The nicotinic allosteric potentiating ligand galantamine facilitates synaptic transmission in the mammalian central nervous system
The nicotinic allosteric potentiating ligand galantamine facilitates synaptic transmission in the mammalian central nervous system
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DOI：
10.1124/mol.61.5.1222
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发表时间：
2002-05-01
影响因子：
3.6
通讯作者：
Albuquerque, EX
中科院分区：
文献类型：
--
作者：
Santos, MD;Alkondon, M;Albuquerque, EX
在这项研究中，膜片钳技术被用来确定加兰他敏，胆碱酯酶抑制剂和用于治疗阿尔茨海默病的烟碱变构增强配体（APL），对脑片突触传递的影响。在大鼠海马和人类大脑皮层切片中，1 μ M加兰他敏，作为一个烟碱APL，增加γ-氨基丁酸（GABA）释放触发的10 μ M乙酰胆碱（ACh）。同样地，1 μ M加兰他敏作为APL作用于突触前定位的烟碱受体（nAChR），其具有张力活性，增强大鼠海马切片中Schaffer侧支和CA 1神经元之间的GABA能或GABA能传递。胆碱酯酶抑制剂rivastigmine、多奈哌齐和metrifonate不具有烟碱APL作用，不影响突触传递。ACh的外源性应用表明，高和低水平的nAChR激活的Schaffer侧支抑制和促进，分别，谷氨酸释放到CA 1神经元。nAChR拮抗剂甲基甘草次酸和二氢-β-赤藓定促进Schaffer侧支和CA 1神经元之间的突触能传递，这一发现表明，在单个海马切片中，某些突触能纤维中强张力激活的nAChR的抑制作用优于其他突触能纤维中弱张力激活的nAChR与给定神经元突触的促进作用。已知加兰他敏通过低浓度而非高浓度激动剂使nAChR对活化敏感。因此，在1 μ M时，加兰他敏可能通过弱的、紧张性激活的nAChR增加突触传递的促进作用，刚好足以克服强的、紧张性激活的nAChR的抑制作用。总之，烟碱APL作用可能是加兰他敏治疗效果的重要决定因素。
In this study, the patch-clamp technique was used to determine the effects of galantamine, a cholinesterase inhibitor and a nicotinic allosteric potentiating ligand (APL) used for treatment of Alzheimer's disease, on synaptic transmission in brain slices. In rat hippocampal and human cerebral cortical slices, 1 muM galantamine, acting as a nicotinic APL, increased gamma-aminobutyric acid (GABA) release triggered by 10 muM acetylcholine (ACh). Likewise, 1 muM galantamine, acting as an APL on presynaptically located nicotinic receptors (nAChRs) that are tonically active, potentiated glutamatergic or GABA-ergic transmission between Schaffer collaterals and CA1 neurons in rat hippocampal slices. The cholinesterase inhibitors rivastigmine, donepezil, and metrifonate, which are devoid of nicotinic APL action, did not affect synaptic transmission. Exogenous application of ACh indicated that high and low levels of nAChR activation in the Schaffer collaterals inhibit and facilitate, respectively, glutamate release onto CA1 neurons. The finding then that the nAChR antagonists methyllycaconitine and dihydro-beta-erythroidine facilitated glutamatergic transmission between Schaffer collaterals and CA1 neurons indicated that in a single hippocampal slice, the inhibitory action of strongly, tonically activated nAChRs in some glutamatergic fibers prevails over the facilitatory action of weakly, tonically activated nAChRs in other glutamatergic fibers synapsing onto a given neuron. Galantamine is known to sensitize nAChRs to activation by low, but not high agonist concentrations. Therefore, at 1 muM, galantamine is likely to increase facilitation of synaptic transmission by weakly, tonically activated nAChRs just enough to override inhibition by strongly, tonically activated nAChRs. In conclusion, the nicotinic APL action can be an important determinant of the therapeutic effectiveness of galantamine.