Thesis (Ph.D.)--Boston University / PLEASE NOTE: Boston University Libraries did not receive an Authorization To Manage form for this thesis or dissertation. It is therefore not openly accessible, though it may be available by request. If you are the author or principal advisor of this work and would like to request open access for it, please contact us at open-help@bu.edu. Thank you. / The overall goal of this dissertation was to determine the role of the subthalamic nucleus (STN) in regulating the release of dopamine in the substantia nigra (SN). Experiments first established the existence of a direct connection between subthalamic neurons and SN dopaminergic cells. Further experiments showed that this connection triggers the dopamine release in the SN, and the mechanisms involved in this release were determined.
Whole-cell current clamp recordings were performed in parasagittal brain slices obtained from 10 to 16 day-old rat pups. Electrical stimulations of the STN reliably triggered excitatory post-synaptic potentials (EPSPs) in dopaminergic neurons of the SN pars compacta (SNc). Pharmacological experiments with specific receptor antagonists indicated that this EPSP was mediated by NMDA, non-NMDA and metabotropic glutamate receptors.
Stimulations of the subthalamic input triggered the release of dopamine. In a subset of neurons in the SN pars reticulata (SNr), repetitive stimulations of the STN produced a summating EPSP that was followed by an inhibitory postsynaptic potential (IPSP). A D2 receptor antagonist blocked this IPSP suggesting that it represents the D2 receptor-mediated response of the recorded cell to dopamine released upon stimulation of the STN. Pharmacological experiments using this assay indicated that NMDA, non-NMDA or metabotropic glutamate receptors were individually not required for dendritic release of dopamine; however, each contributed to this release.
In dopaminergic neurons located in the SN pars compacta, the inhibitory effect of dopamine was revealed following block of L-type Ca channels, NMDA and non-NMDA glutamate receptors. These results indicated that dopaminergic neurons located both in the SNc and SNr respond to the dendritic release of dopamine triggered upon stimulations of the STN.
Finally, a specific blocker of the dopamine transporter (GBR12935) blocked the IPSP reversibly in both SNr and SNc dopaminergic neurons. If release occurred by exocytosis, block of the transporter should increase extracellular levels of dopamine and produce an increase in the size of the recorded IPSP. Therefore, these results suggest that dopamine dendritic release triggered by activation of the subthalamic input was mediated by reversed transport of dopamine rather than by exocytosis. / 2031-01-01
| Identifer | oai:union.ndltd.org:bu.edu/oai:open.bu.edu:2144/36754 |
| Date | January 2001 |
| Creators | Barstow, Karen L. |
| Publisher | Boston University |
| Source Sets | Boston University |
| Language | en_US |
| Detected Language | English |
| Type | Thesis/Dissertation |
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