NEUROBIOLOGY OF OPIOID-DOPAMINE INTERACTIONS

阿片类药物-多巴胺相互作用的神经生物学

• 批准号: 3211584
• 负责人: DWIGHT C. German
• 金额: $ 12.33万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 1989
• 资助国家: 美国
• 起止时间: 1989-03-01 至 1992-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3211584
• 关键词: autoradiography; dopamine receptor; drug addiction; drug addiction antagonist; histochemistry /cytochemistry; in situ hybridization; laboratory rat; morphine; naloxone; neuropeptide receptor; opioid receptor; psychological reinforcement; tegmentum

Drugs of abuse produce strong positive reinforcing effects which are mediated, in part, by the ventral tegmental area (VTA) dopaminergic (DA) neurons. Rats, for example, will self-administer heroin or morphine directly into the VTA and systemically administered opioid- or DA-antagonists will attenuate this behavior. Microiontophoretic application of morphine directly onto VTA DA neurons produces excitation which is blocked by the opioid antagonist naloxone. Because these neurons are an important part of the brain's endogenous reward system, drugs which activate them (such as opiates, stimulants, alcohol, and nicotine) possess a high abuse potential. The present grant will utilize the following techniques to characterize the structural properties of the endogenous opioid systems which regulate VTA DA neuronal output in the rat: (1) light microscopic immunohistochemical staining techniques will be used to determine the location of the axon terminals of the three opioid peptide-containing neurons (enkephalin, beta-endorphin and dynorphin) within the 3-dimensional space of the VTA; (2) electron microscopic immunohistochemical staining techniques will be used to determine whether the opioid synaptic contacts are made with DA and/or non-DA neurons within the VTA; (3) retrograde neuroanatomical tracing and in situ hybridization techniques will be used together to determine the location of the opioid peptide-containing somata which innervate the VTA; and (4) quantitative receptor autoradiography techniques will be used to determine the location of the opioid receptor subtypes (mu delta, kappa) within the 3-dimensional space of the VTA, and their numbers and affinities. Elucidation of the structural relationships between the opioid and VTA DA neurons will provide an important step toward understanding the neuronal circuits which make up the brain's endogenous reward mechanism/s, and provide a foundation for rational drug abuse treatment approaches.

滥用药物会产生强烈的积极加强作用，这 部分由腹侧侧距区域（VTA）介导 多巴胺能（DA）神经元。 例如，老鼠会自我管理 海洛因或吗啡直接进入VTA并系统地进入 管理的阿片类药物或DA-Antagonists将衰减此 行为。 吗啡直接应用于微托管 VTA DA神经元产生激发，而阿片类药物阻止 拮抗剂纳洛酮。 因为这些神经元是重要的部分 大脑的内源奖励系统，激活它们的药物 （例如阿片类药物，兴奋剂，酒精和尼古丁） 虐待潜力。 目前的赠款将利用以下 表征该结构特性的技术 调节VTA DA神经元输出的内源性阿片类药物系统 大鼠：（1）光显微镜免疫组织化学染色 技术将用于确定轴突的位置 三个含阿片类肽神经元的末端 （Enkephalin，Beta-endorphin和dynorphin）在三维中 VTA的空间； （2）电子显微镜免疫组织化学 染色技术将用于确定阿片类药物是否 突触接触是用DA和/或非DA神经元内的 vta; （3）逆行神经解剖学跟踪和原位 杂交技术将一起使用以确定 含阿片类肽的somata的位置 VTA; （4）定量受体放射自显影技术 将用于确定阿片受体的位置 亚型（MU Delta，kappa）在3维空间内 VTA及其数字和亲和力。 阐明 阿片类药物和VTA DA神经元之间的结构关系将 提供了了解神经元的重要一步 构成大脑内源奖励机制的电路 并为理性药物滥用治疗提供基础 方法。