NEUROPHARMACOLOGY OF ETHANOL REINFORCEMENT

乙醇强化的神经药理学

• 批准号: 3112531
• 负责人: George F. Koob
• 金额: $ 18.35万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 1990
• 资助国家: 美国
• 起止时间: 1990-04-01 至 1993-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3112531
• 关键词: afferent nerve; alcoholic beverage consumption; alcoholism /alcohol abuse; alcoholism /alcohol abuse chemotherapy; blood chemistry; cholecystokinin; cocaine; dopamine; drug abuse; drug adverse effect; drug receptors; efferent nerve; ethanol; experimental brain lesion; glutamates; histology; intercellular connection; laboratory rat; microinjections; neuropeptides; neuropharmacology; neurophysiology; neurotensin; neurotransmitters; nucleus accumbens; preference; psychological reinforcement; reinforcer; statistics /biometry

Ethanol has reinforcing properties in man that presumably contribute to alcohol abuse and alcoholism. In rats ethanol is readily self-administered orally when taste factors are minimized by pre-exposing the rats to sweetened solutions. Non-dependent and non-deprived rats will choose ethanol over water in limited access situations and will self-administer sufficient quantities to produce meaningful blood ethanol levels. Work attempting to identify specific neurotransmitters involved in ethanol reinforcement has recently shown that low doses of ethanol can release dopamine in the region of the nucleus accumbens and that dopamine agonists appear to reduce ethanol preference without decreasing water intake. The nucleus accumbens is one of the converging points for a limbic-forebrain- extrapyramidal circuit upon which other reinforcing drugs such as cocaine and heroin may act to produce their reinforcing effects. The purpose of the present proposal is to examine the role of the nucleus accumbens and its afferent and efferent connections in ethanol reinforcement. Non- deprived male Wistar and male Alcohol Preferring (P) rats will be trained to self-administer ethanol in daily 30 min sessions using a saccharin fade out procedure. The role of the mesocorticolimbic dopamine projections to the nucleus accumbens will be tested using 6-hydroxydopamine lesions to the nucleus accumbens. The role of other afferents to the nucleus accumbens will be examined using cell body (ibotenic acid) lesions of the amygdala and hippocampus. The role of neural circuitry efferent to the nucleus accumbens will be examined using cell body (ibotenic acid) lesions of the nucleus accumbens itself, the ventral pallidum, and other efferent connections. The function of specific neurotransmitters hypothesized to modulate this circuitry will be examined by microinjection of agonists and antagonists of opioid peptides, neurotensin, glutamate and cholecystokinin into either the nucleus accumbens or ventral pallidum. These proposed studies parallel published or ongoing studies on the neuropharmacology of psychomotor and opiate reinforcement and as such will provide a means to evaluate the similarities and uniqueness of the substrates for ethanol reinforcement. These results should have important implications not only for our understanding of the neurobiology of ethanol intoxication but may lead to the development of viable pharmacological intervention in alcoholism.

乙醇对人体具有增强作用，可能有助于 酗酒和酗酒。 在大鼠中，乙醇很容易自行给药 当通过将大鼠预先暴露于味觉因素最小化时，口服 甜化解决方案。 非依赖和非剥夺的老鼠会选择 在受限情况下使用乙醇代替水，并且会自我管理 足够的量以产生有意义的血液乙醇水平。 工作 试图识别乙醇中涉及的特定神经递质 最近的研究表明，低剂量的乙醇可以释放 伏隔核区域的多巴胺和多巴胺激动剂 似乎在不减少水摄入量的情况下减少了对乙醇的偏好。 这 伏隔核是边缘系统-前脑系统的交汇点之一 其他增强药物（如可卡因）的锥体外系循环 和海洛因可能会产生增强作用。 目的 目前的建议是研究伏隔核和 其在乙醇强化中的传入和传出连接。 非- 将训练被剥夺的雄性 Wistar 和雄性酒精偏好 (P) 大鼠 使用糖精淡化剂每天 30 分钟自行施用乙醇 出程序。 中皮质边缘多巴胺投射的作用 伏隔核将使用 6-羟基多巴胺损伤进行测试 伏隔核。 其他传入神经对伏隔核的作用 将使用杏仁核的细胞体（鹅膏菌酸）病变进行检查 和海马体。 传出至细胞核的神经回路的作用 将使用伏隔核的细胞体（鹅膏菌酸）病变进行检查 伏隔核本身、腹侧苍白球和其他传出神经 连接。 假设特定神经递质的功能 调节该电路将通过显微注射激动剂进行检查 阿片肽、神经降压素、谷氨酸和胆囊收缩素的拮抗剂 进入伏隔核或腹侧苍白球。 这些建议 研究与已发表或正在进行的神经药理学研究并行 精神运动和鸦片强化，因此将提供一种手段 评估乙醇底物的相似性和独特性 加强。 这些结果不仅应该具有重要意义 帮助我们了解乙醇中毒的神经生物学，但可能 导致可行的药物干预的发展 酗酒。