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You searched for +publisher:"University of Toronto" +contributor:("George, Susan R"). Showing records 1 – 2 of 2 total matches.

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University of Toronto

1. Yeung, Pok Yik. The Role of the Dopamine D5 Receptor and D1-D2 Receptor Heterooligomer Signalling in Rodent Prefrontal Cortex and Cognition.

Degree: 2015, University of Toronto

The dopamine D5 receptor is highly expressed in rodent prefrontal cortex (PFC) a region involved in cognition. We have previously shown that acute activation of the Gq-coupled dopamine D5 and D1-D2 receptor heteromer by the agonist SKF 83959 inhibited glycogen synthase kinase- 3 (GSK-3) activity in PFC, a protein that mediates cognitive performance in this region. Specifically, the dopamine D5 receptor suppressed GSK-3 activity through a mechanism dependent on brain-derived neurotrophic factor (BDNF) signaling, whereas inhibition of GSK-3 activity by D1-D2 heteromer appears to be independent of BDNF signaling in the PFC. We have demonstrated that SKF83959 improved cognitive performance in male rats using the egocentric learning task in the small Morris water maze. These studies potentially offer a novel therapeutic drug target to treat cognitive deficits in Alzheimer's disease and schizophrenia through activation of the dopamine D5 receptor signaling pathway involving increased BDNF signaling and inhibition of GSK-3 activity.

M.Sc.

Advisors/Committee Members: George, Susan R, Pharmacology.

Subjects/Keywords: Akt; BDNF; Cognition; Dopamine Receptor; GSK3β; Prefrontal Cortex; 0419

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6th Edition):

Yeung, P. Y. (2015). The Role of the Dopamine D5 Receptor and D1-D2 Receptor Heterooligomer Signalling in Rodent Prefrontal Cortex and Cognition. (Masters Thesis). University of Toronto. Retrieved from http://hdl.handle.net/1807/70741

Chicago Manual of Style (16th Edition):

Yeung, Pok Yik. “The Role of the Dopamine D5 Receptor and D1-D2 Receptor Heterooligomer Signalling in Rodent Prefrontal Cortex and Cognition.” 2015. Masters Thesis, University of Toronto. Accessed November 22, 2017. http://hdl.handle.net/1807/70741.

MLA Handbook (7th Edition):

Yeung, Pok Yik. “The Role of the Dopamine D5 Receptor and D1-D2 Receptor Heterooligomer Signalling in Rodent Prefrontal Cortex and Cognition.” 2015. Web. 22 Nov 2017.

Vancouver:

Yeung PY. The Role of the Dopamine D5 Receptor and D1-D2 Receptor Heterooligomer Signalling in Rodent Prefrontal Cortex and Cognition. [Internet] [Masters thesis]. University of Toronto; 2015. [cited 2017 Nov 22]. Available from: http://hdl.handle.net/1807/70741.

Council of Science Editors:

Yeung PY. The Role of the Dopamine D5 Receptor and D1-D2 Receptor Heterooligomer Signalling in Rodent Prefrontal Cortex and Cognition. [Masters Thesis]. University of Toronto; 2015. Available from: http://hdl.handle.net/1807/70741

2. Kabli, Noufissa. Uncovering the Functional Implications of Mu- and Delta-opioid Receptor Heteromerization in the Brain.

Degree: 2013, University of Toronto

Opioid Receptors (ORs) are involved in the pathophysiology of several neuropsychiatric conditions yet remain an untapped therapeutic resource. Although only mu-, delta-, and kappa-OR types have been cloned, additional subtypes result from complexes generated by direct receptor-receptor interactions. Mu- and delta-ORs form a heteromeric receptor complex with unique pharmacological and signalling properties distinct from those of mu- and delta-OR homomers. In these studies, we sought to characterize the ligand binding pocket and agonist-induced internalization profile of the mu-delta heteromer, to investigate mu-delta heteromer-specific signalling in brain, and to interrogate the contribution of this receptor complex to opioid-mediated behavioural effects. In competition radioligand binding studies, delta-agonists displaced high affinity mu-agonist binding from the mu-delta heteromer but not the muOR homomer, suggestive of delta-agonists occupying or allosterically modulating the muOR ligand binding pocket within the heteromer. Delta-agonists induced internalization of the mu-delta heteromer in a dose-dependent, pertussis toxin resistant, and muOR- and deltaOR-dependent manner from the cell surface via the clathrin and dynamin endocytic machinery. Agonist-induced internalization of the mu-delta heteromer persisted following chronic morphine treatment conditions which desensitized the muOR homomer. Using Galpha-specific GTPgammaS binding assays, we demonstrated that mu-delta heteromer signalling previously characterized in cell lines was present in the striatum and hippocampus, and did not desensitize following prolonged morphine treatment conditions which desensitized muOR homomer-mediated signalling. Since delta-agonists which also target the mu-delta heteromer possess antidepressant-like and anxiolytic-like properties, we investigated the role of this receptor complex in mood regulation. We devised a strategy to selectively analyze the effects of the mu-delta heteromer by dissociating it using a specific interfering peptide aimed at a sequence implicated in mu-delta heteromerization. The interfering peptide abolished the unique pharmacological and trafficking properties of delta-agonists at the mu-delta heteromer and dissociated this receptor complex in vitro. Intra-accumbens administration of the interfering peptide disrupted the mu-delta interaction in vivo and allowed for isolation of the mu-delta heteromer contribution to the mood-regulatory effects of a delta-agonist with activity at the heteromer. Activation of the mu-delta heteromer in the nucleus accumbens produced antidepressant-like and anxiolytic-like actions in animal models of depression and anxiety.

PhD

Advisors/Committee Members: George, Susan R., O'Dowd, Brian F., Pharmacology.

Subjects/Keywords: mu opioid receptor; delta opioid receptor; heteromer; depression; anxiety; brain; chronic morphine; G protein coupled receptor; mood; binding; internalization; interaction; 0419; 0317

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6th Edition):

Kabli, N. (2013). Uncovering the Functional Implications of Mu- and Delta-opioid Receptor Heteromerization in the Brain. (Doctoral Dissertation). University of Toronto. Retrieved from http://hdl.handle.net/1807/65509

Chicago Manual of Style (16th Edition):

Kabli, Noufissa. “Uncovering the Functional Implications of Mu- and Delta-opioid Receptor Heteromerization in the Brain.” 2013. Doctoral Dissertation, University of Toronto. Accessed November 22, 2017. http://hdl.handle.net/1807/65509.

MLA Handbook (7th Edition):

Kabli, Noufissa. “Uncovering the Functional Implications of Mu- and Delta-opioid Receptor Heteromerization in the Brain.” 2013. Web. 22 Nov 2017.

Vancouver:

Kabli N. Uncovering the Functional Implications of Mu- and Delta-opioid Receptor Heteromerization in the Brain. [Internet] [Doctoral dissertation]. University of Toronto; 2013. [cited 2017 Nov 22]. Available from: http://hdl.handle.net/1807/65509.

Council of Science Editors:

Kabli N. Uncovering the Functional Implications of Mu- and Delta-opioid Receptor Heteromerization in the Brain. [Doctoral Dissertation]. University of Toronto; 2013. Available from: http://hdl.handle.net/1807/65509

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