Gulat-Marnay C, Lafitte A, Arrang J M, Schwartz J C
Laboratoire de Physiologie, Faculté de Pharmacie, (U. 109) de l'INSERM, Centre Paul Broca, Paris, France.
J Neurochem. 1989 Jan;52(1):248-54. doi: 10.1111/j.1471-4159.1989.tb10924.x.
The cholinergic modulation of histamine release and synthesis was studied in rat brain slices or synaptosomes labeled with L-[3H]histidine. Carbachol in increasing concentrations progressively reduced the K+-induced [3H]histamine release from cortical slices. Pirenzepine, a preferential M1-receptor antagonist, reversed the carbachol effect in an apparently competitive manner and with Ki values of 1-6 X 10(-8) M. 11-[(2-[(Diethylamino)methyl]-1-piperidinyl)acetyl]-5,11-dihydro-6H- pyrido[2,3-b][1,4]benzodiazepine-6-one (AF-DX 116), considered a preferential M2-receptor antagonist, reversed the carbachol effect with a mean Ki of approximately 2 X 10(-7) M. Oxotremorine behaved as a partial agonist in the modulation of histamine release. Neostigmine, an acetylcholinesterase inhibitor, inhibited the K+-induced release of [3H]histamine from cortical slices, and the effect was largely reversed by pirenzepine, an observation suggesting a modulation by endogenous acetylcholine. The effects of carbachol and pirenzepine were observed with slices of other brain regions known to contain histaminergic nerve terminals or perikarya, as well as with cortical synaptosomes. The two drugs also modified, in opposite directions, [3H]histamine formation in depolarized cortical slices. In vivo oxotremorine inhibited [3H]histamine formation in cerebral cortex, and this effect was reversed by scopolamine. When administered alone, scopolamine failed to enhance significantly the 3H- labeled amine formation, a finding suggesting that muscarinic receptors are not activated by endogenous acetylcholine released under basal conditions. It is concluded that muscarinic heteroreceptors, directly located on histaminergic nerve terminals, control release and synthesis of histamine in the brain. These receptors apparently belong to the broad M1-receptor category and may correspond to a receptor subclass displaying a rather high affinity for AF-DX 116.
在标记有L-[3H]组氨酸的大鼠脑片或突触体中研究了组胺释放和合成的胆碱能调节。浓度不断增加的卡巴胆碱逐渐减少了钾离子诱导的皮质切片中[3H]组胺的释放。哌仑西平是一种选择性M1受体拮抗剂，以明显的竞争性方式逆转了卡巴胆碱的作用，其Ki值为1 - 6×10(-8)M。11-[(2-[(二乙氨基)甲基]-1-哌啶基)乙酰基]-5,11-二氢-6H-吡啶并[2,3-b][1,4]苯并二氮杂卓-6-酮(AF-DX 116)被认为是一种选择性M2受体拮抗剂，以约2×10(-7)M的平均Ki逆转了卡巴胆碱的作用。氧化震颤素在组胺释放的调节中表现为部分激动剂。新斯的明是一种乙酰胆碱酯酶抑制剂，抑制了钾离子诱导的皮质切片中[3H]组胺的释放，而哌仑西平在很大程度上逆转了这种作用，这一观察结果表明内源性乙酰胆碱参与了调节。在已知含有组胺能神经末梢或核周体的其他脑区切片以及皮质突触体中也观察到了卡巴胆碱和哌仑西平的作用。这两种药物还以相反的方向改变了去极化皮质切片中[3H]组胺的形成。在体内，氧化震颤素抑制了大脑皮质中[3H]组胺的形成，而这种作用被东莨菪碱逆转。单独给药时，东莨菪碱未能显著增强3H标记胺的形成，这一发现表明毒蕈碱受体不会被基础条件下释放的内源性乙酰胆碱激活。结论是，直接位于组胺能神经末梢上的毒蕈碱异受体控制着大脑中组胺的释放和合成。这些受体显然属于广义的M1受体类别，可能对应于对AF-DX 116显示出相当高亲和力的受体亚类。
