Lesion of the nigrostriatal dopamine system in rats produce a syndrome of aphasia, adipsia, bradykinesia, and profound sensorimotor neglect, symptoms similar to those seen if Parkinson's Disease. Grafts of dopamine-rich tissue in or near the striatum have been reported to alleviate many of the behavioral deficits produced by the destruction of nigrostriatal dopamine neurons. Experiments will investigate the neurochemical processes associated with behavioral recovery of function induced by grafts of adrenal medulla or fetal substantia nigra tissue in animals with nigrostriatal dopamine depletions. It is hypothesized that dopamine released from adrenal medulla grafts gins assess to the adjacent striatum via a compromised blood-brain-barrier to mediate the behavioral effects of these grafts. In contrast grafts of fetal tissue are thought to induce behavioral recovery by the formation of synaptic contacts. Experiments are proposed to test these hypotheses. with microdialysis in freely moving rats, experiments with adrenal medulla grafts will examine whether the blood-brain-barrier to dopamine is compromised and if so. whether this is correlated with the behavioral and neurochemical efficacy of these grafts. Experiments will then attempt to dissociate dopamine release them graft vs host of prier to determine whether there are changes in the activity of host dopaminergicneurons (e.g. neurochemical corelates of sprouting). In animals with bilateral dopamine depletion. The effect of unilateral adrenal medulla grafts on bilateral recovery of behavioral and neurochemical function will be tested. Finally, we will examine whether changes in host cholinergic activity is associated with behavioral recovery in animals with adrenal medulla grafts. The behavioral and neurochemical effects of fetal nigra grafts will be investigated using microdialysis to study the relations between graft-associated recovery of function and changes in the neurochemical function of grafted and host neurons. The relations between dopamine and acetylcholine in the straitum of animals with fetal nignal grafts amy reveal the extent of functional synaptic innervation by fetal nignal graft that occurs. Since it s well known that there is a delicate balance between dopamine and aceryicholine in the striatum, these relations may be of fundamental importance for behavioral recovery of function. Grafts of both adrenal medulla and fetal nigra tissue have already been applied clinically for the treatment of patients with severe Parkinson's Disease. The reports of the success of these grafts remains mixed. Answers about the neural mechanisms that mediate behavioral recovery of functions in animals with adrenal medulla and fetal grafts may be of fundamental importance for improving graft efficacy. The experiments proposed are a first step towards achieving this goal.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
2R01NS022157-04A1
Application #
3404224
Study Section
Neurology B Subcommittee 1 (NEUB)
Project Start
1985-04-01
Project End
1991-11-30
Budget Start
1988-12-01
Budget End
1989-11-30
Support Year
4
Fiscal Year
1989
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
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
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; 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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