This Program Project represents an integrated exploration of key aspects of the neurobiology of the basal ganglia, both in intact animals and in animals sustaining lesions of the dopamine (DA)- containing nigrostriatal projections. In many animals, the neurotoxin 6-hydroxydopamine will be administered intracerebrally to adult rats to produce an animal models of Parkinsonism. We have identified seven interrelated themes, each of which appear in most if not all of the projects; (1) nonsynaptic interactions between neuronal elements in striatum; (2) direct versus indirect output pathways of dorsal striatum (3) the relation between D1 and D2 receptors on medium spiny neurons of straitum; (4) DA-interactions with other neurochemically defined neuronal elements; (5) pathology and pathogenesis related to Parkinsonism; (6) compensations that occur in response to partial lesions of monoaminergic pathways; and (7) the impact of L-DOPA on neural functioning and on behavior. As part of this endeavor, a multi-disciplinary characterization of many aspects of the normal basal ganglia will be required. Include in this characterization will be an anatomical and neurochemical examination of the interactions among dopaminergic, cholinergic, glutamatergic, and GABAergic neurons. An in-depth study of the catecholamine-synthesizing enzyme, tyrosine hydroxylase also will be carried out. Among the clinically-related issues to be examined are (1) the neurobiological basis of the pre-clinical and the clinical phase of Parkinsonism and related disorders, (2) mechanisms of action of L-DOPA in Parkinsonism, and (3) the underlying basis of the selective vulnerability of nigrostriatal DA neurons. It is expected that these studies will provide insights into the relation between neuropathology and symptomatology in a variety of neurodegerative disorders will be of value in developing new modes of therapy for these conditions, and will add important new information concerning the neurobiology of the basal ganglia.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Program Projects (P01)
Project #
5P01NS019608-16
Application #
2891618
Study Section
Neurological Disorders Program Project Review B Committee (NSPB)
Program Officer
Murphy, Diane
Project Start
1983-07-01
Project End
2002-04-30
Budget Start
1999-05-01
Budget End
2000-04-30
Support Year
16
Fiscal Year
1999
Total Cost
Indirect Cost
Name
University of Pittsburgh
Department
Neurosciences
Type
Schools of Arts and Sciences
DUNS #
053785812
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Jaumotte, Juliann D; Wyrostek, Stephanie L; Zigmond, Michael J (2016) Protection of cultured dopamine neurons from MPP(+) requires a combination of neurotrophic factors. Eur J Neurosci 44:1691-9
Ayadi, Amina El; Zigmond, Michael J; Smith, Amanda D (2016) IGF-1 protects dopamine neurons against oxidative stress: association with changes in phosphokinases. Exp Brain Res 234:1863-1873
Napier, T Celeste; Corvol, Jean-Christophe; Grace, Anthony A et al. (2015) Linking neuroscience with modern concepts of impulse control disorders in Parkinson's disease. Mov Disord 30:141-9
Zigmond, Michael J; Smeyne, Richard J (2014) Exercise: is it a neuroprotective and if so, how does it work? Parkinsonism Relat Disord 20 Suppl 1:S123-7
Jaumotte, Juliann D; Zigmond, Michael J (2014) Comparison of GDF5 and GDNF as neuroprotective factors for postnatal dopamine neurons in ventral mesencephalic cultures. J Neurosci Res 92:1425-33
Ahrens, Allison M; Nobile, Cameron W; Page, Lindsay E et al. (2013) Individual differences in the conditioned and unconditioned rat 50-kHz ultrasonic vocalizations elicited by repeated amphetamine exposure. Psychopharmacology (Berl) 229:687-700
Zigmond, Michael J; Cameron, Judy L; Hoffer, Barry J et al. (2012) Neurorestoration by physical exercise: moving forward. Parkinsonism Relat Disord 18 Suppl 1:S147-50
Cohen, Ann D; Zigmond, Michael J; Smith, Amanda D (2011) Effects of intrastriatal GDNF on the response of dopamine neurons to 6-hydroxydopamine: time course of protection and neurorestoration. Brain Res 1370:80-8
El Ayadi, Amina; Zigmond, Michael J (2011) Low concentrations of methamphetamine can protect dopaminergic cells against a larger oxidative stress injury: mechanistic study. PLoS One 6:e24722
Allen, Erika; Carlson, Kirsten M; Zigmond, Michael J et al. (2011) L-DOPA reverses motor deficits associated with normal aging in mice. Neurosci Lett 489:1-4

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