NEUROPHARMACOLOGY OF ETHANOL REINFORCEMENT

乙醇强化的神经药理学

• 批准号: 3112532
• 负责人: George F. Koob
• 金额: $ 17.68万
• 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/3112532
• 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.

乙醇在人类中具有加强特性，大概有助于 酗酒和酗酒。 在老鼠中，乙醇很容易自我管理 口服味觉因素通过预先暴露的大鼠最小化时 甜味的解决方案。 非依赖和非剥夺大鼠会选择 在有限的通道情况下，乙醇在水上，并将自我管理 足够数量产生有意义的血乙醇水平。 工作 试图识别乙醇涉及的特定神经递质 强化最近表明，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 似乎可以减少乙醇偏好而不减少摄入量。 这 伏隔核是边缘 - 前脑的融合点之一 锥体旁电路，其他增强药物（例如可卡因） 海洛因可以采取行动产生增强作用。 目的 目前的建议是检查伏隔核的作用和 它在乙醇增强中的传入和传出联系。 非- 被剥夺的雄性Wistar和雄性酒精偏爱（P）大鼠将接受训练 每天使用糖精褪色在每天30分钟的课程中自我管理乙醇 淘汰程序。 中皮质降胺多巴胺投影的作用 将使用6-羟基多巴胺病变对伏隔核进行测试 伏隔核。 其他传入对伏隔核的作用 将使用杏仁核的细胞体（ibotenic Acid）病变检查 和海马。 神经回路传播的作用 将使用细胞体（ibotenic Acid）病变检查伏托人 伏隔核本身，腹侧颗粒和其他传出 连接。 假设的特定神经递质的功能 调节该电路将通过对激动剂的显微注射和 阿片类肽，神经辛，谷氨酸和胆囊动蛋白的拮抗剂 进入伏隔核或腹侧颗粒。 这些提议 研究平行于发表或正在进行的有关神经药理的研究 精神运动和鸦片加强，因此将为 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的影响 为了理解乙醇中毒的神经生物学，但可能 导致有可行的药理学干预的发展 酗酒。