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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS029629-05
Application #
2702997
Study Section
Diagnostic Radiology Study Section (RNM)
Program Officer
Kitt, Cheryl A
Project Start
1992-04-01
Project End
2000-04-30
Budget Start
1998-05-01
Budget End
1999-04-30
Support Year
5
Fiscal Year
1998
Total Cost
Indirect Cost
Name
Mcgill University
Department
Type
DUNS #
City
Montreal
State
PQ
Country
Canada
Zip Code
H3 0-G4
Pivac, Nela; Diksic, Mirko (2011) The lumped constant of ?-methyl-l-tryptophan is not influenced by drugs acting through serotonergic system. Neurochem Int 58:826-32
Skelin, Ivan; Sato, Hiroki; Diksic, Mirko (2010) Acute challenge with d-fenfluramine decreases regional cerebral glucose utilization in Sham, but not in OBX, rats: an autoradiographic study. Brain Res 1310:162-71
Nishi, Kyoko; Kanemaru, Kazuya; Diksic, Mirko (2009) A genetic rat model of depression, Flinders sensitive line, has a lower density of 5-HT(1A) receptors, but a higher density of 5-HT(1B) receptors, compared to control rats. Neurochem Int 54:299-307
Kanemaru, Kazuya; Nishi, Kyoko; Hasegawa, Shu et al. (2009) Chronic citalopram treatment elevates serotonin synthesis in flinders sensitive and flinders resistant lines of rats, with no significant effect on Sprague-Dawley rats. Neurochem Int 54:363-71
Kanemaru, Kazuya; Nishi, Kyoko; Diksic, Mirko (2009) AGN-2979, an inhibitor of tryptophan hydroxylase activation, does not affect serotonin synthesis in Flinders Sensitive Line rats, a rat model of depression, but produces a significant effect in Flinders Resistant Line rats. Neurochem Int 55:529-35
Nishi, Kyoko; Kanemaru, Kazuya; Hasegawa, Shu et al. (2009) Both acute and chronic buspirone treatments have different effects on regional 5-HT synthesis in Flinders Sensitive Line rats (a rat model of depression) than in control rats. Neurochem Int 54:205-14
Nguyen, Khanh Q; Tohyama, Yoshihiro; Watanabe, Arata et al. (2009) Acute effects of combining citalopram and pindolol on regional brain serotonin synthesis in sham operated and olfactory bulbectomized rats. Neurochem Int 54:161-71
Kanemaru, Kazuya; Hasegawa, Shu; Nishi, Kyoko et al. (2008) Acute citalopram has different effects on regional 5-HT synthesis in FSL, FRL, and SDP rats: an autoradiographic evaluation. Brain Res Bull 77:214-20
Skelin, Ivan; Yamane, Fumitaka; Diksic, Mirko (2008) Flesinoxan challenge suggests that chronic treatment with paroxetine in rats does not desensitize receptors controlling 5-HT synthesis. Neurochem Int 53:236-43
Natsume, Jun; Bernasconi, Neda; Aghakhani, Yahya et al. (2008) Alpha-[11C]methyl-L-tryptophan uptake in patients with periventricular nodular heterotopia and epilepsy. Epilepsia 49:826-31

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