Depletion of brain dopamine (DA) in rats produces a syndrome of aphagia, adipsia, bradykinesia, and profound sensorimotor neglect. This bradykinesia and sensorimotor neglect is not due to a primary sensory or motor deficit, but has been characterized as a deficit in sensory-motor integration. These symptoms are very similar to those seen in Parkinson's Disease, which is thought to be due to a loss of DA-containing neurons in the substantia nigra. Although rats with bilateral DA depletion have provided many insights into the function of brain DA neurons, they are difficult to maintain, requiring extensive post-operative care. However, rats with unilateral nigrostriatal DA depletion have provided a very useful animal model of Parkinson's Disease. These animals neglect stimuli presented to the contralateral body surface or space, and when treated with DA-mimetic drugs display a highly quantifiable behavioral asymmetry known as rotational (circling) behavior. Recently, it has been shown that grafts of fetal substantia nigra or adrenal medulla tissue placed in or near the denervated striatum can at least partially reverse these behavioral asymmetries. The evidence available to date suggests that these grafts alleviate the symptoms of DA depletion by releasing catecholamines, but this hypothesis has never been directly tested. In this application we propose a series of experiments to do so. In the first series of experiments we propose to develop a push-pull perfusion technique to measure the efflux of catecholamine metabolites into the lateral ventricle as an index of catecholamine release. Next, we will compare the ability of fetal substantia nigra, adrenal medulla or fetal tectal tissue grafts placed into the lateral ventricle to release catecholamines and/or catecholamine metabolites into the lateral ventricle, over time following the transplant. Thirdly, we will use a series of pharmacological manipulations to determine: (1) if there is any relation between the ability of catecholamine-rich tissue grafts to release catecholamines and their ability to attenuate the rotational behavior imbalance produced by unilateral DA depletion; and (2) whether any of the normal mechanisms governing catecholamine release are operative in tissue grafts.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS022157-03
Application #
3404228
Study Section
Neurology B Subcommittee 1 (NEUB)
Project Start
1985-04-01
Project End
1988-11-30
Budget Start
1987-04-01
Budget End
1988-11-30
Support Year
3
Fiscal Year
1987
Total Cost
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Type
Schools of Arts and Sciences
DUNS #
791277940
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Johnson, R E; Schallert, T; Becker, J B (1999) Akinesia and postural abnormality after unilateral dopamine depletion. Behav Brain Res 104:189-96
Johnston, R E; Becker, J B (1999) Behavioral changes associated with grafts of embryonic ventral mesencephalon tissue into the striatum and/or substantia nigra in a rat model of Parkinson's Disease. Behav Brain Res 104:179-87
Johnston, R E; Becker, J B (1997) Intranigral grafts of fetal ventral mesencephalic tissue in adult 6-hydroxydopamine-lesioned rats can induce behavioral recovery. Cell Transplant 6:267-76
Bazzett, T J; Falik, R C; Becker, J B et al. (1996) Chronic intrastriatal administration of quinolinic acid produces transient nocturnal hypermotility in the rat. Brain Res Bull 39:69-73
Galasso, J M; Bazzett, T J; Becker, J B et al. (1995) Synergistic effect of intrastriatal co-administration of L-NAME and quinolinic acid. Neuroreport 6:1505-8
Bazzett, T J; Falik, R C; Becker, J B et al. (1995) Chronic administration of malonic acid produces selective neural degeneration and transient changes in calbindin immunoreactivity in rat striatum. Exp Neurol 134:244-52
Bazzett, T J; Becker, J B; Falik, R C et al. (1994) Chronic intrastriatal quinolinic acid produces reversible changes in perikaryal calbindin and parvalbumin immunoreactivity. Neuroscience 60:837-41
Bergdall, V K; Becker, J B (1994) Effects of nerve growth factor infusion on behavioral recovery and graft survival following intraventricular adrenal medulla grafts in the unilateral 6-hydroxydopamine lesioned rat. J Neural Transplant Plast 5:163-7
Bazzett, T J; Becker, J B; Kaatz, K W et al. (1993) Chronic intrastriatal dialytic administration of quinolinic acid produces selective neural degeneration. Exp Neurol 120:177-85
Curran, E J; Albin, R L; Becker, J B (1993) Adrenal medulla grafts in the hemiparkinsonian rat: profile of behavioral recovery predicts restoration of the symmetry between the two striata in measures of pre- and postsynaptic dopamine function. J Neurosci 13:3864-77

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