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，即可滥用物质，包括 乙醇，他们的部分滥用责任来自神经药物 大脑奖赏回路的便利化。一些工人报告说 外源乙醇有力地降低了大脑刺激的奖励阈值， 而另一些人报告说，经验因素是乙醇的附加因素 脑奖赏的药理促进作用。我们和其他人有 最近发现，在实验大鼠中自我给予乙醇 与外源性给药相比，更有力地增强了大脑奖励。它是 同样公认的是，不同种族之间存在显著的遗传差异 关于酒精偏好的老鼠品系。一株喜欢酒精的菌株， 刘易斯大鼠对吗啡和可卡因也异常敏感， 显示出对吗啡和可卡因的偏好明显高于 其他品系的老鼠。我们已经证明，刘易斯鼠也是独一无二的 对脑奖赏的增强作用敏感 Delta(9)-四氢大麻酚(Delta(9)-THC)，精神活性成分 在大麻中，这种对大脑奖励的独特敏感性 易化与Lewis大鼠对 胞外DA在核内奖赏相关位点的易化作用 伏隔，奖赏相关多巴胺的重要前脑边缘会聚区 电路。目前拟议的工作的总体目标是 推广和推广所有这些先前的发现，希望 识别可能与高酒精相关的前脑DA机制 偏好，并确定是否有可能调节这些 药理机制--因此有望开辟新的 酒精成瘾和滥用药物治疗的可能性。这个 具体目标是1)研究外源性给药的效果 乙醇对细胞外DA外流的影响(测量结果) 通过活体脑微渗析和体内伏安法) 奖赏相关DA前脑部位--伏核、前额内侧核 2)研究了品系差异的影响 (偏爱酒精的Lewis大鼠与不偏爱F344的大鼠) 外源性和自体给药乙醇诱导 这三个与奖赏相关的DA前脑基因座的细胞外DA外流； 3)在1)和2)在正常动物和 长期戒断动物；以及4)研究可能的药理作用 调节(通过5-羟色胺能、多巴能和脑啡肽能操作) 在1)、2)和3)中看到的效果。此应用程序针对特定的 NIAAA申请申请书RFA-AA-92-01规定的研究需求 [酒精中毒的药物治疗研究]与NIAAA计划 公告PA-91-97[勘探性/开发性补助金(R21) 酒精中毒病因学研究](..目标包括澄清 酒精渴求的基础，以便更有效的治疗剂，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。 ..需要进行研究来具体描述代理人的潜力 改变多巴胺能功能..和..以确定精确的机制 通过阿片系统改变饮酒行为..)。