Research is proposed which will investigate information processing in input (caudate nucleus) and output (entopeduncular nucleus, globus pallidus) areas of the basal ganglia of cats exposed to the dOpaminergic toxin N-methyl-4-phenyl-1,2,3,6- tetrahydropyridine (MPTP). Following MPTP administration, cats acutely become akinetic, freeze during movement, and have drastically reduced responsiveness to various types of external stimulation. This distinct behavioral syndrome is accompanied by a greater than 90% striatal dopamine depletion and loss of substantia nigra pars compacta neurons. Over the course of several weeks to months, cats enter into subacute and chronic phases of this syndrome during which time gross motor behavior approximates normal while substantia nigra pathology remains extensive and striatal dopamine loss is greater than 70% The presently proposed research is designed to investigate electrophysiological, biochemical, and behavioral aspects of MPTP-induced nigrostriatal damage and the resultant recovery of this system over time. Chronic extracellular single unit recordings will allow examination of spontaneous neural activity, response to stimulation of afferent brain structures and sensory information processing in basal ganglia input and output structures under normal circumstances and at various phases of the MPTP-induced behavioral syndrome. Physiological findings will be correlated with results from detailed neurological and behavioral testing. Additionally, some of the possible neurochemical mechanisms leading to behavioral recovery will be assessed chronically by examining levels of catecholamine metabolites in CSF through the different phases of the MPTP syndrome and by examining the state of pre- and post-synaptic mechanisms in the striatum. These experiments should provide useful information on the functioning of the impaired basal ganglia and give insight into how the dopamine depleted basal ganglia responds to and processes inputs and what these responses mean for behavior. Information on the compensatory mechanisms leading to behavioral recovery following damage to the nigrostriatal system could have relevance for understanding the pathophysiology Parkinson's disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS023980-04
Application #
3408188
Study Section
Neurology B Subcommittee 2 (NEUB)
Project Start
1988-07-01
Project End
1992-12-31
Budget Start
1990-07-01
Budget End
1992-12-31
Support Year
4
Fiscal Year
1990
Total Cost
Indirect Cost
Name
Allegheny University of Health Sciences
Department
Type
Schools of Medicine
DUNS #
City
Philadelphia
State
PA
Country
United States
Zip Code
19129
Wade, Timothy V; Schneider, Jay S (2004) Striatal preprotachykinin gene expression reflects parkinsonian signs. Neuroreport 15:2481-4
Schroeder, Joseph A; Schneider, Jay S (2002) GABA(A) and mu-opioid receptor binding in the globus pallidus and endopeduncular nucleus of animals symptomatic for and recovered from experimental Parkinsonism. Brain Res 947:284-9
Schroeder, J A; Schneider, J S (2002) GABA-opioid interactions in the globus pallidus: [D-Ala2]-Met-enkephalinamide attenuates potassium-evoked GABA release after nigrostriatal lesion. J Neurochem 82:666-73
Rothblat, D S; Schroeder, J A; Schneider, J S (2001) Tyrosine hydroxylase and dopamine transporter expression in residual dopaminergic neurons: potential contributors to spontaneous recovery from experimental Parkinsonism. J Neurosci Res 65:254-66
Schroeder, J A; Schneider, J S (2001) Alterations in expression of messenger RNAs encoding two isoforms of glutamic acid decarboxylase in the globus pallidus and entopeduncular nucleus in animals symptomatic for and recovered from experimental Parkinsonism. Brain Res 888:180-183
Wade, T V; Rothblat, D S; Schneider, J S (2001) Changes in striatal dopamine D3 receptor regulation during expression of and recovery from MPTP-induced parkinsonism. Brain Res 905:111-9
Wade, T; Rothblat, D S; Schneider, J S (2000) Changes in striatal dopamine D(2) receptors in relation to expression of and recovery from experimental parkinsonism. Brain Res 871:281-7
Schroeder, J A; Schneider, J S (2000) Striatal enkephalin gene expression does not reflect parkinsonian signs. Neuroreport 11:1799-802
Rothblat, D S; Schneider, J S (1999) Regional differences in striatal dopamine uptake and release associated with recovery from MPTP-induced parkinsonism: an in vivo electrochemical study. J Neurochem 72:724-33
Schneider, J S; Schroeder, J A; Rothblat, D S (1998) Differential recovery of sensorimotor function in GM1 ganglioside-treated vs. spontaneously recovered MPTP-treated cats: partial striatal dopaminergic reinnervation vs. neurochemical compensation. Brain Res 813:82-7

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