Wu Min, Newton Samuel S, Atkins Joshua B, Xu Changqing, Duman Ronald S, Alreja Meenakshi
Department of Psychiatry, CMHC 335A, Yale University School of Medicine, 34 Park Street, New Haven, CT 06508, USA.
J Pharmacol Exp Ther. 2003 Nov;307(2):535-43. doi: 10.1124/jpet.103.052514. Epub 2003 Sep 9.
Acetylcholinesterase (AChE) inhibitors, which increase synaptic levels of available acetylcholine (ACh) by preventing its degradation, are the most extensively prescribed drugs for the treatment of Alzheimer's disease. In animals, AChE inhibitors improve learning and memory, reverse scopolamine-induced amnesia, and produce hippocampal theta rhythm. The medial septum/diagonal band of Broca (MSDB), which maintains hippocampal theta rhythm and associated mnemonic functions via the septohippocampal pathway, is considered a critical locus for mediating the effects of AChE inhibitors. Using electrophysiological recordings and fluorescent labeling techniques to identify living septohippocampal neurons in rat brain slices, we report that AChE inhibitors, in the absence of exogenous ACh, produce a profound excitation in 94% of septohippocampal GABAergic neurons and an inhibition in 24% of septohippocampal cholinergic neurons. The inhibitory and excitatory effects of AChE inhibitors, presumably, occur due to accumulation of ACh that is released locally within the MSDB via axon collaterals of septohippocampal cholinergic neurons. The excitatory effects of AChE inhibitors on septohippocampal GABAergic neurons were blocked by muscarinic but not nicotinic receptor antagonists, especially by the M3 receptor antagonist, 4-diphenylacetoxy-N-methylpiperidine mustard, and not by M1 or M2/M4 muscarinic receptor antagonists. M3 muscarinic receptor mRNA colocalized with the calcium-binding protein, parvalbumin, a marker of septohippocampal GABAergic neurons. These findings may be useful in designing therapeutic strategies that do not depend on endogenous ACh and may therefore be effective in situations where AChE inhibitors cease to be effective, such as in progressive neurodegeneration.
乙酰胆碱酯酶（AChE）抑制剂通过阻止乙酰胆碱（ACh）降解来提高突触中可用乙酰胆碱的水平，是治疗阿尔茨海默病最广泛使用的药物。在动物中，AChE抑制剂可改善学习和记忆，逆转东莨菪碱诱导的失忆，并产生海马θ节律。内侧隔区/布罗卡斜带（MSDB）通过隔海马通路维持海马θ节律及相关的记忆功能，被认为是介导AChE抑制剂作用的关键位点。利用电生理记录和荧光标记技术识别大鼠脑片中的活体隔海马神经元，我们发现，在没有外源性ACh的情况下，AChE抑制剂可使94%的隔海马GABA能神经元产生强烈兴奋，并使24%的隔海马胆碱能神经元受到抑制。AChE抑制剂的抑制和兴奋作用可能是由于通过隔海马胆碱能神经元的轴突侧支在MSDB局部释放的ACh积累所致。AChE抑制剂对隔海马GABA能神经元的兴奋作用被毒蕈碱受体拮抗剂而非烟碱受体拮抗剂阻断，尤其是被M3受体拮抗剂4-二苯基乙酰氧基-N-甲基哌啶芥子气阻断，而不是被M1或M2/M4毒蕈碱受体拮抗剂阻断。M3毒蕈碱受体mRNA与钙结合蛋白小白蛋白共定位，小白蛋白是隔海马GABA能神经元的标志物。这些发现可能有助于设计不依赖内源性ACh的治疗策略，因此在AChE抑制剂不再有效的情况下（如进行性神经退行性变）可能有效。
