DOPAMINE-OPIOD RECEPTOR INTERACTIONS IN BASAL FOREBRAIN

基底前脑中的多巴胺-阿片受体相互作用

• 批准号: 3213270
• 负责人: LYNN D CHURCHILL
• 金额: $ 7.2万
• 依托单位: WASHINGTON STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1990
• 资助国家: 美国
• 起止时间: 1990-07-01 至 1992-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3213270
• 关键词: G protein; adenylate cyclase; autoradiography; basal ganglia; basal metabolism; brain metabolism; calcium channel; cocaine; dopamine receptor; guanine nucleotide binding protein; inhibitor /antagonist; laboratory rat; neurochemistry; neuropeptides; neurotransmitter metabolism; pertussis toxin; potassium channel; second messengers

Dopamine and opioid receptors in the nucleus accumbens are, at least partially, responsible for increases in locomotor activity following the administration of cocaine or opioids. Although the opioid system does not depend upon dopamine for its actions, the depletion of dopamine will augment opioid-induced locomotor activity. The neurochemical basis for this peptide-amine interaction has not yet been elucidated. The coupling of dopamine and opioid receptors in the same postsynaptic neurons may result in an upregulation of opioid receptors in response to dopamine depletion. Preliminary data support this hypothesis. The anatomical localization of any increases in opioid receptor affinity or number will be analyzed by quantitative receptor autoradiography. Another hypothesis is that the dopamine and opioid receptors share a second messenger or ion channel whose activity is enhanced by the dopamine depletion. Modification in the number of Ca+2-activated K+ channels, guanine nucleotide binding proteins or alterations in the opioid inhibition of dopamine-stimulated adenylate cyclase after dopamine depletion might enhance the response of the cell to opioids. The number of Ca+2-activated K+ channels will be determined by specific binding of the bee venom toxin, [125I]apamin. The number of guanine nucleotide binding (Go or Gi) proteins will be measured by [32P]ADP-ribosylation in the presence of pertussis toxin. Opioid agonist inhibition of dopamine-sensitive adenylate cyclase will be analyzed in plasma membrane fractions from nucleus accumbens. If alterations in these neurochemical parameters occur 10 days after the dopaminergic lesion,, then a time course of dopamine depletion will be correlated with the neurochemical alterations. To further evaluate the behavioral role of the Ca+2-activated K+ channels and of guanine nucleotide binding proteins, the opioid-induced augmentation in locomotor activity after dopamine depletion will be evaluated after apamin or pertussis toxin injections into the nucleus accumbens. Understanding the neurochemical basis for these dopamine-opioid interactions will provide mechanistic information in drug abuse situations where the use of cocaine and opioids has been combined.

伏隔核中的多巴胺和阿片受体至少 部分，负责增加自发活动后， 服用可卡因或阿片类药物。 虽然阿片系统不 依赖于多巴胺的作用，多巴胺的消耗将 增强阿片类药物诱导的自发活动。 神经化学基础 这种肽-胺相互作用尚未阐明。 耦合 多巴胺和阿片受体在同一突触后神经元中的表达可能 导致阿片受体对多巴胺的反应上调 耗尽 初步数据支持这一假设。 解剖 阿片受体亲和力或数量的任何增加的定位将是 通过定量受体放射自显影分析。 另一个假说是 多巴胺和阿片受体共享第二信使或离子 多巴胺缺乏会增强其活性。 修改 在Ca+2激活的K+通道数量、鸟嘌呤核苷酸结合 蛋白质或改变阿片类药物抑制多巴胺刺激的 多巴胺耗竭后腺苷酸环化酶可能会增强 细胞分泌阿片类药物 Ca+2激活的K+通道的数量将是 由蜂毒毒素[125 I]蜂毒蛋白的特异性结合确定。 的 将测量鸟嘌呤核苷酸结合（Go或Gi）蛋白的数量 在百日咳毒素存在下通过[32 P] ADP-核糖基化。 阿片 将分析多巴胺敏感性腺苷酸环化酶的激动剂抑制 细胞核的质膜组分中。 如果更改 这些神经化学参数发生在多巴胺能神经递质 损伤，那么多巴胺耗竭的时间过程将与 神经化学变化。 为了进一步评估 Ca+2激活的K+通道和鸟嘌呤核苷酸结合蛋白， 多巴胺后阿片诱导的自发活动增强 在将蜂毒肽或百日咳毒素注射到 脑桥核 了解这些的神经化学基础 多巴胺-阿片样物质相互作用将为药物治疗提供机制信息。 可卡因和类阿片混合使用的滥用情况。