MARIJUANA & DOPAMINE/ENKEPHALIN BRAIN REWARD SYSTEMS

大麻

• 批准号: 3208158
• 负责人: ELIOT L GARDNER
• 金额: $ 20.59万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 1984
• 资助国家: 美国
• 起止时间: 1984-04-01 至 1992-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3208158
• 关键词: brain mapping; cannabinoids; centrally acting drug; dopamine; dopamine receptor; electrochemistry; experimental brain lesion; inhibitor /antagonist; laboratory rat; limbic system; microinjections; neuropeptide receptor; neurotoxins; neurotransmitter metabolism; opioid receptor; psychopharmacology; reinforcer; self stimulation

The objective of the proposed research is to gain further insights into marijuana's action on brain reward circuits and on dopamine (DA) and enkephalinergic mechanisms involved in marijuana, derive part of their abuse liability from neuropharmacological facilitation of brain reward circuits. During the period of previous NIDA grant support for this work, we demonstrated that delta-9-tetrahydrocannabinol (delta9-THC), the major psychoactive ingredient in marijuana, does the following: (1) lowers direct brain reward thresholds in the medial forebrain bundle, in a rat strain-specific fashion, (2) enhances presynaptic release of known to support brain reward, and (3) interacts noncompetitively with endogenous brain delta and Mu opioid receptors but not Kappa receptors, and the opioid receptor interaction of a series of cannabinoid analogs correlates crudely but not precisely with psychoactive potency. The general aim of the presently proposed work is to carry forward and extend all these findings. The specific aims are to (1) extend ours studies of delta9-THC and analogs on direct brain reward as measured by electrical intracranial self- stimulation in laboratory rats; (2) extend our studies of the effects of delta9-THC and analogs on DA release, in forebrain DA loci supporting direct brain reward, as measured by both in vivo voltammetric electrochemistry and in vivo intracranial microdialysis; and (3) extend our studies of the interaction of delta9-THC and selected analogs with endogenous brain opioid receptors, as measured by receptor binding and quantitative autoradiography. A major aim running throughout is to learn the specific locus in the brain of the already-demonstrated delta9-TCH effects. This proposal addresses specific research needs stipulated in the NIDA Marijuana Research Announcement and in NIDA Grant Announcement DA-87- 24 ("...studies are needed concerning the neurophysiological effects of marijuana, including potential sites and mechanisms of action.." "...research areas of particular importance include...brain reward mechanisms"). By adding to our understanding of marijuana's effects on one of the presumptive principal neurophysiological substrates of drug abuse liability, these studies should yield additional insight into fundamental brain mechanisms underlying marijuana's abuse potential, and to treatment possibilities for marijuana abuse. The health relatedness is clear, given that marijuana is the most widely used illicit drug in the United States, and given the evidence for health consequences of chronic marijuana abuse.

拟议研究的目的是进一步深入了解 大麻对大脑奖赏回路和多巴胺(DA)的作用 参与大麻的脑啡肽能机制，派生出其部分 神经药物促进脑奖赏的滥用倾向 电路。在之前NIDA对这项工作的赠款支持期间， 我们证明了三角洲-9-四氢大麻酚(Delta9-THC)，主要的 大麻中的精神活性成分具有以下作用：(1)降低 大鼠内侧前脑束的直接脑奖赏阈值 特定菌株的方式，(2)增强已知的突触前释放 支持脑奖励，以及(3)与内源性的非竞争性相互作用 脑三角洲和Mu阿片受体，而不是Kappa受体和阿片类药物 一系列大麻素类似物的受体相互作用粗略相关 但并不完全具有精神活性。该计划的总体目标 目前拟议的工作是继承和推广所有这些调查结果。 具体目的是(1)扩展我们对Delta9-THC及其类似物的研究 脑电自体测量的直接脑奖赏研究 对实验大鼠的刺激；(2)扩大我们对 Delta9-THC及其类似物对前脑DA基因座DA释放的影响 在体伏安法测量的直接脑奖赏 电化学和体内颅内微透析；以及(3)扩大我们的 Delta9-THC与部分类似物相互作用的研究 内源性脑阿片受体，通过受体结合和 定量放射自显影。贯穿始终的一个主要目标是学习 已经证实的Delta9-Tch在大脑中的特定位置 效果。这项建议满足了《 NIDA大麻研究公告和NIDA赠款公告DA-87- 24(“……需要进行有关神经生理效应的研究。 大麻，包括潜在的场所和作用机制。 “……特别重要的研究领域包括……大脑奖励。 通过增加我们对大麻对一个人的影响的理解 药物滥用的主要神经生理学底物 负债，这些研究应该会对基本面有更多的洞察 大麻潜在滥用的大脑机制及其治疗 大麻滥用的可能性。与健康相关的很明显，给出了 大麻是美国使用最广泛的非法药物， 并给出了长期滥用大麻对健康造成影响的证据。