Embryonic ventral mesencephalic grafts improve levodopa-induced dyskinesiain a rat model of Parkinson's disease

We investigated the role of dopamine neurons in the manifestation of levodo pa-induced dyskinesia in a rat model of Parkinson's disease. Daily treatmen t with a subthreshold dose of levodopa gradually induced abnormal involunta ry movements (AIM) in 6-hydroxydopamine-lesioned rats, which included stere otypy and contraversive rotation, After ii weeks of levodopa treatment, rat s with mild and severe AIM were assigned to two treatment subgroups, The gr aft subgroup received embryonic ventral mesencephalic tissue into the stria tum, whilst the sham-graft subgroup received vehicle only. Rats continued t o receive levodopa treatment for 3 months post-graft. Brain sections at the level of the basal ganglia were processed for autoradiography using a liga nd for dopamine transporter, and in situ hybridization histochemistry for m RNAs encoding postsynaptic markers. Levodopa-induced AIM, significantly imp roved in grafted rats. The severity of AIR;I correlated inversely with the density of dopamine nerve terminals in the striatum (P < 0.001), with almos t no AIM when the density of dopamine nerve terminals was >10-20% of normal . Embryonic dopamine neuronal grafts normalized not only mRNA expression fo r preproenkephalin (PPE) in the indirect pathway, but also mRNA expression for prodynorphin (PDyn) in the direct pathway, which was upregulated by lev odopa treatment. AIM scores correlated linearly with expression of PPE mRNA in the indirect pathway (P < 0.001) and also with PDyn mRNA in the direct pathway (P < 0.001), We conclude that embryonic dopamine neuronal grafts ma y improve levodopa-induced dyskinesia by restoring altered activities of po stsynaptic neurons, resulting not only from dopamine denervation, but also from levodopa therapy, provided that the density of striatal dopaminergic n erve terminals is restored above a 'threshold' level.