Animal models with partial lesions of the dopaminergic nigrostriatal pathway may be
useful for developing neuroprotective and neurotrophic therapies for Parkinson's disease.
To develop such a model, different doses of 6-hydroxydopamine (0.0, 0.625, 1.25, 2.5
and 5.0 micrograms/microliters in 3.5 microliters of saline) were unilaterally injected
into the striatum of rats. Animals that received 1.25 to 5.0 micrograms/microliters
6-hydroxydopamine displayed dose-dependent amphetamine and apomorphine-induced circling.
6-Hydroxydopamine also caused dose-dependent reductions in [3H]mazindol-labeled dopamine
uptake sites in the lesioned striatum and ipsilateral substantia nigra pars compacta
(up to 93% versus contralateral binding), with smaller losses in the nucleus accumbens,
olfactory tubercle and ventral tegmental area. In the substantia nigra pars compacta
and the ventral tegmental area, the number of Nissl-stained neurons decreases in parallel
with the reduction in [3H]mazindol binding. The reduction in [3H]mazindol binding
in the striatum and the nucleus accumbens, and the reduction in [3H]mazindol binding
and in the number of Nissl-stained neurons in the substantia nigra pars compacta and
the ventral tegmental area is stable for up to 12 weeks after the lesion. Macroscopically,
forebrain coronal sections showed normal morphology, except for rats receiving 5.0
micrograms/microliters 6-hydroxydopamine in which striatal cross-sectional area was
reduced, suggesting that this high dose non-specifically damages intrinsic striatal
neurons. Nissl-stained sections revealed an area of neuronal loss and intense gliosis
centered around the needle track, which increased in size with the dose of neurotoxin.
Striatal [3H]sulpiride binding was increased by 2.5 micrograms/microliters and 5.0
micrograms/microliters 6-hydroxydopamine, suggesting up-regulation of dopamine D2
receptors. Striatal binding of [3H]CGS 21680-labeled adenosine A2a receptors, but
not of [3H]SCH 23390-labeled dopamine D1 receptors, was reduced at the highest dose,
suggesting preservation of the striatal 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 microliters of 2.5
micrograms/microliters 6-hydroxydopamine appears to be particularly useful as a general
model of early Parkinson's disease, since it induces a lesion characterized by robust
drug-induced rotation, changes in binding consistent with approximately 70% dopamine
denervation, approximately 19% dopamine D22 receptor up-regulation, negligible intrinsic
striatal damage and stability for at least 12 weeks. This study outlines a technique
for inducing partial lesions of the nigrostriatal dopamine pathway in rats.(ABSTRACT
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