DR. DORIS J. DOUDET
My main interest resides in understanding the role and function of the monoaminergic systems, with particular emphasis on dopamine (DA). My lab uses a variety of techniques to that effect.
For a number of years, I have taken advantage of the possibility to use positron emission tomography (PET) to study in vivo, longitudinally, compensatory changes in the DA system induced by aging, lesion of the DA nigro-striatal system as in Parkinson's Disease (PD) or drugs of abuse in primates. These studies are performed in collaboration with the UBC/TRIUMF PET program and use a n umber of radioactive tracers specific for DA but also serotonin and opiates. Current projects are directed to the evaluation of new scanning methods as well as of experimental therapies for PD, especially to follow over time the effect of transplants of human retinal pigmented epithelial (hRPE) cells in a model of PD. This type of transplant is very new and little is known about the potential of these cells.
The second main aspect of my lab is to pursue in rodents investigation of some of the findings that we found by PET in human and non-human primates. Thus, a part of my lab is focused in studying the mechanism of action of the hRPE cells transplant in a 6-OHDA model of PD in rats, using behavior, immunohistochemistry and electron microscopy and more recently, in vivo MRI cell labeling methods. Another project is to study the effects and mechanism of action of electroconvulsive therapy (ECT/ECS), a very effective treatment for depression as well as some of the symptoms of parkinsonism.
The methodologies employed cover both behavioral assessment, binding assays using autoradiographic techniques with a phosphor imaging device, microdialysis in collaboration with Tony Phillips' lab and identification of neurotrophic factors in collaboration with Wolf Tetzlaff's lab. In addition, we have started using in vivo methods in the rat using a new tomograph for rodents (microPET R4).
Most of these projects are funded by CIHR and Titan Pharmaceuticals Inc (hRPE studies).
Doudet, D.J., Chan G.L.Y., Holden J.E., Morrison K.S., Wyatt R.J., Ruth T.J. "Effects of catechol-O-methyltransferase inhibition on the rates of uptake and reversibility of 6-Fluoro-L-Dopa trapping in MPTP-induced parkinsonism in monkeys." Neuropharmacol. 36: 363-371 (1997)
Doudet D.J, Chan G.L.Y, Holden J.E, Pate B.D., Morrison K.S., Calne D.B., Ruth T.J. "Effects of monoamine oxydase and catechol-O-methyltransferase inhibition on dopamine turnover: A PET study with 6-[18F]L-DOPA." Eur. J. Pharmacol. 334: 31-38 (1997)
Doudet D.J., Chan G.L.Y., Holden J.E., Aigner T.G., Wyat R.J., Morrison K.S., Ruth T.J. "6-Fluoro-L-Dopa PET studies of the turnover of dopamine in MPTP-induced parkinsonism in monkeys." Synapse 29: 225-232 (1998)
Cohen R.M., Carson R.E., Aigner T.G., Doudet D.J. "Opiate receptor avidity is reduced in non-motor impaired MPTP-lesioned rhesus monkeys." Brain Res. 802: 292-296 (1998)
Doudet D.J., Holden J.E., Chan G.L.Y., Jivan S., DeJesus O., English C.J., Aigner T., Ruth T.J. "Evaluation of dopaminergic presynaptic integrity: 6-[18F]fluoro-L-DOPA vs 6-[18F]fluoro-L-m-tyrosine." J. Cereb. Blood Flow Metab. 19: 278-287 (1999)
Cohen R.M., Carson R.E., Wyatt R., Doudet D.J. "Opiate receptor is reduced bilaterally in rhesus monkeys unilaterally lesioned with MPTP." Synapse 33: 282-288 (1999)
Fernandez-Ruiz J., Doudet D.J., Aigner T.G. "Cognitive improvement of levodopa in parkinsonian MPTP-treated monkeys." Psychopharmacol. 147: 104-107 (1999)
Sossi V., Holden J.E., Doudet D.J. "A reversible tracer analysis approach to the study of effective dopamine turnover." J. Cereb. Blood Flow Metab. 21: 469-476 (2001)
Cumming P, Munk O.L., Doudet D.J. "Loss of metabolites from monkey striatum during positron emission tomography with FDOPA." Synapse 41: 212-218 (2001)
Doudet D.J., Jivan S., Ruth T.J., Holden J.E.. "Density and affinity of the dopamine D2 receptors in aged symptomatic and asymptomatic MPTP-treated monkeys: PET studies with [11C]raclopride." Synapse 44: 198-202 (2002)
Doudet D.J., Jivan S., Ruth T.J., Wyatt J.R.. "In vivo PET studies of the dopamine D1 receptors in rhesus monkeys with long term MPTP-induced parkinsonism." Synapse 44: 111-115 (2002)
Holden J.E., Jivan S., Ruth T.J., Doudet D.J.." In Vivo receptor assay with multiple ligand concentrations: An equilibrium approach." J. Cereb. Blood Flow Metab. 22: 1132-1141 (2002)
Strome EM, Wheeler GH, Higley D, Loriaux DL, Suomi SJ, Doudet D.J. "Intracerebroventricular corticotrophin-releasing factor increases limbic glucose metabolism and has social context-dependent behavioral effects in non-human primates." PNAS 99: 15749-15754 (2002)
Doudet D.J., Jivan S., Holden J.E. "In vivo measurement of receptor density and affinity: comparison of the routine sequential method with a non sequential method in studies of dopamine D2 receptors with [11C]raclopride." J. Cereb. Blood Flow Metab. 23: 280-284 (2003)
McGeer P.L., Schwab C., Parent A., Doudet D.J., "Presence of reactive microglia in monkey substantia nigra years after MPTP administration." Ann. Neurol. 54: 599-604 (2003)
Doudet D.J., Holden J.E. "Sequential vs non-sequential measurement of density and affinity of dopamine D2 receptors with [11C]raclopride: 1: Effect of methamphetamine." J. Cereb. Blood Flow Metab. 23: 1489-1494 (2003)
Doudet D.J., Holden J.E. "[11C]raclopride PET studies of dopamine release by amphetamine: dependence on presynaptic integrity." Biol. Psychiat. 54: 1193-1199 (2003)
Rosa-Neto P., Doudet D.J., Cumming P. "Gradients of dopamine D1 and D2/3 binding sites in the basal ganglia of pig and monkey measured by PET." NeuroImage 22: 1076-1083 (2004)
Doudet D.J., Allen R., Honey C., Schweikert A., Cornfeldt M. "In vivo evaluation of retinal pigment epithelial cell transplant by PET." Exp. Neurol. 189: 361-368 (2004)
Strome E.M., Jivan S., Doudet D.J. "Quantitative in vitro phosphor imaging using [3H] and [18F] radioligands: effects of chronic desipramine treatment on serotonin 5HT2 receptors." J. Neurosci. Methods 141: 143-154 (2005)
Strome EM, Clark CM, Zis AP, Doudet DJ. "Electroconvulsive shock decreases binding to 5-HT2 receptors in non-human primates: an in vivo PET study with [18F]setoperone1." Biol. Psychiatry 57: 1004-1010 (2005)
Doudet D.J., Ruth T., Holden J.E. "Sequential vs Non sequential measurement of density and affinity of dopamine D2 receptors with [11C]raclopride: 2: Effects of DAT inhibitors." J. Cereb. Blood Flow Metab. 26: 28-37 (2006)