Faculty: Susan R. George, MD, FRCP(C), FACP
Canada Reseach Chair for Molecular Neuroscience
Co-Section Head, Molecular Pharmacology, Neuroscience Department, CAMH
General Research Areas: G protein-coupled Receptors, Signal Transduction, Drug Addiction, Neuropsychiatric Disorders
Molecular Pharmacology of Neurotransmitter Transmitters in Brain and Role in Drug Addiction and Psychiatric Disorders
Many important CNS functions are intimately linked to the function of certain neuro-transmitter systems, such as the dopamine, opioid, serotonin and various neuropeptide neuronal systems. We are particularly interested in the G protein coupled receptors for these neurotransmitters, each of which exists as families of closely related proteins. The research focuses on the regulation of receptor function, receptor homo-oligomerization and hetero-oligomerization, second messenger coupling, structure-activity relationships, and brain distribution of the receptors and mRNA. Receptor gene-deleted animal models are studied to define the specific functions of the closely related receptor subtypes, particularly as models to define the receptor systems contributing to the vulnerability to substance abuse and neuropsychiatric disease. State of the art pharmacological, biochemical and molecular biological methodologies are utilized in our studies.
1. Perreault M.L., Hasbi A., Shen M.Y.F., Navarro G., Fletcher P.J., Franco R., Lanciego J.L. and George S.R. - Disruption of a dopamine receptor complex amplifies the actions of cocaine. Eur Neuropsychopharmacol 26: 1366-1377, 2016.
2. Shen M.Y.F., Perreault M.L., O’Dowd B.F. and George S.R. - The dopamine D1-D2 receptor heteromer exerts tonic inhibitory effects on amphetamine-induced locomotor sensitization. Pharmacol Biochem Behav 128: 33-40, 2015.
3. Perreault M.L., Shen M.Y., Fan T., George S.R. - Regulation of c-fos expression by the dopamine D1-D2 receptor heteromer. Neuroscience 285: 194-203, 2015.
4. Shen M.Y.F., Perreault M.L., Jones-Tabah J., Cheung M., Fan T. and George S.R. - Behavioural characterization of the dopamine D1-D2 receptor heteromer in the modulation of depression- and anxiety-like behaviours. Eur Neuropsychopharmacol 25: 2437-2448, 2015.
5. Hasbi A., Perreault M.L., Shen M.Y.F., Zhang L., To R., Fan T., Nguyen T., Ji. X., O’Dowd B.F. and George S. R. - A peptide targeting an interaction interface disrupts the dopamine D1-D2 receptor heteromer and blocks signaling and function: Effective selective antagonism. FASEB Journal 28: 4806-4820, 2014.
6. Perreault M.L., O’Dowd B.F. and George S.R. - Dopamine D1-D2 receptor heteromer regulates signaling cascades involved in addiction: Potential relevance to adolescent drug susceptibility. Devel Neuroscience 36: 287-296, 2014.
7. Perreault M.L., Hasbi A., O’Dowd B.F., and George S.R. - Heteromeric dopamine receptor signaling complexes: emerging neurobiology and disease relevance. Neuropsychopharmacol 39: 156-168, 2014.
8. Kabli N., Nguyen T., Balboni B.F., O’Dowd B.F. and George S.R. - Antidepressant-like and anxiolytic-like effects following activation of the mu-delta opioid receptor heteromer in the nucleus accumbens. Molec Psychiatry 19: 986-994, 2013.
9. Novak G., Fan T., O’Dowd B.F. and George S.R. - Postnatal maternal deprivation and pubertal stress have additive effects on dopamine D2 receptor and CaMKII beta expression in the striatum. Int J Devel Neuroscience 31: 189-195, 2013.
10. Novak G., Fan T., O’Dowd B.F. and George S.R. - Striatal development involves a switch in gene expression networks, followed by a myelination event: Implications for neuropsychiatric disease. Synapse 67: 179-188, 2013.
11. Perreault M.L., Fan T., Alijaniaram M., O’Dowd B.F. and George S.R. - Dopamine D1R-D2R heteromer in dual phenotype GABA/glutamate-coexpressing striatal medium spiny neurons: Regulation of BDNF, GAD67 and VGLUT1/2. PLoS One 7: e33348, 2012.
12. Verma V., Hasbi A., O’Dowd B.F. and George S.R. - D1-D2 receptor heteromer mediated calcium release is desensitized by D1 receptor occupancy with or without signal activation: A dual functional role for GRK2. J Biol Chemistry 285: 35092-35103, 2010.
13. Perreault M.L., Hasbi A., Alijaniaram M., Fan T., Varghese G., Fletcher P.J., Seeman P., O’Dowd B.F. and George S.R. The dopamine D1-D2 receptor heteromer localizes in dynorphin/enkephalin neurons: Increased high affinity state following amphetamine and in schizophrenia. J Biol Chemistry, 285: 36625-36634, 2010.
14. El-Ghundi M., Fan T., Karasinska J., Yeung J., Zhou M., O’Dowd B.F. and George S.R. - Restoration of amphetamine induced locomotor sensitization in dopamine D1 receptor deficient mice. Psychopharmacol 207: 599-618, 2010.
15. Hasbi A., Fan T., Alijaniaram M., Nguyen T., O’Dowd B.F., George S.R. - Calcium signaling cascade links dopamine D1-D2 receptor heteromer to striatal BDNF production and neuronal growth. Proc Natl Acad Sci USA 106: 21377-21382, 2009.
University of Toronto
Department of Pharmacology and Toxicology
Room 4344, Medical Sciences Building
1 King's College Circle