Department of Psychiatry, Harvard Medical School, McLean Hospital, Belmont, MA, USA.
Neuropsychopharmacology. 2012 Dec;37(13):2809-16. doi: 10.1038/npp.2012.151. Epub 2012 Sep 5.
Stress often disrupts behavior and can lead to psychiatric illness. Considerable evidence suggests that corticotropin-releasing factor (CRF) plays an important role in regulating the effects of stress. CRF administration produces stress-like effects in humans and laboratory animals, and CRF levels are elevated in individuals with stress-related illness. Recent work indicates that κ-opioid receptor (KOR) antagonists can block CRF effects, raising the possibility that at least some of the effects of stress are mediated via KORs. Here we examined the effects of CRF on performance in the 5-choice serial reaction time task (5CSRTT), a test used to quantify attention in rodents, as well as functional interactions between CRF and KORs. Male Sprague-Dawley rats were trained in the 5CSRTT and then each was implanted with an intracerebroventricular (ICV) cannula. After recovery and restabilization of performance, they received a single intraperitoneal (IP) injection of vehicle or JDTic (10 mg/kg), a KOR antagonist with long-lasting (>14 days) effects. In subsequent sessions, rats received ICV infusions of CRF (0.25-1.0 μg) or vehicle and were tested 60 min later. CRF dose-dependently disrupted performance as reflected by decreases in correct responding, increases in omission errors, increases in latencies to respond correctly, and increases in time to complete the session. JDTic attenuated each of these CRF-induced deficits while having no effects on its own. The persistent ability of JDTic to disrupt KOR function was confirmed using the tail immersion assay. These findings indicate that KOR antagonists can prevent acute stress-related effects that degrade performance in tasks requiring attention.
压力常常会扰乱行为，并可能导致精神疾病。大量证据表明，促肾上腺皮质释放因子（CRF）在调节压力的影响方面起着重要作用。CRF 的给药会在人类和实验动物中产生类似于压力的效应，并且在与压力相关的疾病患者中，CRF 水平升高。最近的研究表明，κ-阿片受体（KOR）拮抗剂可以阻断 CRF 的作用，这提高了至少某些压力效应是通过 KOR 介导的可能性。在这里，我们研究了 CRF 对 5 选择连续反应时间任务（5CSRTT）中表现的影响，5CSRTT 是一种用于量化啮齿动物注意力的测试，以及 CRF 和 KOR 之间的功能相互作用。雄性 Sprague-Dawley 大鼠在 5CSRTT 中接受训练，然后每个大鼠都被植入脑室内（ICV）套管。在恢复和性能稳定后，它们接受单次腹腔内（IP）注射载体或 JDTic（10mg/kg），这是一种具有持久（>14 天）作用的 KOR 拮抗剂。在随后的会议中，大鼠接受 CRF（0.25-1.0μg）或载体的 ICV 输注，并在 60 分钟后进行测试。CRF 剂量依赖性地破坏了表现，表现为正确反应减少，遗漏错误增加，正确反应的潜伏期增加，以及完成会议的时间增加。JDTic 减轻了这些 CRF 引起的缺陷中的每一个，而对自身没有影响。使用尾部浸入测定法确认了 JDTic 持续破坏 KOR 功能的能力。这些发现表明，KOR 拮抗剂可以预防急性与压力相关的效应，这些效应会降低需要注意力的任务的表现。
