AMNESTIC/IMMOBILIZING EFFECTS OF INHALED ANESTHETICS

这项建议侧重于原型吸入剂的遗忘和固定效果。 麻醉剂异氟醚，将这些效果与其他麻醉剂的效果进行对比。是这样的 我们建议通过对比来揭示吸入麻醉作用的机制。这个 异氟醚产生行为效应的机制尚不清楚。异氟醚对许多离子通道的作用可能会导致失忆或静止。本计划中的此项目 格兰特项目(PPG)发现，几个这样的渠道可能并不调节静止不动，但 甘氨酸和NMDA受体以及钠通道仍然是合理的靶点。没有受体或离子通道被确定或排除为遗忘症的主要媒介。 因为许多GABA能药物(如苯二氮卓类)和NMDA抑制剂 由于吸入麻醉剂对GABAA和NMDA受体也有同样的影响，该假设认为吸入麻醉剂通过改变GABAA和/或NMDA受体功能而干扰记忆。对这一假说提出了一项测试，使用了转基因小鼠，动物接受了GABAA和NMDA受体调节剂。初步数据表明，甘氨酸受体在异氟烷诱导的不动中起作用。这些研究将在含有甘氨酸受体的敲打小鼠身上继续进行，这些受体对甘氨酸正常反应，但异氟醚没有增强作用。类似的研究将检查钠通道对异氟醚的遗忘和固定作用的作用。健忘症将使用巴甫洛夫恐惧条件反射和MAC不动进行评估，MAC是在50%的受试者中对伤害性刺激产生不动的最低麻醉剂肺泡浓度。

This proposal focuses on the amnestic and immobilizing effects of a prototypic inhaled anesthetic, isoflurane, contrasting those effects with the effects of other anesthetics. Such contrasts are proposed to reveal the mechanisms underlying inhaled anesthetic actions. The mechanism by which isoflurane produces its behavioral effects is unknown. Isoflurane's actions on many ion channels could plausibly produce amnesia or immobility. This project in the Program Project Grant (PPG) found that several such channels probably do not mediate immobility but that glycine and NMDA receptors and sodium channels remain reasonable targets. No receptors or ion channels have either been identified or excluded as primary mediators of amnesia. Because many GABAergic drugs (e.g., benzodiazepines) and NMDA inhibitors have profound amnestic effects, and because inhaled anesthetics share these effects on GABAA and NMDA receptors, this proposal hypothesizes that inhaled anesthetics interferes with memory by altering GABAA and/or NMDA receptor function. A test of this hypothesis is proposed using genetically modified mice, and animals administered GABAA and NMDA receptor modulators. Preliminary data suggest a role for glycine receptors to isoflurane-induced immobility. These investigations will be continued using knockin mice harboring glycine receptors that respond normally to glycine but are not enhanced in effect by isoflurane. Similar studies will examine the role of sodium channels to the amnestic and immobilizing effect of isoflurane. Amnesia will be evaluated using Pavlovian fear conditioning, and immobility by MAC, the minimum alveolar concentration of anesthetic producing immobility in response to a noxious stimulus in 50% of subjects.