Complex Sensorimotor Behavioral Changes after Terminal Striatal 6-OHDA Lesion and Transplantation of Dopaminergic Embryonic Micrografts

Abstract

In this study sensorimotor behavioral changes were monitored in rats following bilateral 6-hydroxydopamine (6-OHDA) axon terminal lesion and uni- or bilateral implantation of embryonic dopaminergic (DA) micrografts. A total of 28 μg of 6-OHDA was distributed over four injection tracts in the dorsolateral part of the caudate-putamen (CPU) bilaterally followed 4 months later by the implantation of DA micrografts spread over seven implantation tracts placed within the denervated area. Bilaterally 6-OHDA-lesioned animals exhibited significantly reduced behavioral performance scores in tests of explorational and stepping behavior as well as in skilled forelimb use. However, in contrast to the established medial forebrain bundle (MFB) lesion model of PD, these animals showed a spontaneous recovery in the side falling and skilled forelimb behavior and no deficits in overnight locomotor activity at 6 months after the lesion. Unilateral DA micrografts elicited a substantial amphetamine-induced rotational bias contralateral to the graft, but led to a significant impairment of contralateral skilled forelimb use and reduced scores in overnight locomotor activity. Bilateral DA micrografts caused a significant, though partial, increase in explorational and backhand stepping behavior, but resulted also in a significant decrease in performance levels in overnight locomotor activity and skilled forelimb use on both paws. In conclusion, DA grafts placed ectopically in the CPU in the partial lesion model of PD result in a double innervation of the GABAergic striatal neurons, arising from the residual nigrostriatal DA projections of the host and from the graft-derived DA efferent fibers. These two DA fiber systems may indeed function in a cooperative and competitive manner depending on their respective and different afferent and efferent connections, which, in turn, may lead to positive or negative influences on basal ganglia function and behavioral performances. The different patterns of 6-OHDA lesion and transplant-induced behavioral changes demonstrated in the present study compared to the “classical” MFB lesion model of PD may thus provide further insights in the complex functional organization of the basal ganglia and, thereby, may help to further optimize restorative strategies for neurodegenerative diseases, such as Parkinson's disease.