THE ROLE OF INTERHEMISPHERIC PATHWAYS IN PARKINSON’S DISEASE AND DRUG-INDUCED DYSKINESIAS

Open Access
Author:
Lieu, Christopher Anson
Graduate Program:
Neuroscience
Degree:
Doctor of Philosophy
Document Type:
Dissertation
Date of Defense:
October 05, 2011
Committee Members:
  • Thyagarajan Subramanian, Dissertation Advisor
  • Thyagarajan Subramanian, Committee Chair
  • James Robert Connor, Committee Member
  • Paul Joseph Eslinger, Committee Member
  • Kent Eugene Vrana, Committee Member
  • Kathy Steece Collier, Committee Member
Keywords:
  • basal ganglia
  • nigrostriatal degeneration
  • movement disorders
  • alternative and complementary medicines
Abstract:
Parkinson’s disease (PD) is the second most common neurodegenerative disorder that is characterized by cell death of the nigrostriatal pathway and loss of dopamine. Although current pharmacological therapies such as levodopa (LD) can significantly ameliorate symptoms in early stages of the disease, patients develop drug-induced motor complications in later stages. One such complication is the emergence of abnormal involuntary movements known as drug-induced dyskinesias (DID), which are disabling and limit effectiveness of anti-PD treatments. Despite significant advances in the field for understanding the mechanisms associated with DID, treatment for DID in PD is largely unsatisfactory for many patients. Advancing our understanding of the pathophysiological basis of DID will allow for better development of novel therapies that reduce or prevent DID. The goals of this dissertation research were: 1) to examine novel experimental therapeutics that do not cause DID in animal models of PD; 2) to examine putative mechanisms through which such therapies exert their effects; 3) to examine the role of interhemispheric pathways in the genesis of DID. In experiment 1, we evaluated if the Ayurvedic medication Mucuna pruriens would reduce DID in the rat and primate models of PD. Our results showed that a water formulation of Mucuna pruriens was highly effective in ameliorating parkinsonian deficits with reduced severity of DID. We also used a novel D1 agonist EFF0311 in both the parkinsonian rat and monkey to show that EFF0311 can significantly decrease parkinsonism and reduce the risk of DID. These two experiments support the use of novel pharmacological agents to mitigate the problem of DID. In experiment 2, we showed that seventeen clinically hemiparkinsonian rhesus monkeys exposed to high doses of LD did not develop DID, and that such monkeys had profound unilateral loss of nigrostriatal neurons (90%). In experiment 3, we explored the putative mechanisms for the resistance of hemiparkinsonian monkeys to DID using single-cell and local field potential electrophysiology in two hemiparkinsonian Rhesus monkeys. We show that chronic intermittent LD did not substantially alter firing rate or patterns in the subthalamic nucleus (a downstream nucleus critically implicated in parkinsonism and in genesis of DID). In experiment 4, we used a variety of tracing techniques (retrograde labeling and optogenetic viral vector systems) to label interhemispheric nigrostriatal connections in normal, partial and completely nigrostriatal lesioned hemiparkinsonian rats. We showed that LD administration to completely lesioned rats (the Ungerstedt model) and severely partial lesioned rats (the Winkler model) caused DID. Histological analysis showed loss of interhemispheric nigrostriatal fibers in these dyskinetic animals. Whereas, the partial striatal lesioned model (Sauer and Oertel model) did not develop DID and retained interhemispheric nigrostriatal fibers. In conclusion, these experiments provide novel insights into the pathophysiological mechanisms that underly DID. Furthermore, this series of experiments show that interhemispheric pathways may play a significant role in the genesis of DID. These findings could potentially lead to improved development of novel therapies that can reduce or prevent DID in patients suffering from PD.