Bymaster Frank P, Carter Petra A, Yamada Masahisa, Gomeza Jesus, Wess Jürgen, Hamilton Susan E, Nathanson Neil M, McKinzie David L, Felder Christian C
Neuroscience Research Division, Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, USA.
Eur J Neurosci. 2003 Apr;17(7):1403-10. doi: 10.1046/j.1460-9568.2003.02588.x.
Muscarinic agonist-induced parasympathomimetic effects, in vivo phosphoinositide hydrolysis and seizures were evaluated in wild-type and muscarinic M1-M5 receptor knockout mice. The muscarinic agonist oxotremorine induced marked hypothermia in all the knockout mice, but the hypothermia was reduced in M2 and to a lesser extent in M3 knockout mice. Oxotremorine-induced tremor was abolished only in the M2 knockout mice. Muscarinic agonist-induced salivation was reduced to the greatest extent in M3 knockout mice, to a lesser degree in M1 and M4 knockout mice, and was not altered in M2 and M5 knockout mice. Pupil diameter under basal conditions was increased only in the M3 knockout mice. Pilocarpine-induced increases in in vivo phosphoinositide hydrolysis were completely absent in hippocampus and cortex of M1 knockout mice, but in vivo phosphoinositide hydrolysis was unaltered in the M2-M5 knockout mice. A high dose of pilocarpine (300 mg/kg) caused seizures and lethality in wild-type and M2-M5 knockout mice, but produced neither effect in the M1 knockout mice. These data demonstrate a major role for M2 and M3 muscarinic receptor subtypes in mediating parasympathomimetic effects. Muscarinic M1 receptors activate phosphoinositide hydrolysis in cortex and hippocampus of mice, consistent with the role of M1 receptors in cognition. Muscarinic M1 receptors appear to be the only muscarinic receptor subtype mediating seizures.
在野生型和毒蕈碱M1 - M5受体基因敲除小鼠中评估了毒蕈碱激动剂诱导的拟副交感神经效应、体内磷酸肌醇水解和癫痫发作情况。毒蕈碱激动剂氧化震颤素在所有基因敲除小鼠中均诱导出明显的体温过低，但在M2基因敲除小鼠中体温过低情况有所减轻，在M3基因敲除小鼠中减轻程度较小。氧化震颤素诱导的震颤仅在M2基因敲除小鼠中消失。毒蕈碱激动剂诱导的唾液分泌在M3基因敲除小鼠中减少程度最大，在M1和M4基因敲除小鼠中减少程度较小，在M2和M5基因敲除小鼠中未改变。基础条件下瞳孔直径仅在M3基因敲除小鼠中增大。毛果芸香碱诱导的体内磷酸肌醇水解在M1基因敲除小鼠的海马体和皮质中完全不存在，但在M2 - M5基因敲除小鼠中体内磷酸肌醇水解未改变。高剂量毛果芸香碱（300 mg/kg）在野生型和M2 - M5基因敲除小鼠中引起癫痫发作和致死，但在M1基因敲除小鼠中均未产生这些效应。这些数据表明M2和M3毒蕈碱受体亚型在介导拟副交感神经效应中起主要作用。毒蕈碱M1受体激活小鼠皮质和海马体中的磷酸肌醇水解，这与M1受体在认知中的作用一致。毒蕈碱M1受体似乎是介导癫痫发作的唯一毒蕈碱受体亚型。
