Nakamura K, Kurasawa M, Tanaka Y
CNS Supporting Laboratory, Nippon Roche Research Center, Kanagawa Prefecture, Japan.
Eur J Pharmacol. 1998 Jan 26;342(2-3):127-38. doi: 10.1016/s0014-2999(97)01457-x.
Aging-, disease- and medication-related imbalance of central dopaminergic neurons causes functional impairment of cognition and neuropsychological delirium in humans. We attempted to develop a new delirium model using the direct dopamine agonist, apomorphine, and a choice reaction performance task performed by middle-aged rats. The psychological properties of the model were assessed by determining behavioral measures such as choice reaction time, % correct and % omission. Apomorphine (0.03-0.3 mg/kg s.c.) produced a dose-dependent impairment of task performance. The dose of 0.1 mg/kg prolonged choice reaction time, decreased % correct and increased % omission, indicating that rats had attentional deficits and a reduced arousal or vigilance but no motor deficits or reduced food motivation. This psychological and behavioral impairment of performance resembled that of clinically defined delirium. In this model, the cholinomimetic, aniracetam (10 mg/kg p.o.), reversed the performance impairment induced by apomorphine. Its two metabolites, 2-pyrrolidinone (10 and 30 mg/kg p.o.) and N-anisoyl-gamma-aminobutyric acid (GABA, 10 mg/kg p.o.), effectively reversed the performance impairment as the intact drug did. Another pyrrolidinone derivative, nefiracetam (10 and 30 mg/kg p.o.), tended to worsen the apomorphine effect. The cholinesterase inhibitor, tacrine (10 mg/kg p.o.), markedly worsened all of the behavioral measures. Neuroleptics, haloperidol (0.025 mg/kg s.c.), tiapride (30 mg/kg p.o.) and sulpiride (10 and 30 mg/kg p.o.), antagonized the apomorphine effect. The present results suggest that apomorphine-induced behavioral disturbances in the choice reaction performance task seems to be a useful delirium model and aniracetam may improve delirium through the action of 2-pyrrolidinone and N-anisoyl-GABA, presumably by facilitating dopamine release in the striatum by acting as an AMPA or metabotropic glutamate receptor agonist.
中枢多巴胺能神经元与衰老、疾病和药物相关的失衡会导致人类认知功能障碍和神经心理性谵妄。我们试图使用直接多巴胺激动剂阿扑吗啡和中年大鼠执行的选择反应性能任务来开发一种新的谵妄模型。通过确定诸如选择反应时间、正确百分比和遗漏百分比等行为指标来评估该模型的心理特性。阿扑吗啡（0.03 - 0.3毫克/千克，皮下注射）产生剂量依赖性的任务性能损害。0.1毫克/千克的剂量延长了选择反应时间，降低了正确百分比并增加了遗漏百分比，表明大鼠存在注意力缺陷以及觉醒或警觉性降低，但没有运动缺陷或食物动机降低。这种心理和行为性能损害类似于临床定义的谵妄。在该模型中，拟胆碱药阿尼西坦（10毫克/千克，口服）逆转了阿扑吗啡诱导的性能损害。其两种代谢物，2 - 吡咯烷酮（10和30毫克/千克，口服）和N - 茴香酰基 - γ - 氨基丁酸（GABA，10毫克/千克，口服），与完整药物一样有效地逆转了性能损害。另一种吡咯烷酮衍生物奈非西坦（10和30毫克/千克，口服）倾向于使阿扑吗啡的作用恶化。胆碱酯酶抑制剂他克林（10毫克/千克，口服）显著恶化了所有行为指标。抗精神病药物，氟哌啶醇（0.025毫克/千克，皮下注射）、硫必利（30毫克/千克，口服）和舒必利（10和30毫克/千克，口服）拮抗了阿扑吗啡的作用。目前的结果表明，阿扑吗啡在选择反应性能任务中诱导的行为障碍似乎是一种有用的谵妄模型，并且阿尼西坦可能通过2 - 吡咯烷酮和N - 茴香酰基 - GABA的作用改善谵妄，大概是通过作为AMPA或代谢型谷氨酸受体激动剂促进纹状体中多巴胺的释放。
