Anesthesiology. 2021 Apr 1;134(4):588-606. doi: 10.1097/ALN.0000000000003713.
Cholinergic drugs are known to modulate general anesthesia, but anesthesia responses in acetylcholine-deficient mice have not been studied. It was hypothesized that mice with genetic deficiency of forebrain acetylcholine show increased anesthetic sensitivity to isoflurane and ketamine and decreased gamma-frequency brain activity.
Male adult mice with heterozygous knockdown of vesicular acetylcholine transporter in the brain or homozygous knockout of the transporter in the basal forebrain were compared with wild-type mice. Hippocampal and frontal cortical electrographic activity and righting reflex were studied in response to isoflurane and ketamine doses.
The loss-of-righting-reflex dose for isoflurane was lower in knockout (mean ± SD, 0.76 ± 0.08%, n = 18, P = 0.005) but not knockdown (0.78 ± 0.07%, n = 24, P = 0.021), as compared to wild-type mice (0.83 ± 0.07%, n = 23), using a significance criterion of P = 0.017 for three planned comparisons. Loss-of-righting-reflex dose for ketamine was lower in knockout (144 ± 39 mg/kg, n = 14, P = 0.006) but not knockdown (162 ± 32 mg/kg, n = 20, P = 0.602) as compared to wild-type mice (168 ± 24 mg/kg, n = 21). Hippocampal high-gamma (63 to 100 Hz) power after isoflurane was significantly lower in knockout and knockdown mice compared to wild-type mice (isoflurane-dose and mouse-group interaction effect, F[8,56] = 2.87, P = 0.010; n = 5 to 6 mice per group). Hippocampal high-gamma power after ketamine was significantly lower in both knockout and knockdown mice when compared to wild-type mice (interaction effect F[2,13] = 6.06, P = 0.014). The change in frontal cortical gamma power with isoflurane or ketamine was not statistically different among knockout, knockdown, and wild-type mice.
These findings suggest that forebrain cholinergic neurons modulate behavioral sensitivity and hippocampal gamma activity during isoflurane and ketamine anesthesia.
已知胆碱能药物可调节全身麻醉，但尚未研究乙酰胆碱缺乏小鼠的麻醉反应。据推测，大脑前脑乙酰胆碱基因敲除的小鼠对异氟烷和氯胺酮的麻醉敏感性增加，γ 频率脑活动减少。
雄性成年小鼠脑内囊泡乙酰胆碱转运体杂合敲低或基底前脑内转运体纯合敲除与野生型小鼠进行比较。研究异氟烷和氯胺酮剂量对海马和额皮质电图活动和翻正反射的影响。
与野生型小鼠（0.83 ± 0.07%，n = 23）相比，敲除组（0.76 ± 0.08%，n = 18，P = 0.005）而非敲低组（0.78 ± 0.07%，n = 24，P = 0.021）的异氟烷失去翻正反射剂量较低，使用三个计划比较的 P = 0.017 的显著性标准。与野生型小鼠（168 ± 24 mg/kg，n = 21）相比，敲除组（144 ± 39 mg/kg，n = 14，P = 0.006）而非敲低组（162 ± 32 mg/kg，n = 20，P = 0.602）的氯胺酮失去翻正反射剂量较低。与野生型小鼠相比，异氟烷后海马高频（63 至 100 Hz）功率在敲除和敲低小鼠中显著降低（异氟烷剂量和小鼠组相互作用效应，F[8,56] = 2.87，P = 0.010；每组 n = 5 至 6 只小鼠）。与野生型小鼠相比，氯胺酮后海马高频功率在敲除和敲低小鼠中均显著降低（相互作用效应 F[2,13] = 6.06，P = 0.014）。异氟烷或氯胺酮对额皮质γ 功率的影响在敲除、敲低和野生型小鼠之间无统计学差异。
这些发现表明，前脑胆碱能神经元调节异氟烷和氯胺酮麻醉期间的行为敏感性和海马γ 活动。
