Anxiolytic-Like effects of κ-opioid receptor antagonists in models of unlearned and learned fear in rats
Anxiolytic-Like effects of κ-opioid receptor antagonists in models of unlearned and learned fear in rats
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DOI：
10.1124/jpet.107.127415
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发表时间：
2007-12-01
影响因子：
3.5
通讯作者：
Carlezon, William A., Jr.
中科院分区：
文献类型：
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作者：
Knoll, Allison T.;Meloni, Edward G.;Carlezon, William A., Jr.
内源性阿片系统调节对威胁刺激的神经生物学反应。刺激kappa-阿片受体（KORs）在多种动物模型中产生镇痛作用，但诱导类似抑郁的作用。相反，KOR拮抗剂具有抗抑郁样作用。KORs及其内源性配体运动啡在整个涉及恐惧和焦虑的大脑区域表达，包括扩展的杏仁核。在这里，我们研究了KOR拮抗剂是否会影响升高迷宫（EPM）和开放领域（OF）范式中的非习得性恐惧（焦虑），以及恐惧增强惊吓（FPS）范式中的习得性恐惧。这些研究的目的是为了适应典型的KOR拮抗剂盐酸甲萘哌胺（norBNI）和JDTic [(3R)-7-羟基- n -[(1S)-1-[[(3R,4R)-4-（3-羟基苯基）-3,4-二甲基-1-哌啶基]甲基]-2-甲基丙基]-1,2,3,4-四氢-3-异喹啉-盐酸carboxamide]的缓慢起效（类似于24小时）和延长病程（bbb -3周）。大鼠在EPM试验前48 h ig注射norBNI （3.0 ~ 30 mg/kg）或JDTic （1.0 ~ 10 mg/kg）。一天后，他们接受OF测试，5和7天后，他们接受FPS范式的训练和测试。两种KOR拮抗剂均剂量依赖性地增加EPM的开放臂探查，而不影响OF行为。它们还减少了FPS范例中的条件性恐惧。在EPM中，KOR拮抗剂的抗焦虑样作用在质量上与苯二氮卓类氯二氮环氧化物相似。选择性5 -羟色胺再摄取抑制剂氟西汀对EPM无影响，对OF无焦虑样作用。我们的研究结果表明，KOR拮抗剂产生一种独特的抗抑郁和抗焦虑样作用的组合，并表明这类药物可能对治疗共病性抑郁和焦虑障碍特别有效。
Endogenous opioid systems regulate neurobiological responses to threatening stimuli. Stimulation of kappa-opioid receptors (KORs) produces analgesia but induces prodepressive-like effects in a variety of animal models. In contrast, KOR antagonists have antidepressant-like effects. KORs and their endogenous ligand dynorphin are expressed throughout brain areas involved in fear and anxiety, including the extended amygdala. Here, we examined whether KOR antagonists would affect unlearned fear ( anxiety) in the elevated plus maze (EPM) and open field (OF) paradigms and learned fear in the fear-potentiated startle (FPS) paradigm. These studies were designed to accommodate the slow onset (similar to 24 h) and extended time course (>3 weeks) of the prototypical KOR antagonists nor-binaltorphimine hydrochloride (norBNI) and JDTic [(3R)-7-hydroxy-N-[(1S)-1-[[(3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl]methyl]-2-methylpropyl]-1,2,3,4-tetrahydro-3-isoquinoline-carboxamide hydrochloride]. Rats received an i.p. injection of norBNI (3.0-30 mg/kg) or JDTic (1.0-10 mg/kg) 48 h before EPM testing. One day later, they were tested in the OF, and 5 and 7 days later, they were trained and tested in the FPS paradigm. Both KOR antagonists dose-dependently increased open arm exploration in the EPM without affecting OF behavior. They also decreased conditioned fear in the FPS paradigm. The anxiolytic-like effects of KOR antagonists were qualitatively similar to those of the benzodiazepine chlordiazepoxide in the EPM. The selective serotonin reuptake inhibitor fluoxetine had no effect in the EPM and anxiogenic-like effects in the OF. Our results indicate that KOR antagonists produce a unique combination of antidepressant-and anxiolytic-like effects and suggest that this class of drugs may be particularly effective for the treatment of comorbid depressive and anxiety disorders.