Glutamate uptake blockade induces striatal dopamine release in 6-hydroxydopamine rats with intrastriatal grafts: evidence for host modulation of transplanted dopamine neurons.
The transplantation of fetal dopamine neurons has previously been shown to ameliorate locomotor deficits in laboratory animals with nigrostriatal dopamine lesions. These studies have also demonstrated a reinstatement of striatal dopamine synthesis and release associated with the graft-to-host fiber innervation. More recent studies in the intact striatum indicate that striatal dopamine release can be regulated by corticostriatal glutamatergic projections. In the present study we hypothesized that secretion of dopamine by grafted neurons may also be regulated by similar mechanisms. To test this hypothesis we have measured dopamine release in the striatum of rats with unilateral 6-hydroxydopamine (6-OHDA) lesions of the nigrostriatal pathway and grafts containing dopamine neurons. Intrastriatal dopamine levels were determined using methods of in vivo microdialysis. The administration of dihydrokainic acid, an inhibitor of glutamate uptake, resulted in the release of striatal dopamine in grafted and normal rats. In contrast, dopamine was not detectable in animals with 6-OHDA lesions alone. Additional studies were conducted to determine the type of glutamate receptor mediating the release of striatal dopamine. Kainic acid administration into the perfusate of the dialysis probe resulted in the release of striatal dopamine in a dose-dependent fashion in both grafted and normal rats. N-methyl-D-aspartate had no effect on dopamine release except at abnormally high concentrations. These results demonstrate that dopamine neurons which are transplanted into the striatum of rats with 6-OHDA lesions become functionally incorporated into the neural circuitry of the host brain, and that the release of dopamine by grafted neurons can be regulated by afferent fibers from the host brain.(ABSTRACT TRUNCATED AT 250 WORDS)
Kondoh
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Department of Neurosurgery, University of Minnesota Medical School, Minneapolis 55455.
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D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000378:metabolism*; D001927:Brain Diseases / Q000139:chemically induced* / Q000378:metabolism; D016380:Brain Tissue Transplantation; D003342:Corpus Striatum / Q000378:metabolism*; D004298:Dopamine / Q000493:pharmacokinetics*; D018691:Excitatory Amino Acid Antagonists; D005971:Glutamates / Q000493:pharmacokinetics*; D018698:Glutamic Acid; D007608:Kainic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D008297:Male; D008636:Mesencephalon / Q000378:metabolism / Q000637:transplantation*; D016202:N-Methylaspartate / Q000494:pharmacology; D009474:Neurons / Q000201:enzymology / Q000378:metabolism; D016627:Oxidopamine; D051381:Rats; D014446:Tyrosine 3-Monooxygenase / Q000032:analysis
D018691:Excitatory Amino Acid Antagonists; D005971:Glutamates; D015102:3,4-Dihydroxyphenylacetic Acid; D018698:Glutamic Acid; C020889:dihydrokainic acid; D016202:N-Methylaspartate; D016627:Oxidopamine; D014446:Tyrosine 3-Monooxygenase; D007608:Kainic Acid; D004298:Dopamine