title: A continuous striatal infusion of 6-hydroxydopamine produces a terminal axotomy and delayed behavioral effects.
abstract: Rat models of Parkinson's disease typically employ a rapid nigral injection of 6-hydroxydopamine (6-OHDA) to produce a near-complete loss of nigrostriatal dopamine neurons, and thus, model end stage disease. The present report describes the use of a continuous, low dose infusion of 6-OHDA into the striatum which produces a terminal axotomy of nigrostriatal dopamine neurons and protracted behavioral response. A solution of 6-OHDA in 0.4% ascorbate, delivered at 37 degrees C from osmotic minipumps, was stable for 8 days as determined by its retained toxicity to a dopaminergic neuroblastoma cell line. The continuous infusion of 0.2 mu g 6-OHDA per h did not affect the striatal uptake of [3H]%GABA, [3H]choline, or [3H]glutamate but reduced [3H]dopamine uptake by 55% within 1.5 days after the start of the infusion. The striatal infusion of 6-OHDA produced a dose-dependent reduction of striatal dopamine and DOPAC levels but did not alter HVA, 5-HT, or 5-HIAA. An increase in amphetamine-induced ipsiversive rotations occurred within 1.5 days after the acute striatal injection of 20 mu g or 30 mu g of 6-OHDA but required 4 days to develop with the continuous 6-OHDA infusion. The topography of the lesion mapped by [3H]mazindol binding showed that, beginning by 1.5 days, a diffuse depletion of terminals encompassed much of the striatum in the 30 mu g acute injection group, whereas in the continuously infused rats, the lesion was apparent only by 4 days and was restricted to a smaller and more completely lesioned area. Unlike acutely lesioned animals, continuously infused rats revealed no obvious loss of dopamine neurons in the pars compacta by 5 weeks after 6-OHDA. The continuous striatal infusion of 6-OHDA can produce a topographically limited terminal axotomy of dopamine neurons and a protracted behavioral impairment.
authors.affiliation: Regeneron Pharmaceuticals, Inc., Tarrytown, NY 10591, USA.
authors.forename: B E
authors.initials: BE
authors.lastname: Jones
authors.forename: C B
authors.initials: CB
authors.lastname: Boylan
authors.forename: M
authors.initials: M
authors.lastname: Fritsche
authors.forename: M
authors.initials: M
authors.lastname: Juhasz
authors.forename: C
authors.initials: C
authors.lastname: Jackson
authors.forename: S J
authors.initials: SJ
authors.lastname: Wiegand
authors.forename: C
authors.initials: C
authors.lastname: Hyman
authors.forename: R M
authors.initials: RM
authors.lastname: Lindsay
authors.forename: C A
authors.initials: CA
authors.lastname: Altar
mesh_terms: D000818:Animals; D001345:Autoradiography; D001369:Axons / Q000187:drug effects*; D001522:Behavior, Animal / Q000187:drug effects*; D001667:Binding, Competitive; D015306:Biogenic Monoamines / Q000378:metabolism; D002460:Cell Line / Q000187:drug effects; D002794:Choline / Q000378:metabolism; D003342:Corpus Striatum / Q000378:metabolism / Q000502:physiology*; D003714:Denervation; D018698:Glutamic Acid / Q000378:metabolism; D007150:Immunohistochemistry; D008297:Male; D008454:Mazindol / Q000378:metabolism; D016627:Oxidopamine / Q000008:administration & dosage* / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013239:Stereotyped Behavior / Q000502:physiology; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
chemical_list: D015306:Biogenic Monoamines; D018698:Glutamic Acid; D005680:gamma-Aminobutyric Acid; D016627:Oxidopamine; D008454:Mazindol; D014446:Tyrosine 3-Monooxygenase; D002794:Choline