The long term objective of the work described in this application is to use positron emission tomography (PET) to study various aspects of 5- HT (serotonin) metabolism in the human brain in order to obtain more information about the role of 5-HT in the biology of neurological and/or mental disorders and their treatment. In this application, we are proposing human studies that will use a new method for measuring the rat of 5-HT synthesis in discreet areas in the living human brain. The measurements of the 5-HT synthesis rate in the living human brain should give us a better understanding of the biochemistry underlining different brain diseases associated with a dysfunction of the brain 5HT system, as well as therapies used to alleviate the brain- 5-HT-related diseases. The principle of the method used in the proposed study is based on the irreversible trapping of a radioactively labelled tracer, an analog of the essential amino acid tryptophan, alpha-methyl-L-tryptophan. We have methylserotonin. Alpha- Methylserotonin is not a substrate for brain monoamine oxidase and as such gets trapped in the brain, permitting easier measurement of the brain radioactivity and easier biological modeling. We are using the acute tryptophan depletion technique. It is hypothesized that the rate of 5-HT synthesis in the brain of depressed patients is lower than that in normals. In addition, we are proposing to study how the rate of 5- HT synthesis is controlled by the 5-HT1A receptors in human brain. The latter could have special relevance to understanding the action of some antidepressants and the underlining biochemistry of depression. We are also proposing human studies, as well as some further animal studies, which will help in the interpretation of the PET human studies, as well as some further animal studies that will pave the way for future human PET studies. However these studies, the influence of """"""""Ecstasy"""""""" (MDMA; 3,4-methylendedioxy- N-methylenedioxy-N- methylamphetamine) and fenfluramine, are important by themselves in as much as they will contribute to a better understanding of the selective neurotoxicity of these compounds to the brain serotonergic system.
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