Autoradiographic study of striatal dopamine re-uptake sites and dopamine D1 and D2 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/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.
Puschban
Z
Z
Neurological Research Laboratory, University Hospital, Innsbruck, Austria.
Scherfler
C
C
Granata
R
R
Laboyrie
P
P
Quinn
N P
NP
Jenner
P
P
Poewe
W
W
Wenning
G K
GK
D000661:Amphetamine / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D001058:Apomorphine / Q000494:pharmacology; D001284:Atrophy; D001345:Autoradiography; D001522:Behavior, Animal / Q000187:drug effects; D016380:Brain Tissue Transplantation; D003342:Corpus Striatum / Q000378:metabolism / Q000473:pathology / Q000637:transplantation*; D004298:Dopamine / Q000378:metabolism*; D018491:Dopamine Agonists / Q000494:pharmacology; D018765:Dopamine Uptake Inhibitors / Q000378:metabolism / Q000494:pharmacology; D016332:Fetal Tissue Transplantation; D008297:Male; D008454:Mazindol / Q000378:metabolism / Q000494:pharmacology; D009410:Nerve Degeneration / Q000139:chemically induced / Q000378:metabolism; D009474:Neurons / Q000737:chemistry / Q000378:metabolism; D016627:Oxidopamine; D017378:Quinolinic Acid; D051381:Rats; D017208:Rats, Wistar; D017447:Receptors, Dopamine D1 / Q000032:analysis / Q000378:metabolism*; D017448:Receptors, Dopamine D2 / Q000032:analysis / Q000378:metabolism*; D012399:Rotation; D013378:Substantia Nigra / Q000378:metabolism / Q000473:pathology / Q000637:transplantation*; D013565:Sympatholytics; D014316:Tritium
D018491:Dopamine Agonists; D018765:Dopamine Uptake Inhibitors; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D013565:Sympatholytics; D014316:Tritium; D016627:Oxidopamine; D008454:Mazindol; D000661:Amphetamine; D017378:Quinolinic Acid; D001058:Apomorphine; D004298:Dopamine