Long-term effects of human-to-rat mesencephalic xenografts on rotational behavior, striatal dopamine receptor binding, and mRNA levels.

Fetal ventral mesencephalic grafts have been used as a tool to counteract the symptoms of Parkinson's disease. In this study human fetal ventral mesencephalic xenografts were implanted into the lateral ventricle of unilaterally dopamine-depleted immunosuppressed rats. Rotational behavior elicited by low doses of apomorphine, host striatal dopamine receptor binding, and mRNA levels were investigated. Rotational behavior was reduced beginning 2 months after grafting. After 4 months only a small number of rotations, lasting approximately 30 min, were recorded. Seven months after transplantation, the rotational behavior was completely eleminated. Dopamine D2 receptor binding revealed significantly increased levels in sham-operated 6-hydroxydopamine- (6-OHDA) lesioned control striata. These increased levels decreased, and although still significantly higher at 4 months, normalized at the survival time of 7 months postgrafting. Regional differences were still obvious at 7 months in the dorsolateral quadrant of dorsal striatum. Dopamine D2 receptor mRNA revealed significantly increased levels in the lateral aspects of 6-OHDA-lesioned control striata, reversing by 4 months postgrafting. The D1 receptor binding revealed a moderately reduced signal in striata of lesioned animals. After grafting, this reduction became significantly lower than that seen in the control side, with a continous decrease over time. The same pattern was detected using in situ hybridization for dopamine D1 receptor mRNA, that is, moderate decreases after dopamine depletion and a significant decrease in the dorsomedial part of dorsal striatum 7 months postgrafting. Dopamine D3 receptor binding was increased after dopamine depletion, but reversed already by 4 months postgrafting. Taken together, human ventral mesencephalic xenografts are able to completely reverse apomorphine-induced rotational behavior, provided the grafts are left in vivo for a sufficient time. The increased striatal D2 receptors are reversed after grafting, but the human xenograft further suppressed the D1 receptor subtype both at binding and at mRNA levels. There was no strict correlation in the time courses of dopamine receptor changes and reduction of rotational behavior.