Role of free radicals in the development of behavioural supersensitivity

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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.