There is accumulating evidence that dopamine loss at locations outside of the striatum such as the substantia nigra or the globus pallidus may play a significant role in the development of parkinsonism. Recent studies in animals, primarily rodents) have suggested that dopamine may also act at the level of the subthalamic nucleus (STN). In these animals, a direct dopaminergic projection from the substantia nigra pars compacta to the STN has been demonstrated. Furthermore, it appears that the activity of STN neurons is modulated through actions of dopamine at pre- and post-synaptic dopamine receptors in the STN, and that dopamine depletion in the STN leads to altered firing rates and more intense bursting in this nucleus. The extent and anatomy of the dopaminergic innervation of the STN, the function(s) of dopamine within the STN, and the effects of dopamine loss in the STN in the parkinsonian state have not been explored in primates. With the proposed studies, we will examine the anatomy and function of the dopamine supply to the STN in vivo in primates. With the experiments under aim 1, we will analyze the extent of the dopaminergic innervation and characterize the subcellular localization of dopamine receptors in the STN of normal and MPTP- treated (parkinsonian) monkeys, using a combination of light-microscopic and high resolution electron microscopic immunocytochemical methods. The experiments under aim 2 will study the functional effects of dopaminergic compounds, locally administered in the STN, on the activity of STN neurons in normal and parkinsonian monkeys. We will examine the effects of dopamine receptor agonists and antagonists, injected locally into the STN with a microinjection/recording device. In addition, microdialysis experiments will be carried out to measure the presynaptic effects of dopamine on GABA release in the STN, as well as electrophysiological recordings in the primary targets of STN projections, i.e., the external and internal pallidal segments. Finally, under aim 3, we will study the behavioral effects of dopamine receptor blockade in the STN in normal animals, and activation of dopamine receptors in the STN in parkinsonism, with the expectation that disruption of dopaminergic transmission contributes to parkinsonism, and replacement of dopaminergic function in the parkinsonian state may ameliorate parkinsonian symptoms. Taken together, these studies will provide us with a thorough examination of dopaminergic functions in the primate STN, will help us to understand further the effects of dopamine loss at this extrastriatal site, and may identify the STN as a target for focal dopamine replacement strategies in parkinsonism, such as gene delivery methods or grafting.
The neuronal activity in the subthalamic nucleus is strongly affected by the dopamine depletion in the basal ganglia that occurs in Parkinson's disease, making this nucleus the primary targets of functional neurosurgery to treat parkinsonism. Activity changes in the subthalamic nucleus are usually seen as secondary events, triggered by striatal dopamine loss. However, there is accumulating evidence that dopamine loss within the subthalamic nucleus also contributes to the neuronal activity changes, and to the generation of parkinsonism. We will explore this hypothesis in parkinsonian primates through anatomical, electrophysiologic, biochemical and behavioral experiments. These studies will expand our knowledge of the pathophysiology of parkinsonism, and may identify the subthalamic nucleus as a location at which current dopaminergic therapies work. If significant dopaminergic effects are seen in the subthalamic nucleus, it may emerge as a new target for highly specific local dopamine replacement therapies for parkinsonian patients.
|Smith, Yoland; Wichmann, Thomas; DeLong, Mahlon R (2014) Corticostriatal and mesocortical dopamine systems: do species differences matter? Nat Rev Neurosci 15:63|
|Galvan, Adriana; Hu, Xing; Rommelfanger, Karen S et al. (2014) Localization and function of dopamine receptors in the subthalamic nucleus of normal and parkinsonian monkeys. J Neurophysiol 112:467-79|
|Wichmann, T; Dostrovsky, J O (2011) Pathological basal ganglia activity in movement disorders. Neuroscience 198:232-44|
|Wichmann, Thomas; Delong, Mahlon R (2011) Deep-Brain Stimulation for Basal Ganglia Disorders. Basal Ganglia 1:65-77|