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.

滥用药物产生强烈的积极强化作用， 部分由腹侧被盖区（VTA）介导 多巴胺能神经元。 比如说，老鼠会自我管理 海洛因或吗啡直接进入腹侧被盖区并全身注射 给予阿片样物质或DA拮抗剂将减弱这种作用。 行为 吗啡直接微离子导入 腹侧被盖区DA神经元产生兴奋，这种兴奋被阿片类药物阻断。 拮抗剂纳洛酮。 因为这些神经元是 大脑的内源性奖励系统， (such如鸦片、兴奋剂、酒精和尼古丁）具有高的 滥用潜力 目前的赠款将用于以下方面 技术来表征的结构特性， 调节腹侧被盖区DA神经元输出的内源性阿片系统 大鼠：（1）光镜免疫组化染色 技术将被用来确定轴突的位置 三种含阿片肽神经元的终末 （脑啡肽、β-内啡肽和强啡肽） 腹侧被盖间隙：（2）电镜免疫组化 染色技术将用于确定阿片样物质是否 突触接触与DA和/或非DA神经元内的 （3）逆行神经解剖追踪和原位 杂交技术将一起使用，以确定 含阿片肽的神经元的位置 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）的三维空间内的 以及它们的数量和亲和力。 阐明 阿片样物质和腹侧被盖区DA神经元之间的结构关系将 这是理解神经元的重要一步 构成大脑内源性奖励机制的回路， 为合理的药物滥用治疗提供基础 接近。