BRAIN DOPAMINE SITES STIMULATED BY SUCROSE SHAM FEEDING

蔗糖假喂养刺激大脑多巴胺位点

• 批准号: 3476850
• 负责人: LINDA H SCHNEIDER
• 金额: $ 8.6万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 1987
• 资助国家: 美国
• 起止时间: 1987-04-01 至 1992-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3476850
• 关键词: SCH 23390; antiadrenergic agents; dietary carbohydrates; dopamine receptor; drug administration routes; experimental brain lesion; hypothalamus; laboratory rat; neurochemistry; neurotransmitter metabolism; nutrition related tag; psychological reinforcement; sucrose

Our hypothesis is that brain dopamine D-1 and/or D-2 receptors mediate the positive reinforcing effect of sucrose on eating. We will study sham feeding of sucrose in rats chronically implanted with gastric cannulas (to eliminate post-ingestive effects) and with brain cannulas (for central drug infusions). Four experiments are proposed, the first three use a pharmacological approach, and the fourth, a neurochemical approach. In Experiment 1, the potent, selective D-1 and D-2 receptor antagonists, SCH 23390 and raclopride, respectively, will be infused unilaterally (in separate groups) into a lateral ventricle (i.c.v.). An ID50 for inhibition of sucrose sham feeding will be determined. Necessary controls include: (1) central versus peripheral locus of inhibitory action (ID50 i.c.v. vs i.p.); (2) stereospecificity of inhibition (active vs. inactive enantiomers i.c.v.), and (3) behavioral specificity (sucrose sham feeding vs. water sham drinking). In Experiment 2, the same sequence of testing described in Experiment 1 will be conducted, but the antagonists will be microninjected bilaterally into forebrain dopaminergic terminal zones. These sites have been implicated in the positive reinforceing effects of sucrose in our previous neurochemical experiments, as well as in reinforcement by foods, drugs and electrical stimulation by others. In Experiment 3, sites at which the local applications of selective D-1 and/or D-2 receptor antagonists are found to inhibit sucrose sham feeding in Experiment 2 will be further studied pharmacologically. The chronic destruction of dopaminergic terminals in these sites identified in Experiment 2 will be performed using 6-OHDA infusions bilaterally and the effects of these lesions on sham feeding of sucrose will be determined. Dopamine agonist replacement with dopamine (DA) itself or the selective D-1 (SKF) 38393) and D-2 (LY-141865) agents will be examined. In Experiment 4, we propose to quantify brain dopaminergic metabolism (DOPAC/DA) in discrete micropunched regions corresponding to those studied in Experiments 2 and 3. This will be measured after 9 min of sham feeding sucrose, using HPLC with electrochemical detection. The results of the four experiments will provide converging pharmacological, behavioral and neurochemical evidence to test the hypothesis that specific brain D-1 and/or D-2 sites mediate the positive reinforcing effect of sucrose on sham feeding.

我们的假设是大脑多巴胺D-1和/或D-2受体 介导蔗糖对进食的正强化作用。 我们 将在长期植入的大鼠中研究假喂食蔗糖 使用胃插管（以消除摄食后效应）， 脑插管（用于中央药物输注）。 四个实验 提出，前三个使用药理学方法， 第四种是神经化学方法。 在实验1中，强有力的、选择性的D-1和D-2受体 拮抗剂，SCH 23390和雷氯必利，将分别 单侧（分组）输注至侧脑室 （i.c.v.）。 抑制蔗糖假喂食的ID 50将为 测定 必要的控制包括：（1）中央与 外周抑制作用位点（ID 50 i. c. v. vs i. p.）;（二） 抑制的立体特异性（活性对非活性对映体 i.c.v.），（3）行为特异性（蔗糖假饲vs. 饮用水（sham drinking）。 在实验2中，使用与在 将进行实验1，但拮抗剂将在 双侧前脑多巴胺能末梢微量注射 区界限 这些网站都与积极的 增强蔗糖在我们之前的神经化学物质中的作用 实验，以及通过食物，药物和 其他人的电刺激。 在实验3中，选择性地局部应用 发现D-1和/或D-2受体拮抗剂抑制蔗糖 将进一步研究实验2中的假饲养 - 是的 多巴胺能神经元的慢性破坏 实验2中确定的这些站点中的终端将被 使用双侧6-OHDA输注进行， 将测定蔗糖假喂食时的这些损伤。 多巴胺受体激动剂替代多巴胺（DA）本身或 选择性D-1（SKF）38393）和D-2（LY-141865）试剂将被 考察 在实验4中，我们提出定量脑多巴胺能神经元的数量， 离散微穿孔区域的代谢（DOPAC/DA） 与实验2和3中研究的那些相对应。 这将 在假喂食蔗糖9分钟后，使用HPLC测量 电化学检测。 四个实验的结果将提供收敛 药理学、行为学和神经化学证据， 假设特定的脑D-1和/或D-2位点介导 蔗糖对假摄食的正强化作用。