REGULATION OF MESOLIMBIC DOPAMINE BY ENDOGENOUS COMPOUND

内源性化合物对中脑边缘多巴胺的调节

• 批准号: 3379236
• 负责人: Peter W Kalivas
• 金额: $ 7.69万
• 依托单位: WASHINGTON STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1985
• 资助国家: 美国
• 起止时间: 1985-01-01 至 1987-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3379236
• 关键词: acetylcholine; cholecystokinin; chordate locomotion; decarboxylase inhibitor; dopamine; ethology; gamma aminobutyrate; high performance liquid chromatography; immunochemistry; microinjections; microscopy; neuropharmacology; neurotensin; neurotransmitter metabolism; schizophrenia; tegmentum; thyrotropin releasing hormone; tyrosine 3 monooxygenase

Schizophrenia is recognized as a major health problem in this country and the world. The mesolimbic dopamine system, which has neuronal perikarya in the ventral tegmental area and axonal terminals in the nucleus accumbens, has been postulated to have a pathogenic role in schizophrenia. In addition to dopamine, the ventral tegmental area and nucleus accumbens contain a variety of other putative neurotransmitters, including; acetylcholine, Gamma-aminobutyric acid, cholecystokining, enkephalin, neurotensin substance P and thyrotropin-releasing hormone. This poses the possibility that these substances may modulate mesolimbic dopaminergic function, and thereby play a role in schizophrenia. I have outlined experiments in this proposal which will evaluate the capacity of these putative neurotransmitters to modulate the mesolimbic dopamine system. This will be performed by acute microinjection of the compound of interest into the ventral tegmental area and/or nucleus accumbens of the rat. After microinjection, I will assess effects on the mesolimbic dopamine system by neurochemical measurements of dopamine release, synthesis and turnover, and by behavioral measurements of locomotion and rearing. Compounds found to alter mesolimbic dopaminergic function will be chronically injected into the ventral tegmental area or nucleus accumbens, and neurochemical and behavioral changes monitored. Concurrent with these studies, I will conduct anatomical experiments employing immunohistochemistry which will provide a detailed light microscopic map of the location of putative neurotransmitter systems relative to the mesolimbic dopamine system. Further, retrograde transport of horseradish peroxidase coupled with immunohistochemistry will be used to define the neurochemical nature of afferents to the mesolimbic system. These studies can provide insight into the neurobiology of schizophrenia by evaluating how endogenous neurotransmitter systems affect the mesolimbic dopamine system. Further, compounds found to decrease mesolimbic dopaminergic function may ultimately provide a new generation of psychopharmacological therapy in the treatment of schizophrenia.

精神分裂症在这个国家被认为是一个主要的健康问题， 世界 中脑边缘多巴胺系统，其中有神经元胞体， 腹侧被盖区和轴突终末位于延髓背核， 被认为在精神分裂症中具有致病作用。 在 除了多巴胺外，腹侧被盖区和延髓核 含有多种其他假定的神经递质，包括; 乙酰胆碱，γ-氨基丁酸，胆囊收缩素，脑啡肽， 神经降压素P物质和促甲状腺激素释放激素。 这就构成了 这些物质可能调节中脑边缘多巴胺能 功能，从而在精神分裂症中发挥作用。 我在这个建议中概述了一些实验，这些实验将评估 这些假定的神经递质调节中脑边缘的能力 多巴胺系统 这将通过急性微量注射 目的化合物进入腹侧被盖区和/或核 老鼠的尾巴 显微注射后，我将评估对 中脑边缘多巴胺系统的多巴胺神经化学测定 释放，合成和营业额，并通过行为测量 运动和饲养。 发现改变中脑边缘多巴胺能的化合物 功能将被慢性注入腹侧被盖区或 神经核，并监测神经化学和行为变化。 在进行这些研究的同时， 利用免疫组织化学技术， 假定神经递质系统位置的显微图 相对于中脑边缘多巴胺系统。 此外，逆行运输 辣根过氧化物酶结合免疫组织化学将用于 定义传入到中脑边缘系统的神经化学性质。 这些研究可以提供深入了解精神分裂症的神经生物学， 评估内源性神经递质系统如何影响中脑边缘系统 多巴胺系统 此外，发现降低中边缘细胞的化合物 多巴胺能功能可能最终提供新一代的 精神药物疗法治疗精神分裂症。