Doctor of Philosophy
MacDonald, Penny A.
Dopaminergic therapy prescribed to address motor symptoms in Parkinson’s disease (PD) is done at the expense of some cognition functions. It has been hypothesized that whether a given function is improved or impaired by medication depends on the baseline dopamine levels within underlying brain regions. Areas most affected by PD and severely dopamine depleted are predicted to benefit from dopaminergic therapy. Regions with less dopamine deficiency are predicted to worsen from excessive dopamine stimulation. This theoretical framework is known as the dopamine overdose hypothesis. The central aim of this thesis was to critically test the straightforward predictions put forward by this overdose account. First, I examined the effects of dopaminergic therapy on stimulus-reward and reversal learning in groups of PD patients that differed in severity of their disease and extent of dopamine deficiency. Learning impairments were found in late-stage PD at baseline and in early-stage PD with dopaminergic therapy, replicating previous findings. Predicted medication-related improvements in late-stage PD were not found, however. Next, I tested the effects of a dopamine challenge with L-dopa on reward learning in groups of healthy volunteers differentially affected by age-related dopamine decline. I found age- related baseline learning impairments in older compared to younger adults. L- dopa worsened learning similarly in both age groups, however. Last, I explored the effects of L-dopa on learning and associated brain activity in a sample of healthy young volunteers who are presumed to have optimal endogenous dopamine levels. Learning and associated brain activity was reduced following L-dopa administration, but decision enactment was unaffected. Taken together, these studies provide partial support for the dopamine overdose hypothesis but suggest a less straightforward scenario than initially predicted.
Summary for Lay Audience
Parkinson’s disease is marked by the loss of brain cells that produce the neurochemical dopamine, giving rise to motor symptoms such as tremor and rigidity. Dopaminergic therapy is prescribed to address this dopamine deficiency and improve motor function; however, this is done at the expense of some cognitive functions. The dopamine overdose hypothesis predicts that functions of brain regions with low dopamine levels will be improved by medication whereas those with high dopamine levels will worsen. The central aim of this thesis was to critically test this claim by comparing the effects of dopaminergic therapy on cognitive function in groups of participants that differed in their degree of dopamine deficiency. First, I tested how more severe dopamine depletion in late- compared to early-stage Parkinson’s disease influenced the effects of medication on reward-based learning. Next, I examined how normal age-related declines in dopamine affected reward learning and responses to dopaminergic therapy in healthy older versus younger adults. Last, I explored how learning, decision- making, and associated brain activity were impacted by dopaminergic therapy when administered in healthy young adults with optimal dopamine levels. Across these three separate studies, I found only partial support for the dopamine overdose hypothesis. The effects of dopaminergic therapy on cognition are far more complex and less straightforward than initially predicted by this theoretical framework. Understanding these nuances will help clinicians guide treatment strategies in Parkinson’s disease towards improving patient care and quality of life.
Vo, Andrew, "Putting 'Dopamine Overdose' To The Test: A Psychopharmacological Investigation in Parkinson's Disease and Healthy Volunteers" (2020). Electronic Thesis and Dissertation Repository. 6803.
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Available for download on Saturday, January 01, 2022