From gene to brain and behavior: Dopaminergic effects on motor sequence learning in Parkinson's disease

Parkinson's disease (PD) is a neurodegenerative disorder affecting the dopamine neurotransmitter system which is crucial for motor control and cognitive function. Dopaminergic medications alleviate Parkisonian motor symptoms however evidence shows that they also interfere with normal functioning in other domains. The current dissertation aimed to determine the effect of dopaminergic medication on motor sequence learning which underlies daily motor adaptability. In order to gain a thorough understanding of the nature of medication effects on sequence learning behavior, I performed four separate studies using behavioral, pharmacological, functional brain imaging and genetics approaches.;The first study determined the behavioral effects of medication over the time course of motor sequence learning. I report a selective medication-associated learning impairment in the early acquisition phase of sequence learning. The second study addressed the neural underpinnings of L-DOPA medication effects during motor sequence learning. The results showed an L-DOPA associated decrease in ventral putamen activation which correlated with the degree of L-DOPA associated motor sequence learning impairment at the early phase. The last two studies aimed to identify how factors contributing to the endogenous level of dopamine transmission interact with L-DOPA associated sequence learning changes. In the third study, the level of nigrostriatal dopaminergic denervation (assessed with 11C-DTBZ PET) was used as an index of endogenous dopamine availability whereas in the fourth study, COMT and DRD2 polymorphisms were studied as genetic factors contributing to dopamine availability and D2 receptor expression. The results of the last two studies showed that the deleterious effect of L-DOPA on sequence learning is more significant in individuals with higher endogenous dopamine transmission.;Collectively, the results of the current dissertation have significant implications for understanding and treating the pathophysiology of PD suggesting careful use of dopaminergic medication taking into account factors such as one's disease progression and genotype.