The studies in this proposal are designed to determine if slight, presymptomatic lesions of the brain dopaminergic and/or serotonergic neurons can be assessed (i.e. unmasked) through the use of sensitive behavioral paradigms combined with drug challenge. Long-Evans rats will be used as subjects and they will be treated with the systemically administered neurotoxins 1- methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) or methamphetamine. By varying the dose of these toxins, the magnitude of the lesion can be varied. The lesion magnitude for the dopaminergic system will range from 0% (i.e. control) to a maximum 75% depletion. These dopaminergic lesions will be accompanied by serotonergic lesions (simultaneously induced by both toxins) ranging in magnitude from 0% up to approximately 60% depletion. Both of these toxins have proven invaluable in advancing our understanding of the factors which lead to the degeneration of central dopaminergic and serotonergic neurons and, as such, have served as excellent models of Parkinson's disease. However, the use of rodents to explore these models has been somewhat restricted by the failure to demonstrate behavioral deficits associated with the toxin-induced damage. In this regard, however, the PI has obtained some degree of success stemming from use of carefully chosen behavioral paradigms used in conjunction with drug challenge tests. The demonstration that rodents with MPTP or methamphetamine-induced dopaminergic lesions do exhibit behavioral deficits has provided support for the validity of these models.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS026099-03
Application #
3411738
Study Section
Biopsychology Study Section (BPO)
Project Start
1988-04-01
Project End
1992-03-31
Budget Start
1990-04-01
Budget End
1992-03-31
Support Year
3
Fiscal Year
1990
Total Cost
Indirect Cost
Name
Rutgers University
Department
Type
Schools of Arts and Sciences
DUNS #
038633251
City
New Brunswick
State
NJ
Country
United States
Zip Code
08901
Walsh, S L; Wagner, G C (1992) Motor impairments after methamphetamine-induced neurotoxicity in the rat. J Pharmacol Exp Ther 263:617-26
Johnson, S K; Medina, D; Wagner, G C (1992) The effects of deprenyl on methamphetamine-induced dopamine depletions. J Neural Transm Gen Sect 89:123-7
De Vito, M J; Wagner, G C (1989) Methamphetamine-induced neuronal damage: a possible role for free radicals. Neuropharmacology 28:1145-50
De Vito, M J; Wagner, G C (1989) Functional consequences following methamphetamine-induced neuronal damage. Psychopharmacology (Berl) 97:432-5
Walsh, S L; Wagner, G C (1989) Age-dependent effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP): correlation with monoamine oxidase-B. Synapse 3:308-14