VOLUME TRANSMISSION OF DOPAMINE OVER LARGE DISTANCES MAY CONTRIBUTE TO RECOVERY FROM EXPERIMENTAL PARKINSONISM

Administration of the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydrop yridine (MPTP) to cats results in a parkinsonian syndrome that spontan eously recovers by 6 weeks after induction. Striatal dopamine depletio ns in these animals are heterogenous with more extensive damage dorsol aterally than ventromedially. Measures of extracellular dopamine level s by in vivo microdialysis showed that dopamine released from a relati vely preserved ventral striatal innervation can diffuse over a distanc e of 5.5 mm to 7.0 mm to the more extensively denervated dorsolateral striatum, where it may influence sensorimotor activities and contribut e to functional recovery. Diffusion of dopamine through a large volume of striatal tissue was observed in cats 6 weeks after an MPTP-induced lesion and in normal cats with pharmacologically induced dopamine reu ptake inhibition, but not in normal animals without reuptake inhibitio n. In cats recovered from MPTP-induced parkinsonism, a great amount of dopamine was recovered from the extracellular fluid in the dorsolater al caudate following stimulated release of dopamine from the ventromed ial striatum than after stimulated release locally in the dorsolateral caudate. These results suggest volume transmision of dopamine over la rge distances is possible and perhaps an important contributor to func tional recovery from a large dopamine-depleting lesion. These results may also form the basis for understanding how limited reinnervation of the striatum by grafts or trophic factor therapies may lead to signif icant functional improvement.