LOSS OF STRIATAL DA INNERVATION INCREASES STRIATAL TROPHIC ACTIVITY DIRECTED AT DA NEURONS IN CULTURE

Male rats received intraventricular infusions of the dopamine (DA) neu rotoxin 6-hydroxydopamine (6-OHDA; 0, 75, 150, and 250 mu g) in order to determine if DA neuron loss was associated with an increase in stri atal trophic activity. After 4 weeks, the animals were sacrificed and perfused with normal saline, and the brains were removed, immediately frozen, and processed. Intraventricular infusions of 6-OHDA were assoc iated with a dose-dependent reduction in striatal DA content and tyros ine hydroxylase-immunoreactive (THir) cell counts in the substantia ni gra while striatal DA activity ([HVA]/[DA]) was increased. Extracts of the striatum hom these animals increased the survival of E15 primary, dissociated rostral mesencphalic cultures growing at low cell density . This growth effect was positively correlated with the dose of 6-OHDA infused. THir cell counts present in high-cell-density mesencephalic cultures following 72 h of extract incubation were similarly correlate d to 6-OHDA dose but inversely correlated with striatal DA content and THir cell counts in the substantia nigra. Trophic activity in the cer ebellar extracts from these animals was significantly lower than that present in striatal extracts and was not influenced by 6-OHDA lesions. These data suggest that loss of DA innervation in the striatum is ass ociated with an increase in striatal trophic activity directed at DA n eurons. A compensatory response to the loss of DA neurons involving in creased striatal trophic activity may result in increased DA terminal sprouting of remaining viable DA neurons that, in turn, would serve to help reinstate normal DA tone. (C) 1996 Academic Press, Inc.