Autoradiographic study of striatal dopamine re-uptake sites and dopamine D-1 and D-2 receptors in a 6-hydroxydopamine and quinolinic acid double-lesion rat model of striatonigral degeneration (multiple system atrophy) and effects of embryonic ventral mesencephalic, striatal or co-grafts

The influence of embryonic mesencephalic, striatal and mesencephalic/striat al co-grafts on amphetamine- and apomorphine-induced rotation behaviour was assessed in a rat model of multiple system atrophy/striatonigral degenerat ion type using dopamine D-1 ([H-3]SCH23390) and D-2 ([H-3]spiperone) recept or and dopamine re-uptake ([H-3]mazindol) autoradiography. Male Wistar rats subjected to a sequential unilateral 6-hydroxydopamine lesion of the media l forebrain bundle followed by a quinolinic acid lesion of the ipsilateral striatum were divided into four treatment groups, receiving either mesencep halic, striatal, mesencephalic/striatal co-grafts or sham grafts. Amphetami ne- and apomorphine-induced rotation behaviour was recorded prior to and up to 10 weeks following transplantation. 6-Hydroxydopamine-lesioned animals showed ipsiversive amphetamine-induced a nd contraversive apomorphine-induced rotation behaviour. Amphetamine-induce d rotation rates persisted after the subsequent quinolinic acid lesion, whe reas rotation induced by apomorphine was decreased. In 11 of 14 animals rec eiving mesencephalic or mesencephalic/striatal co-grafts, amphetamine induc ed rotation scores were decreased by >50% at the 10-week post-grafting time -point. In contrast, only one of 12 animals receiving non-mesencephalic (st riatal or sham) grafts exhibited diminished rotation rates at this time-poi nt. Apomorphine-induced rotation rates were significantly increased followi ng transplantation of mesencephalic, striatal or sham grafts. The largest i ncrease of apomorphine-induced rotation rates approaching post-6-hydroxydop amine levels were observed in animals with striatal grafts. In contrast, in the co-graft group, there was no significant increase of apomorphine-induc ed rotation compared to the post-quinolinic acid time-point. Morphometric a nalysis revealed a 63-74% reduction of striatal surface areas across the tr eatment groups. Striatal [H-3]mazindol binding on the lesioned side (exclud ing the demarcated graft area) revealed a marked loss of dopamine reuptake sites across all treatment groups, indicating missing graft-induced dopamin ergic re-innervation of the host. In eight (73%) of the 11 animals with mes encephalic grafts and reduced amphetamine-induced circling, discrete areas of [H-3]mazindol binding ("hot spots") were observed, indicating graft surv ival. Dopamine D-1 and D-2 receptor binding was preserved in the remaining lesioned striatum irrespective of treatment assignment, except for a signif icant reduction of D-2 receptor binding in animals receiving mesencephalic grafts. "Hot spots" of dopamine D-1 and D-2 receptor binding were observed in 10 (83%) and nine (75%) of 12 animals receiving striatal grafts or co-gr afts, consistent with survival of embryonic primordial striatum grafted int o a severely denervated and lesioned striatum. Our study confirms that functional improvement may be obtained from embryon ic neuronal grafts in a double-lesion rat model of multiple system atrophy/ striatonigral degeneration type. Co-grafts appear to be required for revers al 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. T he changes of apomorphine-induced rotation following transplantation are li kely to reflect a complex interaction of graft- and host-derived striatal p rojection pathways and basal ganglia output nuclei. Further studies in a la rger number of animals are required to determine whether morphological para meters and behavioural improvement in the neurotransplantation multiple sys tem atrophy rat model correlate. (C) 1999 IBRO. Published by Elsevier Scien ce Ltd.