The influence of embryonic mesencephalic, striatal and mesencephalic/striatal co-grafts on
amphetamine- and
apomorphine-induced rotation behaviour was assessed in a rat model of
multiple system atrophy/
striatonigral degeneration type using
dopamine D1 ([3H]
SCH23390) and D2 ([3H]
spiperone) receptor and
dopamine re-uptake ([3H]
mazindol) autoradiography. Male Wistar rats subjected to a sequential unilateral
6-hydroxydopamine lesion of the medial forebrain bundle followed by a
quinolinic acid lesion of the ipsilateral striatum were divided into four treatment groups, receiving either mesencephalic, striatal, mesencephalic/striatal co-grafts or
sham grafts.
Amphetamine- and
apomorphine-induced rotation behaviour was recorded prior to and up to 10 weeks following
transplantation. 6-Hydroxydopamine-lesioned animals showed ipsiversive
amphetamine-induced and contraversive
apomorphine-induced rotation behaviour.
Amphetamine-induced rotation rates persisted after the subsequent
quinolinic acid lesion, whereas rotation induced by
apomorphine was decreased. In 11 of 14 animals receiving mesencephalic or mesencephalic/striatal co-grafts,
amphetamine-induced rotation scores were decreased by >50% at the 10-week post-grafting time-point. In contrast, only one of 12 animals receiving non-mesencephalic (striatal or
sham) grafts exhibited diminished rotation rates at this time-point.
Apomorphine-induced rotation rates were significantly increased following
transplantation of mesencephalic, striatal or
sham grafts. The largest increase of
apomorphine-induced rotation rates approaching post-6-hydroxydopamine levels were observed in animals with striatal grafts. In contrast, in the co-graft group, there was no significant increase of
apomorphine-induced rotation compared to the post-
quinolinic acid time-point. Morphometric analysis revealed a 63-74% reduction of striatal surface areas across the treatment groups. Striatal [3H]
mazindol binding on the lesioned side (excluding the demarcated graft area) revealed a marked loss of
dopamine re-uptake sites across all treatment groups, indicating missing graft-induced dopaminergic re-innervation of the host. In eight (73%) of the 11 animals with mesencephalic grafts and reduced
amphetamine-induced circling, discrete areas of [3H]
mazindol binding ("hot spots") were observed, indicating graft survival.
Dopamine D1 and D2 receptor binding was preserved in the remaining lesioned striatum irrespective of treatment assignment, except for a significant reduction of D2 receptor binding in animals receiving mesencephalic grafts. "Hot spots" of
dopamine D1 and D2 receptor binding were observed in 10 (83%) and nine (75%) of 12 animals receiving striatal grafts or co-grafts, consistent with survival of embryonic primordial striatum grafted into a severely denervated and lesioned striatum. Our study confirms that functional improvement may be obtained from embryonic neuronal grafts in a double-lesion rat model of
multiple system atrophy/
striatonigral degeneration type. Co-grafts appear to be required for reversal of both
amphetamine- and
apomorphine-induced rotation behaviour in this model. We propose that the partial reversal of
amphetamine-induced rotation asymmetry in double-lesioned rats receiving mesencephalic or mesencephalic/striatal co-grafts reflects non-synaptic graft-derived
dopamine release. The changes of
apomorphine-induced rotation following
transplantation are likely to reflect a complex interaction of graft- and host-derived striatal projection pathways and basal ganglia output nuclei. Further studies in a larger number of animals are required to determine whether morphological parameters and behavioural improvement in the neurotransplantation
multiple system atrophy rat model correlate.