A CONTINUOUS STRIATAL INFUSION OF 6-HYDROXYDOPAMINE PRODUCES A TERMINAL AXOTOMY AND DELAYED BEHAVIORAL-EFFECTS

Rat models of Parkinson's disease typically employ a rapid nigral inje ction 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 o f 6-OHDA into the striatum which produces a terminal axotomy of nigros triatal dopamine neurons and protracted behavioral response. A solutio n 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 toxicit y to a dopaminergic neuroblastoma cell line. The continuous infusion o f 0.2 mu g 6-OHDA per h did not affect the striatal uptake of [H-3]GAB A, [H-3]choline, or [H-3]glutamate but reduced [H-3]dopamine uptake by 55% within 1.5 days after the start of the infusion. The striatal inf usion of 6-OHDA produced a dose-dependent reduction of striatal dopami ne and DOPAC levels but did not alter HVA, 5-HT, or 5-HIAA. An increas e in amphetamine-induced ipsiversive rotations occurred within 1.5 day s after the acute striatal injection of 20 mu g or 30 mu g of 6-OHDA b ut required 4 days to develop with the continuous 6-OHDA infusion. The topography of the lesion mapped by [H-3]mazindol binding showed that, begining by 1.5 days, a diffuse depletion of terminals encompassed mu ch of the striatum in the 30 mu g acute injection group, whereas in th e continuously infused rats, the lesion was apparent only by 4 days an d was restricted to a smaller and more completely lesioned area. Unlik e acutely lesioned animals, continuously infused rats revealed no obvi ous loss of dopamine neurons in the pars compacta by 5 weeks after 6-O HDA. The continuous striatal infusion of 6-OHDA can produce a topograp hically limited terminal axotomy of dopamine neurons and a protracted behavioral impairment.