Role of free radicals in the development of behavioural supersensitivity

多巴胺是一种存在于哺乳动物大脑中的化合物。在它的新陈代谢过程中，会产生被称为自由基的有害化合物。正是这些自由基的积累产生了氧化应激状态，这是许多动物和人类异常行为的真实的罪魁祸首。这种异常行为的机制尚不清楚。我们最近发现，在线粒体中发现的一种蛋白质在氧化应激反应中被释放并易位到细胞核。这种蛋白质被称为凋亡（细胞死亡）诱导因子。我们发现，在人类和大鼠的大脑中，多巴胺D2受体阻断剂氟哌啶醇会导致这种蛋白质易位到细胞核，从而杀死健康的神经元。这些事件导致大鼠出现行为异常。本研究旨在探讨竞争性阻断多巴胺D2受体引起多巴胺受体超敏反应的机制。这些实验将涉及对实验室大鼠给予氟哌啶醇，捕获多巴胺代谢过程中产生的自由基，测量Streotyped行为，并通过氟哌啶醇治疗期间多巴胺代谢增加确定多动症与自由基形成之间的关系。这些研究结果将：（1）提高我们对氧化应激导致行为异常发展的分子机制的理解;（2）有助于阐明自由基和捕获剂的作用;（3）解释神经毒性效应是否涉及内源性产生的多巴胺诱导的氧化应激;（4）对科学界产生重大影响，特别是研究药物作用、氧化应激和多巴胺代谢的基础神经科学家。该项目将取得技术进步，一些学生将在具有挑战性的生物技术和药理学领域接受培训。这将大大有利于加拿大生物技术公司在药物开发，并大大有利于加拿大人。

Dopamine is a chemical compound present in mammalian brains. During its metabolism, harmful compounds called free radicals are produced. It is the accumulation of these free radicals that produce a state of oxidative stress, which is a real culprit in many animal and human abnormal behaviour. The mechanisms involved in such abnormal behaviour are not yet understood. We have recently discovered that a protein found in the mitochondria is released and translocates to the nucleus in response to oxidative stress. This protein is called apoptosis (cell death) inducing factor. We discovered that both in humans and rat brains, dopamine D2 receptor blocking agent haloperidol causes translocation of this protein to the nucleus and thus kills healthy neurons. These events lead to the development of behavioural abnormalities in rats. The present study will be undertaken to investigate the mechanisms involved in the development of dopamine receptor supersensitivity caused by competitively blocking the dopamine D2 receptors. The experiments will involve the administration of haloperidol to laboratory rats, trapping of free radicals produced during the metabolism of dopamine, measurement of streotyped behaviour and establishment of a relationship between hyperactivity and free radical formation by increased dopamine metabolism during haloperidol treatment. The results of these studies will: (1) enhance our understanding of the molecular mechanisms involved in the development of behavioural abnormalities due to oxidative stress; (2) help in elucidating the role of free radicals and trapping agents; (3) explain whether the neurotoxic effects involve endogenously produced dopamine-induced oxidative stress; (4) have a significant impact on the scientific community, specifically basic neuroscientists studying drug effects, oxidative stress and dopamine metabolism. The project will make technological advances and several students will be trained in challenging fields of biotechnology and pharmacology. This will greatly benefit Canadian Biotech companies in the development of drugs, and significantly benefit Canadians.