Role of free radicals in the development of behavioural supersensitivity

多巴胺是存在于哺乳动物大脑中的一种化合物。在它的新陈代谢过程中，会产生一种叫做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正罪魁祸首。这种异常行为的机制尚不清楚。我们最近发现，线粒体中的一种蛋白质在氧化应激反应中被释放并易位到细胞核中。这种蛋白质被称为细胞凋亡（细胞死亡）诱导因子。我们发现，在人类和老鼠的大脑中，多巴胺D2受体阻滞剂氟哌啶醇会导致这种蛋白质转移到细胞核，从而杀死健康的神经元。这些事件导致大鼠行为异常的发展。本研究将探讨竞争性阻断多巴胺D2受体导致多巴胺受体超敏反应的机制。实验将包括给实验室大鼠注射氟哌啶醇，捕获多巴胺代谢过程中产生的自由基，测量刻板行为，并在氟哌啶醇治疗期间通过增加多巴胺代谢来建立多动症与自由基形成之间的关系。这些研究的结果将：(1)增强我们对氧化应激引起的行为异常发展的分子机制的理解；(2)有助于阐明自由基和诱捕剂的作用；(3)解释内源性多巴胺诱导的氧化应激是否涉及神经毒性作用；(4)对科学界，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有重大影响。该项目将推动技术进步，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开发药物，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.