ALCOHOL REWARD AND BRAIN DOPAMINE--PHARMACO-MODULATIONS

酒精奖励和大脑多巴胺——药物调节

• 批准号: 3443564
• 负责人: ELIOT L GARDNER
• 金额: $ 11.61万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 1992
• 资助国家: 美国
• 起止时间: 1992-09-30 至 1994-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3443564
• 关键词: alcoholism antagonist; alcohols; behavioral medicine; brain metabolism; corpus striatum; dopamine; drug withdrawal; electrochemistry; electrostimulus; enkephalins; frontal lobe /cortex; genetic strain; high performance liquid chromatography; laboratory rat; microdialysis; microinjections; neuropharmacology; nucleus accumbens; reinforcer; self stimulation

The objective of this research is to gain further insight into alcohol's action on brain reward circuits and on dopamine (DA) and enkephalinergic mechanisms involved in direct brain reward. This work derives from the hypothesis that abusable substances, including ethanol, derive part of their abuse liability from neuropharmacological facilitation of brain reward circuits. Some workers report that exogenous ethanol robustly lowers brain-stimulation reward thresholds, while others report that experiential factors are additive to ethanol's pharmacological facilitation of brain-reward. We and others have recently found that self-administration of ethanol in laboratory rats more robustly enhances brain reward than exogenous administration. It is also well-established that significant genetic differences exist among rat strains regarding alcohol preference. One alcohol-preferring strain, the Lewis rat, is also unusually sensitive to morphine and cocaine, and shows significantly higher preferences for morphine and cocaine than other rat strains. We have shown that the Lewis rat is also uniquely sensitive to the brain-reward enhancing effects of delta(9)-tetrahydrocannabinol (delta(9)-THC), the psychoactive ingredient in marijuana, and that this unique sensitivity to brain-reward facilitation correlates highly with a unique sensitivity of Lewis rats to facilitation of extracellular DA in reward-relevant loci in the nucleus accumbens, a crucial forebrain limbic convergence of reward-related DA circuitry. The general aim of the presently proposed work is to carry forward and extend all these previous findings, with the hope of identifying forebrain DA mechanisms that may correlate with high ethanol preference, and determine whether it is possible to modulate those mechanisms pharmacologically - thus hopefully opening up new possibilities of pharmacotherapy for alcohol addiction and abuse. The specific aims are to 1) study the effect of exogenously-administered versus self-administered ethanol on extracellular DA efflux (as measured by in vivo brain microdialysis and in vivo voltammetry) in three reward-relevant DA forebrain loci - nucleus accumbens, medial prefrontal cortex, and neostriatum; 2) study the effect of strain differences (alcohol-preferring Lewis rats versus non-preferring F344 rats) on exogenously-administered and self-administered ethanol-induced extracellular DA efflux in these three reward-relevant DA forebrain loci; 3) study effects seen in 1) and 2) in both normal animals and protracted-abstinence animals; and 4) study possible pharmacological modulations (by serotonergic, DAergic, and enkephalinergic manipulations) of effects seen in 1), 2), and 3). This application addresses specific research needs stipulated in NIAAA Request for Applications RFA-AA-92-01 [Research on Pharmacologic Treatments for Alcoholism] and NIAAA Program Announcement PA-91-97 [Exploratory/Developmental Grants (R21) for Research on the Etiology of Alcoholism] ("..Goals include clarifying the basis for alcohol craving so that more effective therapeutic agents, such as dopaminergic agonists and serotonin uptake inhibitors, can be tested.. ..Research is required to specifically delineate the potential of agents that alter dopaminergic function..and..to identify the precise mechanisms by which the opioid system alters drinking behavior..").

这项研究的目的是为了进一步了解酒精的 对大脑奖赏回路和多巴胺的作用 (DA)和脑啡肽能机制参与直接脑奖励。 这项工作源于一种假设，即可滥用的物质，包括 乙醇，从神经药理学中获得部分滥用倾向 促进大脑奖励回路。 一些工人报告说， 外源性乙醇强烈降低脑刺激奖励阈值， 而另一些人报告说，经验因素是乙醇的添加剂， 大脑奖赏的药理学促进作用。 我们和其他人已经 最近发现，在实验室大鼠中， 比外源性给药更有力地增强了大脑的奖赏。 是 也很好地建立了显着的遗传差异存在于 老鼠对酒精的偏好 一种嗜酒精的菌株， 刘易斯大鼠对吗啡和可卡因也异常敏感， 对吗啡和可卡因的偏好明显高于 其他老鼠品种 我们已经证明，刘易斯大鼠也是独特的 对大脑奖赏增强效应敏感 delta（9）-tetrahydrocannabinol（delta（9）-THC），精神活性成分 这种对大脑奖赏的独特敏感性 易化与刘易斯大鼠对 细胞外DA在核内奖赏相关位点的易化作用 奖励相关DA的重要前脑边缘会聚 电路 目前拟议工作的总体目标是进行 我们继续并扩展所有这些先前的发现，希望 确定可能与高乙醇相关的前脑DA机制 偏好，并确定是否有可能调整这些 因此，有希望开辟新的 酒精成瘾和滥用药物治疗的可能性。 的 具体目的是1）研究外源性施用的效果 与自我给药乙醇对细胞外DA流出的影响（如测量的 通过体内脑微透析和体内伏安法）在三个 奖赏相关DA前脑位点-内侧前额叶背侧核 皮质和新纹状体; 2）研究应变差异的影响 （酒精偏好刘易斯大鼠与非酒精偏好F344大鼠） 外源性给药和自我给药乙醇诱导 这三个奖赏相关DA前脑位点的细胞外DA流出; 3)在1）和2）正常动物中观察到的研究效应， 长期禁欲动物;和4）研究可能的药理学 调节（通过多巴胺能、DA能和脑啡肽能操作） 在1），2）和3）中看到的效果。 该应用程序针对特定的 NIAAA申请书RFA-AA-92 - 01中规定的研究需求 [酒精中毒药物治疗研究]和NIAAA计划 公告PA-91 - 97 [探索/发展赠款（R21） 酒精中毒的病因学研究（"...目标包括澄清 酒精渴望的基础，使更有效的治疗剂，如 作为多巴胺能激动剂和5-羟色胺摄取抑制剂，可以进行测试。 ..需要进行研究，以具体描述药物的潜力 会改变多巴胺功能然后..来确定 阿片系统通过它改变饮酒行为。").