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Please use this identifier to cite or link to this item: http://hdl.handle.net/11375/8159
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dc.contributor.advisorMazurek, Michael F.en_US
dc.contributor.authorGarside, Sarahen_US
dc.date.accessioned2014-06-18T16:42:01Z-
dc.date.available2014-06-18T16:42:01Z-
dc.date.created2010-10-06en_US
dc.date.issued1997-04en_US
dc.identifier.otheropendissertations/3387en_US
dc.identifier.other4400en_US
dc.identifier.other1594839en_US
dc.identifier.urihttp://hdl.handle.net/11375/8159-
dc.description.abstract<p>The striatum is part of a neural feedback network that modifies the functioning of the cerebral cortex. The importance of the striatum is underlined by the clinical consequences of striatal dysfunction: disordered signaling in the striatum gives rise to the clinical syndrome of Parkinson's disease, while degeneration of striatal output neurons produces the clinical manifestations of Huntington's disease. The striatum is a complex structure comprised of two major populations of neurons: the spiny projection neurons that carry the striatal output to other nuclei in the basal ganglia; and several subtypes of aspiny cells that project locally within the striatum to modify striatal output. The two major inputs to the striatum are the glutamatergic pathway from the cerebral cortex and the dopaminergic pathway from the substantia nigra. The goal of my research is to explore the nature and functional significance of dopamine-glutamate signaling and its role in the striatum and basal ganglia. My first series of studies in vivo demonstrated that altering dopaminergic tone in the striatum by D2-dopamine receptor blockade or by 6-hydroxy-dopamine lesion of the nigrostriatal dopamine projection in the rat could modify the pathological, neurochemical and behavioural consequences of glutamate-receptor-mediated-stimulation. In order to investigate the details of this interaction, I developed an in vitro tissue culture system. I showed initially that the growth of striatal neurons in serum free culture parallels their in vivo development. I then went on to use this in vitro system to demonstrate the differential effects of selective glutamate receptor agonists on transmitter release from subpopulations of the two major classes of striatal neurons: (i) those in which somatostatin and neuropeptide Y are colocalised with nitric oxide and (ii) the substance P-containing spiny projection neurons. This series of studies demonstrated that substance P release was selectively stimulated through the N-methyl-D-aspartate (NMDA) subtype of glutamate receptor while somatostatin and neuropeptide Y release were selectively provoked by stimulation of the kainate receptor. Stimulation of the metabotropic glutamate receptor had little effect on the release of any of the three peptides. My final series of experiments examined the differential effects of selective dopamine receptor stimulation on glutamate-receptor-induced release of substance P, somatostatin and neuropeptide Y. The D1 agonist SKF 38393, and to a significantly lesser extent the D2 agonist quinpirole, attenuated glutamatergic release of substance P from the spiny neurons. In contrast, the D2 agonist quinpirole potentiated the release of neuropeptide Y and somatostatin from aspiny neurons. The D1 agonist SKF 38393 attenuated glutamate receptor stimulated release of neuropeptide Y, without significantly affecting the release of somatostatin from the same cultures. This latter result indicates that dopamine can differentially regulate transmitter release not only from separate populations of striatal neurons but also differentially control release of transmitter that are colocalised within a single population of neurons. To my knowledge these studies are the first to demonstrate this differential regulation in the striatum, and implies that the delicate balance required for both normal cognition and movement may be intimately related to the balance of signaling between the intrinsic (somatostatin-neuropeptide Y-containing) and extrinsic (substance P-containing) neuronal populations in the striatum.</p>en_US
dc.subjectNeuroscience and behavioral Sciencesen_US
dc.subjectNeuroscience and Neurobiologyen_US
dc.subjectSocial and Behavioral Sciencesen_US
dc.subjectNeuroscience and Neurobiologyen_US
dc.titleDopamine-glutamate interactions in the striatumen_US
dc.typethesisen_US
dc.contributor.departmentNeurosciencesen_US
dc.description.degreeDoctor of Philosophy (PhD)en_US
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