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Nesbit, Maya

University of British Columbia

Cognitive impairment is a debilitating feature of psychiatric disorders including schizophrenia, mood disorders and substance use disorders. Despite cognitive impairment being the strongest predictor of functional outcomes in patients, there is a substantial lack of effective cognitive therapies. This thesis examines the pharmacological effects of d-govadine (d-GOV), a tetrahydroprotoberberine recently demonstrated to significantly enhance working memory and behavioural flexibility in several prefrontal cortex (PFC)-dependent rodent tasks. d-GOV also has high, selective affinity for dopamine (DA) D1 receptors (D1DRs), and selectively potentiates DA efflux in the PFC. This unique pharmacology sets it apart from many dopaminergic drugs and likely contributes to its cognitive effects. However, it is unclear how d-GOV selectively elevates PFC DA or what the functional effects of d-GOV binding to D1DRs are in the PFC. The aim of this thesis was to advance our understanding of these key aspects of d-GOV’s mechanism(s) in the PFC. I first found that d-GOV reverse dialyzed in the PFC, but not the ventral tegmental area (VTA), was sufficient to elevate PFC DA levels. Either PFC delivery or systemic administration of d-GOV preferentially potentiated DA vs NE efflux in the PFC, which differentiates d-GOV’s mechanism from known potentiators of PFC DA. Furthermore, the potentiating effects of d-GOV on PFC DA were ameliorated when glutamatergic transmission was disrupted in either the PFC or the VTA. These results suggest that d-GOV primarily acts in the PFC to potentiate local DA efflux, and that this mechanism likely involves the mesocortical feedback loop involving prefrontal glutamatergic projections to a population of VTA DA neurons that project back to the PFC. Moreover, d-GOV significantly potentiated whole-cell NMDA current in PFC slices in a D1DR-dependent manner. Additional evidence for the D1DR-mediated potentiation of NMDA currents by d-GOV was found in HEK293 cells co-expressing D1DRs and NMDARs. Specifically, d-GOV potentiated GluN2A-mediated currents in D1-GluN1/GluN2A-expressing cells when glutamate and d-GOV concentrations were low. d-GOV did not affect currents recorded from D1-GluN1/GluN2B-expressing cells, or when D1Rs were not expressed. These collective mechanisms through which d-GOV modulates PFC DA function are novel and further endorses it as a treatment for cognitive impairment.

Text

2023-09-28

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/86050

Neuroscience

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/