MARIJUANA & DOPAMINE/ENKEPHALIN BRAIN REWARD SYSTEMS

拟议研究的目的是进一步了解 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，衍生出他们的一部分， 脑奖励的神经药理学促进的滥用倾向 电路. 在以前NIDA对这项工作的资助期间， 我们证明了δ-9-四氢大麻酚（δ 9-THC）， 大麻中的精神活性成分，有以下作用：（1）降低 大鼠内侧前脑束的直接脑奖励阈值 应变特异性的方式，（2）增强突触前释放已知的 支持大脑奖励，（3）与内源性非竞争性相互作用 大脑δ和Mu阿片受体，但不是Kappa受体， 一系列大麻素类似物的受体相互作用与 但并不完全具有精神活性。 的总体目标 目前建议的工作是将这些研究成果加以推广和发扬。 具体目的是（1）扩展我们对delta9-THC及其类似物的研究 通过颅内自我电测量的直接大脑奖励， 刺激实验大鼠;（2）扩大我们的研究的影响， δ 9-THC和类似物对DA释放的影响，在前脑DA位点支持 直接大脑奖励，如通过体内伏安法和 电化学和体内颅内微透析;和（3）扩展我们的 δ 9-THC和所选类似物与 内源性脑阿片受体，如通过受体结合和 定量放射自显影 贯穿始终的一个主要目的是学习 已经证实的delta9-TCH在大脑中的特定位点 方面的影响. 本建议针对《公约》规定的具体研究需要， NIDA Maritime Research Announcement and in NIDA Grant Announcement DA-87- 24（".需要研究的神经生理学影响的 大麻，包括潜在的网站和作用机制。" "...特别重要的研究领域包括……大脑奖励 机制"）。 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基础 责任，这些研究应该产生额外的洞察力，基本 大麻滥用潜力的大脑机制，以及治疗 大麻滥用的可能性。 健康相关性是明确的，鉴于 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的健康后果的证据。

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.