagonists has produced somewhat varied results that may be explained, in part, by the testing method. When animals are stressed prior to behavioral testing, CRF(1) receptor antagonists appear to have anxiolytic-like effects. In addition, chronic dosing with CRF(1) 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. CRF(1) 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 CRF(1) receptor densities after treatment. Similar methods-CRF(2) knockouts, CRF(2) antisense oligonucleotides, and CRF(2) antagonists-were used to evaluate the function of CRF(2) receptors in emotionality. In comparison to the large number of CRF(1) receptor studies, fewer CRF(2) receptor investigations have been conducted and these studies have yielded mixed results. However, recent work demonstrating a robust reduction in CRF(2) receptors using a CRF(2) antisense oligonucleotide with minimal toxicity, and dose response studies using a peptide CRF(2) antagonist suggest that CRF(2) receptors play a role in stress-induced and spontaneous anxiety. Furthermore, inhibiting the actions of both CRF(1) and CRF(2) receptors produces a greater reduction in stress-induced behavior than inhibition of either receptor alone. Thus, current data suggest that CRF(1) and CRF(2) receptors are involved in the mediation of fear and anxiety behavior.
恐惧和焦虑是常见的情绪，可能由压力引发。本文回顾了研究特定促肾上腺皮质激素释放因子（CRF）受体在介导这些情绪表达中所起作用的相关工作。从CRF(1)转基因敲除小鼠、CRF(1)反义寡核苷酸研究以及CRF(1)受体拮抗剂研究中获得的几条证据表明，CRF的焦虑诱导作用是由CRF(1)受体介导的。在这三种方法中，使用转基因CRF(1)敲除小鼠的研究结果似乎最为一致。相比之下，使用特定CRF(1)拮抗剂的研究结果有所不同，部分原因可能是测试方法。当动物在行为测试前受到应激时，CRF(1)受体拮抗剂似乎具有抗焦虑样作用。此外，与急性给药程序相比，长期给予CRF(1)拮抗剂可能具有更强的抗焦虑样作用，尤其是在自发性焦虑动物模型中。自发性焦虑被定义为完全由测试情境引发的行为，而不存在当前或先前的厌恶或明确诱导的应激。CRF(1)反义寡核苷酸的研究结果难以解释，因为反义寡核苷酸可能产生潜在的毒理学副作用，并且在某些情况下，治疗后CRF(1)受体密度没有可验证的降低。类似的方法——CRF(2)敲除、CRF(2)反义寡核苷酸和CRF(2)拮抗剂——被用于评估CRF(2)受体在情绪方面的功能。与大量的CRF(1)受体研究相比，CRF(2)受体的研究较少，这些研究结果也不一致。然而，最近的研究表明，使用毒性最小的CRF(2)反义寡核苷酸可使CRF(2)受体显著减少，并且使用肽类CRF(2)拮抗剂的剂量反应研究表明，CRF(2)受体在应激诱导的和自发性焦虑中发挥作用。此外，抑制CRF(1)和CRF(2)受体的作用比单独抑制任何一种受体更能显著减少应激诱导的行为。因此，目前的数据表明，CRF(1)和CRF(2)受体参与了恐惧和焦虑行为的介导。
