MUSCARINIC RECEPTORS, COEXISTENCE AND PSYCHOACTIVE DRUGS

该项目的长期目标是探索功能 乙酰胆碱与血管活性肠共存的意义 大脑皮层及周围神经元中的多肽(VIP)。我们 希望了解多个物种共存的含义 一个神经元中的信号物质对这些神经元的功能和功能障碍的影响 神经系统，意在发现新的位置或模式 毒品行动。例如，人们可以利用VIP、共存的 肽，以增强中枢胆碱能功能，这将是 阿尔茨海默型老年期痴呆和亨廷顿氏病的治疗价值 舞蹈病。关于共存和共存原则的普遍有效性 神经递质共存神经元在慢性用药过程中的行为 治疗还将研究5-羟色胺/P物质和 去甲肾上腺素/神经肽Y系统，两者都是 抗抑郁药物的作用。这些药物对人的影响 单胺类药物的作用是有据可查的，同时对 多肽在很大程度上是未知的，尽管它们可能在 这些药物的治疗和副作用。这项研究将关注 ACh和VIP对ACh和VIP释放的交叉反馈调节 新鲜的神经外科样本，以及在长期 使用阿托品或具有高抗胆碱能亲和力的抗抑郁药治疗 (例如，Amitinktiline)。ACh/VIP、5-羟色胺/SP和NA/NPY水平及 周转，以及随后受体数量、亲和力和 将对耦合进行研究。我们将研究亚伯拉罕还是 多肽能系统的超敏感性可以引起类似的变化 共存的经典神经递质系统，以及这些 这些变化可以通过精神活性药物的管理来逆转。我们希望 为了定义共存的神经递质的相互关联程度， 并希望找到新的药物类别，可以改变药物的活性 单胺能系统通过作用于共存的神经肽。 继我们对老鼠的研究之后，还将对新鲜人类进行调查 神经外科材料和来自脑部疾病的尸检样本 阿尔茨海默氏型老年痴呆症和精神分裂症。我们还计划 进一步开发中枢活性的、非促肾上腺皮质激素生成的氧托莫林类似物 (BM-5)，它似乎起突触前拮抗剂和突触后拮抗剂的作用 激动剂，因此代表了胆碱能的真正增强 传播，希望它将在治疗混乱中有用 和阿尔茨海默病。

The long-term objective of the project is to explore the functional significance of the coexistence of acetylcholine and vasoactive intestinal polypeptide (VIP) in neurons of the cerebral cortex and the periphery. We wish to understand the implications of the coexistence of more than one signal substance in one neuron on the function and dysfunction of these neuronal systems, with the intention of discovering new sites or modes for drug action. For example, one may be able to utilize VIP, the coexisting peptide, to enhance the central cholinergic function, which would be of therapeutic value in Alzheimer's type senile dementia and Huntington's chorea. The general validity of the principles concerning coexistence and the behavior of neurons with coexisting transmitters during chronic drug treatment will also be studied on the serotonin/ substance P and noradrenaline/Neuropeptide Y systems, both of which are targets of the actions of antidepressant drugs. The effects of these drugs on the monoamines are well-documented, while the effects on the coexisting peptides are largely unknown, although they may play an important role in the therapeutic and side effects of these drugs. The study will concern the cross-feedback regulation of ACh and VIP release by ACh and VIP in fresh neurosurgical samples, as well as in rats which have been chronically treated with atropine or antidepressants with high anticholinergic affinity (e.g. amitryptiline). Changes in ACh/ VIP, 5-HT/ SP and NA/ NPY levels and turnover, and the subsequent changes in receptor number, affinity and coupling will be studied. We shall examine whether sub- or supersensitivity of the peptidergic system can evoke similar changes in the coexisting classical neurotransmitter system, and whether or not these changes could be reversed by administration of psychoactive drugs. We wish to define the degree of interrelatedness of coexisting neurotransmitters, and hope to find new classes of drugs which can change the activity of the monoaminergic system through an action on the coexisting neuropeptides. Our studies on rats will be followed up by investigations on fresh human neurosurgical material and on autopsy samples from brains afflicted by Alzheimer's type senile dementia and schizophrenia. We also plan to further develop a centrally active, non-tremorogenic oxotremorine analog (BM-5), which seems to act as a presynaptic antagonist and a postsynaptic agonist, and thereby represents a true enhancement of cholinergic transmission, with hope that it will be useful in treatment of confusion and Alzheimer disease.