RESTORATION OF COMPLEX SENSORIMOTOR BEHAVIOR AND SKILLED FORELIMB USEBY A MODIFIED NIGRAL CELL-SUSPENSION TRANSPLANTATION APPROACH IN THE RAT PARKINSON MODEL

While intrastriatal transplants of dopamie-rich ventral mesencephalic tissue are effective in reversing a variety of drug-induced behaviors in the rat Parkinson model, previous studies have failed to obtain sig nificant graft-induced effects on deficits in certain aspects of compl ex sensorimotor behaviors. In the present study we have applied a modi fied cell suspension transplantation procedure, which allows more repr oducible and consistent ventral mesencephalic transplants of large siz e, as well as more wide-spread distribution of the ventral mesencephal ic tissue over multiple graft sites within the denervated caudate-puta men. Using this approach it has for the first time been possible to ob tain significant amelioration of the lesion-induced deficits in skille d forelimb use and in the rats ability to switch from one behavior (ea ting) to another (orientation towards tactile stimuli), so-called dise ngage behavior. Rats with unilateral 6-hydroxydopamine lesions of the mesostriatal dopamine pathway received a total of 450,000 fetal ventra l mesenoephalic cells, implanted either as two large deposits along a single injection tract (''Macro'' grafts), or as 18 small deposits alo ng six injection tracts in the head of the denervated caudate-putamen (''Micro'' grafts) and the behavioral changes were studied up to three months after transplantation. On the drug-induced tests, both types o f transplants reversed amphetamine- and D1-receptor agonist-induced tu rning, and produced a partial (50-75%) reduction in apomorphine-induce d and D2-receptor agonist-induced turning. On the spontaneous sensorim otor tests, both types of grafts reversed the deficit in simple sensor imotor orientation. In addition, the Micro-grafted animals (which prod uced the most extensive reinnervation of the denervated striatum) show ed a significant improvement in skilled forelimb use and in response l atency in the disengage behavior test. Although the large sized Macro- grafted animals showed a similar trend, it did not reach significance. Moreover, the Micro grafts had a more pronounced effect on spontaneou s turning behavior in a conditioned response test. The improvement in response latency in the disengage test was significantly correlated wi th the dopamine level in the nucleus accumbens, whereas the magnitude of the conditioned turning response was significantly correlated with the dopamine levels in the head of the caudate-putamen. The results sh ow that intrastriatal nigral transplants, despite their ectopic placem ent, can ameliorate lesion-induced deficits also in more complex senso rimotor behaviors. This improved graft effect is likely to depend on b oth extensive dopaminergic reinnervation throughout the head of the ca udate-putamen, as well as on closer integration of the grafted nigral tissue with the host striatal circuitry.