NIGROTECTAL GABA NEURONS IN ALCOHOL AND KINDLED SEIZURES

酒精和点燃的癫痫发作中的黑质 GABA 神经元

• 批准号: 3069357
• 负责人: JOANNA PERIS
• 金额: $ 6.3万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 1990
• 资助国家: 美国
• 起止时间: 1990-09-28 至 1995-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3069357
• 关键词: GABA receptor; alcoholic beverage consumption; autoradiography; chemical binding; cocaine; density; dopamine receptor; drug abuse; drug interactions; drug withdrawal; electrostimulus; image processing; inferior colliculus; ion exchange chromatography; laboratory rat; mesencephalon; neural transmission; neurons; receptor binding; receptor expression; reflex epilepsy; statistics /biometry; substantia nigra; superior colliculus; toxicology

Dr. Peris is currently an Assistant Professor in the College of Pharmacy at the University of Florida. Her primary research interest is studying the neurochemical basis for behavioral changes, including increases in seizure sensitivity, induced by different chronic drug exposure. She is pursuing this interest in her current R01 grant from NIAAA and is planning future grant proposals along these same lines. The research project described in this proposal will study changes in nigrostriatal and nigrotectal GABAergic neurotransmission that occur with increased seizure sensitivity. The GABAergic striatonigral and nigrotectal pathways appear to play a major role in the control of seizure activity but it is not known if these inhibitory GABAergic pathways are affected similarly by different proconvulsant treatments. Parameters of GABAergic transmission include GABA release, GABA(A) receptor binding and GABA(A) receptor-mediated Cl- flux. These measures will be made in substantia nigra (SN), superior colliculus (SC) and inferior colliculus (IC) in three proconvulsant models that have opposite initial effects on GABA(A) receptor function. The first model of increased seizure susceptibility will use rats chemically kindled with the benzodiazepine inverse agonist, FG7142, which suppresses GABA(A) receptor function. The second model will use alcohol-withdrawn rats with increased susceptibility to handling-induced seizures. Ethanol enhances GABA(A) receptor function. The third model will use rats kindled via repeated electrical stimulation of the amygdala which does not directly affect GABA systems. It is proposed that after each of these proconvulsant treatments, GABA function will decrease in the striatonigral pathway and increase in the nigrotectal pathway and that these changes are not dependent on the occurrence of a seizure. This pattern of changes would greatly increase inhibitory output to the SC, thereby decreasing SC output to reticular formation and spinal cord which and increasing seizure susceptibility. If a similar pattern of changes occurs in GABAergic transmission in the striatonigral and nigrotectal pathways in each of these three models, then a more general role of these GABAergic pathways is indicated. These studies will have important implications in the characterization and potential treatment of seizures. Dr. Peris' future projects include eventual renewal of the R01 described above plus another research proposal to ADAMHA on the neurochemical changes in GABA and dopamine transmission during chronic concurrent ethanol and cocaine exposure. The University of Florida Health Sciences Center has a strong program in the study of alcohol and drug abuse, including faculty in Dr. Peris' department and in the Departments of Pharmacology and Neuroscience in the College of Medicine. This is therefore a strong, supportive environment in which the candidate can interact with more senior faculty. This RSDA will give the candidate the financial support necessary to pursue her research interest as her sole focus in the next 5 years, and to develop her own strong, independent research program.

佩里斯博士目前是药学院的助理教授 佛罗里达大学。她的主要研究兴趣是研究 行为改变的神经化学基础，包括癫痫发作的增加 灵敏度，由不同的慢性药物暴露引起。她正在追求 对她目前的NIAAA赠款的这种兴趣，正在计划未来 批准同样的建议。所描述的研究项目 该提案将研究黑质纹状体和骨直肠直肠gabaergic的变化 随着癫痫发作敏感性的增加而发生的神经传递。这 Gabaergic纹状体和黑直直肠途径似乎起着很大的作用 在控制癫痫活性的控制中的作用，但尚不清楚这些是否存在 抑制性GABA能途径受到不同的影响 突发治疗。 GABA能传输的参数包括GABA 释放，GABA（A）受体结合和GABA（A）受体介导的Cl-通量。 这些措施将在黑质（SN），上丘中进行 （SC）和下丘（IC）（IC） 对GABA（A）受体功能的初始影响相反。第一个模型 癫痫发作易感性提高将使用化学点燃的大鼠 苯二氮卓类激动剂FG7142，抑制GABA（A）受体 功能。第二个模型将使用含酒精的大鼠随着增加 对处理引起的癫痫发作的敏感性。乙醇增强GABA（A） 受体功能。第三个模型将使用重复点燃的大鼠 不直接影响GABA的杏仁核的电刺激 系统。有人提出，在这些浮标治疗中的每一个之后， GABA功能将在纹状体途径中降低并增加 黑骨直肠途径，这些变化并不取决于 癫痫发作的发生。这种变化的模式将大大增加 SC的抑制输出，从而将SC输出降低到网状 形成和脊髓，并增加了癫痫发作的敏感性。如果a 类似的变化模式发生在GABA能传播中 在这三个模型中的每一个中，纹状体和斑纹直肠途径，然后 指出了这些GABA能途径的更一般作用。这些研究 将对特征和潜力具有重要意义 癫痫发作的治疗。 佩里斯博士的未来项目包括最终续订R01 上面加上Adamha关于神经化学变化的另一项研究建议 在慢性并发乙醇期间的GABA和多巴胺传播中 可卡因暴露。佛罗里达大学健康科学中心有一个 在研究酗酒和药物滥用方面的强大计划，包括 佩里斯博士的部门以及药理学部门 医学院的神经科学。因此，这是一个强大的 候选人可以与更多高级互动的支持环境 学院。此RSDA将为候选人提供必要的财务支持 在接下来的5年中，她的研究兴趣是她的唯一重点，并且 制定自己的强大独立研究计划。