Corticotropin-releasing factor receptors CRF1 and CRF2 exert both additive and opposing influences on defensive startle behavior
Corticotropin-releasing factor receptors CRF1 and CRF2 exert both additive and opposing influences on defensive startle behavior
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DOI：
10.1523/jneurosci.5760-03.2004
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发表时间：
2004-07-21
影响因子：
5.3
通讯作者：
Geyer, MA
中科院分区：
文献类型：
--
作者：
Risbrough, VB;Hauger, RL;Geyer, MA
促肾上腺皮质激素释放因子（CRF）受体（CRF1和CRF2）是对应激的生理和行为反应的重要介质。在动物中，CRF1似乎主要介导CRF诱导的焦虑样反应，但CRF2在应激过程中的作用仍不清楚。在这里，我们报告的CRF1和CRF2对小鼠防御性惊吓反应的幅度和可塑性的影响。惊吓可塑性是通过感官刺激对惊吓的抑制来测量的，即，前脉冲抑制（PPI），并在惊恐或创伤后应激障碍患者中被破坏，其中CRF神经传递可能过度活跃。CRF1的药理学阻断逆转了CRF诱导的惊恐增加和CRF诱导的PPI缺陷。CRF2阻断减弱高剂量但不是低剂量CRF诱导的惊吓增加和PPI降低。相反，CRF2的激活增强了PPI。CRF对CRF1基因敲除小鼠的惊吓和PPI升高没有影响。这些数据表明，CRF受体的一致行动，以增加防御惊吓的幅度，但在相反的调节惊吓的灵活性。这些数据支持一个新的模型，各自的CRF受体的作用，在压力相关的行为，这样，虽然这两种受体增强防御反应的幅度，CRF1受体违反，而CRF2受体增强，感官信息对防御行为的影响。我们推测，过度的CRF1激活结合减少CRF2信号可能有助于信息处理缺陷的恐慌和创伤后应激障碍患者和支持CRF1特异性药物治疗。
The corticotropin-releasing factor (CRF) receptors (CRF1 and CRF2) are crucial mediators of physiological and behavioral responses to stress. In animals, CRF1 appears to primarily mediate CRF-induced anxiety-like responses, but the role of CRF2 during stress is still unclear. Here we report the effects of CRF1 and CRF2 on the magnitude and plasticity of defensive startle responses in mice. Startle plasticity is measured by inhibition of startle by sensory stimuli, i.e., prepulse inhibition (PPI), and is disrupted in patients with panic or posttraumatic stress disorders in which CRF neurotransmission may be overactive. Pharmacological blockade of CRF1 reversed both CRF-induced increases in startle and CRF-induced deficits in PPI. CRF2 blockade attenuated high-dose but not low-dose CRF-induced increases in startle and reduced PPI. Conversely, activation of CRF2 enhanced PPI. CRF had no effect on startle and increased PPI in CRF1 knock-out mice. These data indicate that CRF receptors act in concert to increase the magnitude of defensive startle yet in opposition to regulate the flexibility of startle. These data support a new model of respective CRF receptor roles in stress-related behavior such that, although both receptors enhance the magnitude of defensive responses, CRF1 receptors contravene, whereas CRF2 receptors enhance, the impact of sensory information on defensive behavior. We hypothesize that excessive CRF1 activation combined with reduced CRF2 signaling may contribute to information processing deficits seen in panic and posttraumatic stress disorder patients and support CRF1-specific pharmacotherapy.