CORRELATION OF FUNCTIONAL RECOVERY AFTER A 6-HYDROXYDOPAMINE LESION WITH SURVIVAL OF GRAFTED FETAL NEURONS AND RELEASE OF DOPAMINE IN THE STRIATUM OF THE RAT

Female rats were lesioned with 6-hydroxydopamine in the left substantia nigra. At least two weeks later they were tested with amphetamine (5 mg/kg, s.c.) and apomorphine (0.25 mg/kg, s.c.). A cell suspension from the ventral mesencephalon of rat embryos was distributed in three sites in a triangular fashion in the center of the denervated striatum. The amphetamine test was then repeated every month for six months. The pattern of circling to amphetamine before the graft was strictly ipsiversive in all animals. From the first month we observed a progressive change and three patterns of rotation could be observed. In 21% of animals, the total number of ipsiversive turns in 90 min actually increased but during the first 20 min the animals turned contralaterally to the lesion (and to the graft). In 38% of animals, the total number of turns switched from ipsiversive to contraversive with the animals turning initially toward the intact side and during the second half of the test toward the lesion. Finally 41% of rats progressively switched to turning only toward the intact side. In all cases, maximal contraversive turning occurred during the initial 20 min. In these rats, tyrosine hydroxylase-positive cells were detected mainly in the dorsal striatum with a few in the central portion. Moreover there was a strong correlation between the number of surviving grafted neurons and the growth of their fiber into the host striatum and the extent of recovery. Although the basal level of extracellular dopamine measured by microdialysis was normalized by the graft, the rise in dopamine levels on the grafted side after amphetamine was much smaller, suggesting reduced storage capacity. The basal levels of dihydroxyphenylacetic acid and homovallinic acid remained much lower on the lesioned side despite the graft, suggesting a decreased rate of breakdown. Apomorphine given at the fourth month after transplantation still elicited contraversive circling but the number of turns was reduced. This study confirms the value of classifying grafted rats according to their pattern of amphetamine-induced circling and suggests that: (1) even a few grafted cells can provide enough dopamine to allow the maximal level of motor performance during a short period, (2) a greater number of grafted dopaminergic neurons is necessary to maintain an equilibrium between both striata or even favor the lesioned side after the first 20 min of amphetamine stimulation, (3) persistance of dopaminergic receptor supersensitivity could contribute to the preferential dopamine stimulation on the grafted side, (4) localization of the graft in the dorsal striatum could also play a part in the overcompensation of the amphetamine response.