Microsoft word - dr.mirko diksic 来日記念講演会(最終版)083

Dr. Mirko Diksic
SEROTONIN SYNTHESIS MEASURED IN LIVING BRAIN
Dr.Mirko Diksic,
Department of Neurology and Neurosurgery, and Montreal Neurological Institute, McGill University, Montreal, QC, Canada An assessment of the brain serotonergic system in the living brain is now possible with new advances in Single Photon Emission Tomography and Positron Emission Tomography (PET). These advances permit, for the first time, an evaluation of several components of brain serotonergic neurotransmission in the living brain, such as receptor and reuptake site densities, and the synthesis of serotonin itself. We have been working to develop an evaluation method, based on -methyl-L-tryptophan (-MTrp). This analog follows the metabolic conversion of tryptophan (Trp) into 5-HT, and, as such, allows us to estimate brain regional 5-HT synthesis in laboratory animals, using autoradiography, and in living humans, using PET. Our experiments in rats have shown that drugs known to have an effect on the brain serotonergic system (e.g. fluoxetine, reserpine, D-fenfluramine, Ecstasy, buspirone), without having a significant effect on plasma Trp concentration, affected brain 5-HT synthesis in a non-uniform manner; e.g. 5-HT synthesis decreased in the cell bodies while increasing in the terminal areas. Data suggest that 5-HT synthesis is differently controlled in the terminal areas then its control in the cell bodies. Since TPH is not saturated by either Trp or oxygen, the changes in the blood concentration of these substrates resulted in changes in the brain 5-HT as measure by uptake of -[11C]MTrp. Experiments in normal subjects suggest that there are brain structures in males in which 5-HT synthesis is higher than that in females, while other structures show higher 5-HT in females than males. In measurements performed using PET and -[11C]MTrp in living humans, it has been shown that a decrease in the plasma Trp concentration results in a reduction of brain 5-HT synthesis, suggesting that the modulation of 5-HT synthesis is possible through the alteration of plasma Trp concentrations. We have extended these studies to patients diagnosed with major depression (MDD) and borderline personality (BPD) disorder. The patients in both groups fulfilled the DMS-IV criteria for the respective disorders. In the MDD group, we scanned twenty-three patients (11M/12F) and 23 normal subjects. There was no region in which 5-HT synthesis was greater in the patients when compared to the controls, but the synthesis was significantly lower in the left anterior cingulate gyrus and the right prefrontal area when the patients were compared to the controls. This data suggests that an evaluation of 5-HT synthesis in depressed patients before and after a treatment may be quite valuable in getting better understanding of depressive symptoms. The clusters showing significantly different serotonin synthesis between the controls and patients are different in the males than in the females. A particular difference in the cingulate cortex is noticed. In the BPD group, we scanned 14 patients (5M/8F) and compared to the control group of 11 (6M/5F) subjects. Regional 5-HT synthesis was calculated from the PET measurements by an ECAT HR+ scanner after an injection of 6-12 mCi of -[11C]MTrp. The images were collected and reconstructed in 3D, co-registered with the subjects= MRI scan, and transferred into standardized Talairach space. The functional images between the patients and controls were compared using the SPM99 program. Spe2ific differences between males and females, as well as those between the patients and controls will be discussed.

Source: http://www8.plala.or.jp/kurata/abrs/MirkoDiksic.pdf