MUSCARINIC RECEPTORS, COEXISTENCE AND PSYCHOACTIVE DRUGS

该项目的长期目标是探索 乙酰胆碱与血管活性肠肽共存的意义 在大脑皮层和周围神经元中的VIP多肽（VIP）。 我们 希望了解一个以上的共存的影响， 信号物质在一个神经元的功能和功能障碍，这些 神经系统，目的是发现新的网站或模式， 药物作用。 例如，可以利用VIP，共存的 肽，以增强中枢胆碱能功能，这将是 对Alzheimer型老年期痴呆和亨廷顿病的治疗价值 舞蹈病 关于共存和平等的原则的普遍有效性 慢性药物作用下共存递质神经元的行为 治疗也将研究血清素/P物质， 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 单胺是有据可查的，而对共存的 肽在很大程度上是未知的，尽管它们可能在 这些药物的疗效和副作用。 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，以及在大鼠已被长期 用阿托品或具有高抗胆碱能亲和力的抗抑郁药治疗 (e.g.阿米替林）。 ACh/ VIP、5-HT/ SP和NA/ NPY水平的变化， 转换，以及随后的受体数量，亲和力和 将研究耦合。 我们将研究是否子或 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 这些变化可以通过服用精神药物来逆转。 我们希望 为了确定共存神经递质的相互关联程度， 并希望找到新的药物类别，可以改变活动的 单胺能系统通过对共存的神经肽的作用。 我们对大鼠的研究将通过对新鲜人类的研究来跟进。 神经外科材料和尸检样本， 阿尔茨海默型老年痴呆症和精神分裂症。 我们还计划 进一步开发具有中枢活性的非震颤性氧化震颤素类似物， （BM-5），其似乎充当突触前拮抗剂和突触后抑制剂。 激动剂，从而代表胆碱能的真正增强 传输，希望它将有助于治疗混乱 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.