Date of Completion
R. Holly Fitch
Field of Study
Doctor of Philosophy
The central aim of the present research was to characterize aspects of the instigation and treatment of Parkinsonian resting tremor using a pharmacological rodent model, the tremulous jaw movement (TJM) model. These studies employed the TJM model to investigate the neurochemical and electrophysiological changes that are associated with tremorogenesis, and to test novel therapeutic agents for the treatment of resting tremor. Experiment 1 established a mouse model of Parkinsonian resting tremor using the anticholinesterase galantamine. In experiment 2, the novel antiparkinsonian agent safinamide attenuated TJMs induced by the anticholinesterase galantamine, the muscarinic agonist pilocarpine, and the dopamine D2 antagonist pimozide. In experiment 3, the MAO-B inhibitor deprenyl attenuated TJMs induced by the VMAT-2 inhibitor tetrabenazine (TBZ). TBZ administration decreased extracellular DA levels in the ventrolateral striatum (VLS), and co-administration of deprenyl blunted this effect. The aim of experiment 4 was to characterize the effect of the SSRI fluoxetine (FLX) on the motor dysfunctions induced by TBZ and investigate the neural mechanisms involved. Co-administration of FLX increased TBZ-induced TJMs and decreased locomotor activity compared to TBZ alone. Co-administration of the 5-HT2A/2C antagonist mianserin attenuated the increase in TJMs induced by co-administration of TBZ with FLX. Co-administration of TBZ and FLX decreased DA tissue levels in the rat VLS compared to TBZ alone, and co-administration of mianserin with TBZ and FLX attenuated this effect, increasing DA tissue levels compared to the TBZ/FLX condition. The fifth set of studies examined if tremor-related local field potential (LFP) activity could be recorded from motor cortex or subthalamic nucleus (STN) during TJMs
induced by the muscarinic agonist pilocarpine. Pilocarpine induced a robust TJM response that was marked by rhythmic electromyographic activity in the temporalis muscle. TJM epochs were characterized by increased LFP power in the tremor frequency range in both neocortex and STN. Tremor activity was not associated with increased power in the beta frequency band. These studies collectively extended and validated the TJM model, contributing to the ultimate goal of this line of research, which is to characterize the conditions associated with tremorogenesis in order to develop specifically-targeted therapeutic strategies.
Podurgiel, Samantha J., "Characteristics of Tremorogenesis and Tremorolytic Agents in a Pharmacological Rodent Model of Parkinsonism: Evidence from Behavioral, Neurochemical, and Electrophysiological Studies" (2015). Doctoral Dissertations. 783.