Date of Award
Doctor of Philosophy
Dopaminergic neurons of the nigrostriatal dopaminergic system, projecting from the substantia nigra compacta (SNc) to the striatum, serve a critical role in mediating voluntary motor control.Parkinson’s disease is a neurological disorder characterized by progressive degeneration of these dopamine neurons, which leads to dopaminergic deficiencies in the striatum.Reduced striatal dopamine transmission is thought to increase inhibitory basal ganglia output to the thalamus and subsequently reduce excitation of cortical motor areas, resulting in impaired motor functioning.Despite unclear mechanisms, deep brain stimulation (DBS) is an established neurosurgical approach for effectively treating the parkinsonian motor symptoms.Currently the subthalamic nucleus (STN) is the most commonly targeted site in these procedures, while the pedunculopontine tegmental nucleus (PPT) is emerging as a therapeutically beneficial target when stimulated alone or in combination with the STN.Thus, the connectivity between these nuclei and the nigrostriatal dopamine system is the focus of the present paper, with the overarching hypothesis being that the therapeutic benefits of STN/PPT DBS are mediated, at least in part, by activation of surviving nigrostriatal neurons, resulting in striatal dopamine release.The present study investigated several neural pathways and receptor mechanisms involved in mediating STN or PPT stimulation-evoked striatal dopamine release using in vivo fixed potential amperometry with carbon-fiber recording microelectrodes in the striatum of urethane-anesthetized mice.Overall, results indicate that STN stimulation evokes striatal dopamine release directly via excitatory glutamatergic inputs to SNc dopamine cells as well as indirectly by activating excitatory glutamatergic and cholinergic STN-PPT-SNc pathways, while PPT stimulation evokes striatal dopamine release directly by activating glutamatergic and cholinergic pathways to SNc dopamine cells as well as indirectly via activation of glutamatergic and cholinergic PPT-STN-SNc projections.Understanding the influence of the STN and PPT on SNc dopamine cell activity and output of the basal ganglia-thalamocortical motor circuit may lead to novel pharmaceutical therapies as well as a better understanding of the underlying mechanisms of clinical DBS, which could then improve the therapeutic efficacy of treatments for Parkinson’s disease.
Dissertation or thesis originally submitted to the local University of Memphis Electronic Theses & dissertation (ETD) Repository.
Lester, Deranda Brewer, "Neural Pathways and Receptor Mechanisms Mediating Stimulation-Evoked Striatal Dopamine Release: Relevance to Deep Brain Stimulation as a Treatment for Parkinson's Disease" (2011). Electronic Theses and Dissertations. 207.