Fibiger H C, Damsma G, Day J C
Department of Psychiatry, University of British Columbia, Vancouver, Canada.
Adv Exp Med Biol. 1991;295:399-414. doi: 10.1007/978-1-4757-0145-6_23.
Systemically administered cholinergic (muscarinic) receptor antagonists can impair the acquisition and post-acquisition performance of a variety of learned behaviors. acquisition performance of a variety of learned behaviors. At present, there is no consensus about the psychological mechanisms underlying these deficits. Behavioral inhibition, working (short-term) memory, reference (long-term) memory, attention, movement and strategy selection, and stimulus processing are among the constructs that have been proposed as underlying the effects of muscarinic receptor blockade. On the basis of neuroanatomical and neuropharmacological considerations it is contended that debates about the nature of the mediating events are pointless because they are on an anatomy that does not exist. Specifically, given that cholinergic neurons innervate almost the entire neuraxis and that muscarinic cholinergic receptors are distributed throughout the central nervous system, it is virtually certain that systemically applied antimuscarinic drugs will influence a broad spectrum of brain functions. In addition, the nature of the deficits produced by scopolamine and atropine, which are competitive antagonists, will depend on the regional endogenous rate of acetylcholine release, which may in turn be influenced by the particular environment and/or level of training imposed on the animal. As the literature seems to indicate, therefore, the effects of competitive antagonists will vary as a function of both the behavioral test and the level of training. Accordingly, attempts at unitary formulations of central cholinergic function are ill-conceived and illusory. Another approach to understanding central cholinergic function has been based on the use of local injections of excitotoxins into brain regions such as the basal forebrain that contain cholinergic neurons. Recent published reports indicate, that many of the behavioral deficits observed after ibotenic acid lesions of the basal forebrain are due primarily to the loss of non-cholinergic neurons. The inherent limitations of the excitotoxin lesion approach for unravelling the functions of central cholinergic systems are such that they cannot produce definitive information and might best, therefore, be abandoned. At present, a reliable selective toxin for cholinergic neurons is not available and urgently required. Until such a compound is identified, local intracerebral applications of antimuscarinic agents may be the preferred procedure for studying the behavioral correlates of regional blockade of cholinergic activity. Brain microdialysis in freely moving animals also holds considerable promise with respect to defining the circumstances under which acetylcholine is released in discrete regions of the central nervous system. At present, the function of central cholinergic systems and the possible role of each in learning and memory remain poorly understood.
全身给药的胆碱能（毒蕈碱）受体拮抗剂会损害多种习得行为的获得及获得后的表现。目前，对于这些缺陷背后的心理机制尚无共识。行为抑制、工作（短期）记忆、参考（长期）记忆、注意力、运动和策略选择以及刺激处理等概念被认为是毒蕈碱受体阻断作用的潜在机制。基于神经解剖学和神经药理学的考虑，有人认为关于介导事件本质的争论毫无意义，因为这些争论基于一种并不存在的解剖结构。具体而言，鉴于胆碱能神经元几乎支配整个神经轴，且毒蕈碱胆碱能受体分布于整个中枢神经系统，几乎可以肯定全身应用抗毒蕈碱药物会影响广泛的脑功能。此外，东莨菪碱和阿托品作为竞争性拮抗剂所产生的缺陷性质，将取决于乙酰胆碱的区域内源性释放速率，而这又可能反过来受到施加于动物的特定环境和/或训练水平的影响。因此，正如文献所示，竞争性拮抗剂的作用会因行为测试和训练水平的不同而有所变化。相应地，试图对中枢胆碱能功能进行单一表述的做法是欠考虑且虚幻的。理解中枢胆碱能功能的另一种方法是基于向含有胆碱能神经元的脑区（如基底前脑）局部注射兴奋性毒素。最近发表的报告表明，基底前脑经鹅膏蕈氨酸损伤后观察到的许多行为缺陷主要是由于非胆碱能神经元的丧失。兴奋性毒素损伤方法在揭示中枢胆碱能系统功能方面存在固有的局限性，以至于无法产生确切信息，因此最好放弃。目前，尚无可靠的针对胆碱能神经元的选择性毒素，且迫切需要此类毒素。在确定这样一种化合物之前，局部脑内应用抗毒蕈碱剂可能是研究胆碱能活性区域阻断的行为相关性的首选方法。对自由活动动物进行脑微透析在确定乙酰胆碱在中枢神经系统离散区域释放的情况方面也具有很大的前景。目前，中枢胆碱能系统的功能以及每个系统在学习和记忆中可能发挥的作用仍知之甚少。
