DOSE-DEPENDENT LESIONS OF THE DOPAMINERGIC NIGROSTRIATAL PATHWAY INDUCED BY INTRASTRIATAL INJECTION OF 6-HYDROXYDOPAMINE

Animal models with partial lesions of the dopaminergic nigrostriatal p athway may be useful for developing neuroprotective and neurotrophic t herapies for Parkinson's disease. To develop such a model, different d oses of 6-hydroxydopamine (0.0, 0.625, 1.25, 2.5 and 5.0 mu g/mu l in 3.5 mu l of saline) were unilaterally injected into the striatum of ra ts. Animals that received 1.25 to 5.0 mu g/mu l 6-hydroxydopamine disp layed dose-dependent amphetamine and apomorphine-induced circling. 6-H ydroxydopamine also caused dose-dependent reductions in [H-3]mazindol- labeled dopamine uptake sites in the lesioned striatum and ipsilateral substantia nigra pars compacta (up to 93% versus contralateral bindin g), with smaller losses in the nucleus accumbens, olfactory tubercle a nd ventral tegmental area. In the substantia nigra pars compacta and t he ventral tegmental area, the number of Nissl-stained neurons decreas es in parallel with the reduction in [H-3]mazindol binding. The reduct ion in [H-3]mazindol binding in the striatum and the nucleus accumbens , and the reduction in [H-3]mazindol binding and in the number of Niss l-stained neurons in the substantia nigra pars compacta and the ventra l tegmental area is stable for up to 12 weeks after the lesion. Macros copically, forebrain coronal sections showed normal morphology, except for rats receiving 5.0 mu g/mu l 6-hydroxydopamine in which striatal cross-sectional area was reduced, suggesting that this high dose non-s pecifically damages intrinsic striatal neurons. Nissl-stained sections revealed aa area of neuronal loss and intense gliosis centered around the needle track, which increased in size with thedoe of neurotoxin. Striatal [H-3]sulpiride binding was increased by 2.5 mu g/mu l and 5.0 mu g/mu l 6-hydroxydopamine, suggesting up-regulation of dopamine D-2 , receptors. Striatal binding of [H-3]CGS 21680-labeled adenosine A(2a ) receptors, but not of [H-3]SCH 23390-labeled dopamine D-1 receptors, was reduced at the highest dose, suggesting preservation of the stria tal intrinsic neurons with the lower doses. This study indicates that intrastriatal injection of different doses of 6-hydroxydopamine can be used to cause increasing amounts of dopamine denervation, which could model Parkinson's disease of varying degrees of severity. Injecting 3 .5 mu l of 2.5 mu g/mu l 6-hydroxydopamine appears to be particularly useful as a general model of early Parkinson's disease, since it induc es a lesion characterized by robust drug-induced rotation, changes in binding consistent with similar to 70% dopamine denervation, similar t o 19% dopamine D-2 receptor up-regulation, negligible intrinsic striat al damage and stability for at least 12 weeks. This study outlines a t echnique for inducing partial lesions of the nigrostriatal dopamine pa thway in rats. These lesions model early Parkinson's disease, and can be useful for testing protective, preventive, restorative and symptoma tic treatments.