Knoll Allison T, Meloni Edward G, Thomas James B, Carroll F Ivy, Carlezon William A
Department of Psychiatry, Harvard Medical School, McLean Hospital, 115 Mill Street, Belmont, MA 02478, USA.
J Pharmacol Exp Ther. 2007 Dec;323(3):838-45. doi: 10.1124/jpet.107.127415. Epub 2007 Sep 6.
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 (approximately 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.
内源性阿片系统调节对威胁性刺激的神经生物学反应。κ-阿片受体（KORs）的刺激产生镇痛作用，但在多种动物模型中诱发类似抑郁的效应。相反，KOR拮抗剂具有类似抗抑郁的作用。KORs及其内源性配体强啡肽在包括扩展杏仁核在内的参与恐惧和焦虑的整个脑区中表达。在此，我们研究了KOR拮抗剂是否会在高架十字迷宫（EPM）和旷场（OF）范式中影响未习得的恐惧（焦虑），以及在恐惧增强惊吓（FPS）范式中影响习得的恐惧。这些研究旨在适应典型KOR拮抗剂盐酸去甲二氢吗啡酮（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-甲酰胺盐酸盐]的缓慢起效（约24小时）和延长的时程（>3周）。大鼠在EPM测试前48小时腹腔注射norBNI（3.0 - 30 mg/kg）或JDTic（1.0 - 10 mg/kg）。一天后，它们在OF中接受测试，5天和7天后，它们在FPS范式中接受训练和测试。两种KOR拮抗剂均剂量依赖性地增加了EPM中的开放臂探索，而不影响OF行为。它们还降低了FPS范式中的条件性恐惧。KOR拮抗剂的抗焦虑样效应在性质上与EPM中苯二氮䓬类药物氯氮卓相似。选择性5-羟色胺再摄取抑制剂氟西汀在EPM中无作用，在OF中产生致焦虑样效应。我们的结果表明，KOR拮抗剂产生了独特的抗抑郁样和抗焦虑样效应组合，并表明这类药物可能对治疗共病的抑郁和焦虑障碍特别有效。
