The research program will study the biology of neurotransmitter systems in brain, among which are dopamine, serotonin an the opioid and opioid related systems, that may play a role in drug reward. Using the genes encoding the human receptors for these and related transmitters we aim to elucidate aspects of receptor function. Since recent work from this laboratory has provided evidence for receptor dimerization a priority is placed on the elucidation of the role of the homodimers in receptor function, the structural determinants of receptor dimer formation, and to screen for dimer monomer selective drugs. Cotransfection of closely related receptors in cell lines will determine whether heterodimers can also form. The research proposal will also focus on receptor G-protein interactions, second messenger activation, the receptor posttranslational modifications of palmitoylation and phosphorylation, the mechanism of receptor desensitization, visualization of cell surface receptor trafficking using confocal microscopy, and characterization of several newly discovered receptor genes. A method for purification of the dopamine and opioid receptors has been established, using affinity resins, and it is now possible to visualize these receptors. A colony of healthy D1 receptor knockout mice has demonstrated a marked reduction of responding for substances of abuse demonstrating that this single gene disruption can attenuate drug seeking behaviors. The experimental approach will integrate behavioural and genetic studies with the molecular and biochemical approaches, and will study alterations in the behaviour resulting from manipulation or deletion of specific receptor genes and the functional consequences in animal models. Candidate receptor and transporter genes, in the dopamine and serotonin families, have been selected and will be screened using single stranded conformational polymorphism analysis for changes in structure in drug abuse patient populations.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA007223-08
Application #
2770083
Study Section
Human Development Research Subcommittee (NIDA)
Project Start
1991-06-01
Project End
2000-08-31
Budget Start
1998-09-01
Budget End
1999-08-31
Support Year
8
Fiscal Year
1998
Total Cost
Indirect Cost
Name
University of Toronto
Department
Type
DUNS #
259999779
City
Toronto
State
ON
Country
Canada
Zip Code
M5 1-S8
Hasbi, Ahmed; Perreault, Melissa L; Shen, Maurice Y F et al. (2017) Activation of Dopamine D1-D2 Receptor Complex Attenuates Cocaine Reward and Reinstatement of Cocaine-Seeking through Inhibition of DARPP-32, ERK, and ?FosB. Front Pharmacol 8:924
Perreault, Melissa L; Hasbi, Ahmed; Shen, Maurice Y F et al. (2016) Disruption of a dopamine receptor complex amplifies the actions of cocaine. Eur Neuropsychopharmacol 26:1366-1377
Perreault, M L; Shen, M Y F; Fan, T et al. (2015) Regulation of c-fos expression by the dopamine D1-D2 receptor heteromer. Neuroscience 285:194-203
Shen, Maurice Y F; Perreault, Melissa L; Fan, Theresa et al. (2015) The dopamine D1-D2 receptor heteromer exerts a tonic inhibitory effect on the expression of amphetamine-induced locomotor sensitization. Pharmacol Biochem Behav 128:33-40
Hasbi, Ahmed; Perreault, Melissa L; Shen, Maurice Y F et al. (2014) A peptide targeting an interaction interface disrupts the dopamine D1-D2 receptor heteromer to block signaling and function in vitro and in vivo: effective selective antagonism. FASEB J 28:4806-20
Perreault, Melissa L; Hasbi, Ahmed; O'Dowd, Brian F et al. (2014) Heteromeric dopamine receptor signaling complexes: emerging neurobiology and disease relevance. Neuropsychopharmacology 39:156-68
Perreault, Melissa L; Jones-Tabah, Jace; O'Dowd, Brian F et al. (2013) A physiological role for the dopamine D5 receptor as a regulator of BDNF and Akt signalling in rodent prefrontal cortex. Int J Neuropsychopharmacol 16:477-83
Perreault, Melissa L; Fan, Theresa; O'Dowd, Brian F et al. (2013) Enhanced brain-derived neurotrophic factor signaling in the nucleus accumbens of juvenile rats. Dev Neurosci 35:384-95
Ting-A-Kee, Ryan; Mercuriano, Laura E; Vargas-Perez, Hector et al. (2013) Dopamine D1 receptors are not critical for opiate reward but can mediate opiate memory retrieval in a state-dependent manner. Behav Brain Res 247:174-177
O'Dowd, Brian F; Nguyen, Tuan; Ji, Xiaodong et al. (2013) D5 dopamine receptor carboxyl tail involved in D5-D2 heteromer formation. Biochem Biophys Res Commun 431:586-9

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