LONG-TERM EFFECTS OF HUMAN-TO-RAT MESENCEPHALIC XENOGRAFTS ON ROTATIONAL BEHAVIOR, STRIATAL DOPAMINE-RECEPTOR BINDING, AND MESSENGER-RNA LEVELS

Fetal ventral mesencephalic grafts have been used as a tool to counter act the symptoms of Parkinson's disease. In this study human fetal ven tral mesencephalic xenografts were implanted into the lateral ventricl e 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 behavi or was reduced beginning 2 months after grafting. After 4 months only a small number of rotations, lasting approximately 30 min, were record ed. Seven months after transplantation, the rotational behavior was co mpletely eleminated. Dopamine D-2 receptor binding revealed significan tly increased levels in sham-operated 6-hydroxydopamine- (6-OHDA) lesi oned control striata. These increased levels decreased, and although s tilt 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 D-2 receptor mRNA revealed significantly increased levels in the lateral aspects of 6-OHDA-lesioned control striata, reversing by 4 months post grafting. The D-1 receptor binding revealed a moderately reduced signa l in striata of lesioned animals. After grafting, this reduction becam e significantly lower than that seen in the control side, with a conti nous decrease over time. The same pattern was detected using in situ h ybridization for dopamine D-1 receptor mRNA, that is, moderate decreas es after dopamine depletion and a significant decrease in the dorsomed ial part of dorsal striatum 7 months postgrafting. Dopamine D3 recepto r 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 rotatio nal behavior, provided the grafts are left in vivo for a sufficient ti me. The increased striatal D-2 receptors are reversed after grafting, but the human xenograft further suppressed the D-1 receptor subtype bo th at binding and at mRNA levels. There was no strict correlation in t he time courses of dopamine receptor changes and reduction of rotation al behavior.