ALCOHOL AND MESOLIMBIC DOPAMINE PATHWAY

酒精和中脑边缘多巴胺通路

• 批准号: 6460184
• 负责人: QINGSHAN YAN
• 金额: $ 1.5万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-03-01 至 2003-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6460184
• 关键词: central neural pathway /tract; dopamine; dopamine antagonists; ethanol; experimental brain lesion; laboratory rat; limbic system; microdialysis; neural transmission; neuropharmacology; nucleus accumbens; reinforcer; serotonin; tetrodotoxin

DESCRIPTION: (Adapted from the Investigator's Abstract) The long-term goal of this project is to elucidate further the neurochemical basis of the reinforcing effects of ethanol and to develop new strategy aimed at decreasing alcoholism in man. The proposed research will be carried out on freely moving rats by using intracerebral microdialysis technique to monitor in vivo dopamine (DA) release in the nucleus accumbens (NACC), a terminal area of the mesolimbic DA pathway. Pharmacologically relevant doses of ethanol will be administered systemically. First, DA and 5-HT in 5-min dialysate samples from the NACC will be measured simultaneously following acute ethanol to detect any changes in extracellular DA and 5-HT which occur during the ascending phase of the brain ethanol concentration curve. In addition, Ethanol-induced DA release in the NACC will be compared with and without the++ treatments with: 1) perfusion with tetrodotoxin (TTX) or Ca -free medium into the NACC, both of which are known to interrupt membrane depolarization; 2) perfusion with quinpirole, a D2 receptor agonist, into the ventral tegmental area (VTA) to suppress the mesolimbic DA neuronal activity; 3) nomifensine, a DA uptake blocker. This will enable us to determine whether and to what extent a carrier-dependent mechanism is involved in ethanol-induced DA release in the NACC. Furthermore, the effects of suppression (Lesioning with 5,7-DHT) or enhancement (pretreatment with 5-hydroxytryptophan and carbidopa) of the serotonergic transmission on ethanol-induced DA release will be evaluated. This will allow us to asses the possible involvement of the 5-HT system in the reinforcing effects of ethanol, the effects of agonists and antagonists at these subtypes of 5-HT2 receptors in the reinforcing effects of ethanol, the effects of agonists and antagonists at these subtypes of 5-HT receptor on ethanol-induced DA release in the NACC will be investigated. This will elucidate the relative contribution of 5-HT2 receptors to the regulation of ethanol-induced DA release and help to explain the effects of 5-HT2 antagonists on alcohol consumption reported in the literature.

描述：（改编自研究者摘要）长期目标 这个项目的目的是进一步阐明神经化学基础的 加强乙醇的影响，并制定新的战略， 减少人类的酒精中毒。拟议的研究将在 自由活动大鼠脑内微透析技术监测 在体内多巴胺（DA）释放在延髓核（NACC），一个终端 中脑边缘DA通路的区域。 药理学相关剂量 乙醇将被全身施用。 首先，DA和5-HT在5分钟内 NACC的透析液样本将在以下时间点同时测量： 急性乙醇检测细胞外DA和5-HT的任何变化， 在脑乙醇浓度曲线的上升阶段。 在 此外，将乙醇诱导的NACC中DA释放与 在没有用以下++处理的情况下：1）用河豚毒素（TTX）或Ca - 游离培养基进入NACC，已知这两者都中断膜 去极化; 2）用喹吡罗（一种D2受体激动剂）灌注， 腹侧被盖区（VTA）抑制中脑边缘DA能神经元 活性; 3）诺米芬辛，DA摄取阻断剂。 这将使我们能够 确定是否以及在多大程度上依赖于载体的机制 参与了NACC中乙醇诱导的DA释放。 而且 抑制作用（5，7-DHT损伤）或增强作用（预处理 与5-羟色氨酸和卡比多巴）的多巴胺能传递， 将评价乙醇诱导的DA释放。 这将使我们能够 5-HT系统可能参与增强 乙醇、激动剂和拮抗剂对这些5-HT 2亚型的作用 受体在乙醇的增强作用，激动剂的作用， 这些5-HT受体亚型的拮抗剂对乙醇诱导的DA释放的影响 NACC将被调查。 这将解释相对 5-HT_2受体对乙醇诱导的DA的调节作用 帮助解释5-HT 2拮抗剂对酒精的影响 消费在文献中报道。