Lagalwar S, Bordayo E Z, Hoffmann K L, Fawcett J R, Frey W H
Department of Neurology, Alzheimer's Research Center, HealthPartners, Regions Hospital, St. Paul, MN 55101-2595, USA.
J Mol Neurosci. 1999 Aug-Oct;13(1-2):55-61. doi: 10.1385/JMN:13:1-2:55.
Loss of memory and cholinergic transmission are associated with both Alzheimer's disease (AD) and marijuana use. The human brain muscarinic acetylcholine receptor (mAChR), which is involved in memory function and is inhibited by arachidonic acid, is also inhibited by anandamides. Two agonists of the cannabinoid receptor derived from arachidonic acid, anandamide (AEA) and R-methanandamide, inhibit ligand binding to the mAChR. Binding of the mAChR antagonist [3H]quinuclidinyl benzilate ([3H]QNB) is inhibited up to 89% by AEA (half-maximal inhibition at 50 microM). Binding of the more polar antagonist [N-methyl-3H]scopolamine ([3H]NMS) is inhibited by AEA up to 76% (half-maximal inhibition at 44 microM). R-methanandamide inhibits more than 90% of both [3H]QNB binding (I50 = 34 microM) and [3H]NMS binding (I50 = 15 microM) to the mAChR. Both AEA and R-methanandamide stimulate mAChR binding of the agonist [3H]oxotremorine-M at low concentrations (25-75 microM), but significantly inhibit agonist binding at higher concentrations (I50 = 150 microM). The cannabinoid antagonist SR141716A did not alter AEA or R-methanandamide inhibition of [3H]NMS binding to the mAChR, even at concentrations as high as 1 microM. Further, the cannabinoid agonist WIN 55212-2 does not alter antagonist binding to the mAChR. This demonstrates that mAChR inhibition by the anandamides is not mediated by the cannabinoid receptor. Since AEA and R-methanandamide are structurally similar to arachidonic acid, they may interact with the mAChR in a similar manner to inhibit receptor function.
记忆力丧失和胆碱能传递与阿尔茨海默病（AD）及大麻使用均有关联。人脑毒蕈碱型乙酰胆碱受体（mAChR）参与记忆功能且受花生四烯酸抑制，同时也受阿南达莫德抑制。两种源自花生四烯酸的大麻素受体激动剂，即阿南达莫德（AEA）和R-甲酰阿南达莫德，可抑制配体与mAChR的结合。mAChR拮抗剂[3H]喹核醇基苯甲酸酯（[3H]QNB）的结合被AEA抑制高达89%（50微摩尔时半数最大抑制）。极性更强的拮抗剂[N-甲基-3H]东莨菪碱（[3H]NMS）的结合被AEA抑制高达76%（44微摩尔时半数最大抑制）。R-甲酰阿南达莫德对mAChR的[3H]QNB结合（I50 = 34微摩尔）和[3H]NMS结合（I50 = 15微摩尔）的抑制均超过90%。AEA和R-甲酰阿南达莫德在低浓度（25 - 75微摩尔）时均刺激激动剂[3H]氧化震颤素-M与mAChR的结合，但在较高浓度（I50 = 15微摩尔）时显著抑制激动剂结合。大麻素拮抗剂SR141716A即使在高达1微摩尔的浓度下也不会改变AEA或R-甲酰阿南达莫德对[3H]NMS与mAChR结合的抑制作用。此外，大麻素激动剂WIN 55212-2不会改变拮抗剂与mAChR的结合。这表明阿南达莫德对mAChR的抑制并非由大麻素受体介导。由于AEA和R-甲酰阿南达莫德在结构上与花生四烯酸相似，它们可能以类似方式与mAChR相互作用以抑制受体功能。
