STUDIES ON THE STRIATAL DOPAMINE UPTAKE SYSTEM OF WEAVER MUTANT MICE AND EFFECTS OF VENTRAL MESENCEPHALIC GRAFTS

The dopamine (DA) uptake system was investigated in the mesostriatal s ystem of normal and weaver mutant mice, which lose mesencephalic DA ne urons, as well as in weaver mutants with ventral mesencephalic grafts to the striatum. Assays of [H-3]DA uptake in striatal synaptosomal fra ctions in vitro and autoradiography of [H-3]mazindol binding in brain sections were carried out in wild-type mice (+/+) and in the two hemis pheres of homozygous weaver mutants (wv/wv) that had received unilater al grafts of mesencephalic cell suspensions to the right side. Net [H- 3]DA uptake, expressed as pmol/mg-protein/2-min, was on the average 50 .6 in the striatum of wild-type mice, 7.9 in the non-grafted, and 10.1 in the transplanted striatum of weaver mutants. [H-3]DA uptake in wil d-type mice differed significantly from both the grafted and non-graft ed weaver striata (P<0.001). Paired comparisons for [H-3]DA uptake bet ween right and left sides of recipient weaver mice showed a significan t side effect (P<0.02), the right side being 28-38% higher than the le ft side [mean of all individual (R-L)/L values]. The results of amphet amine-induced turning behavior tests were compared with the biochemica l findings; Mice with grafts to the right side rotated an average of 2 2 turns to the left and 7 turns to the right during the five one-minut e sessions; the mean value L/(L+R) was 64%. A plot of (L-R) rotations against (R-L) [H-3]DA uptake gave a correlation coefficient of 0.552 ( P<0.05), indicating that animals with a strong rotational bias to the left tended to have higher [H-3]DA on the right. Similarly, the animal s that were used for [H-3]mazindol binding autoradiographic studies di splayed on the average 72% rotations to the left side. In the [H-3]maz indol binding data, non-grafted weaver mutants showed the severest dep letion relative to wild-type in the dorsomedial and dorsolateral cauda te-putamen (86% and 87%, respectively). Mice with unilateral grafts to the right side showed an increase in [H-3]mazindol binding signal in the transplanted side of 40-64% (depending on dorsoventral topography) over the contralateral, non-grafted side. These findings attest to th e functional effects of the grafts at the anatomical, biochemical, and behavioral levels. The parallel measurements of motor performance and DA uptake in the same animals offers an index of behavioral recovery as a function of transmitter-related activity. Furthermore, by conduct ing measurements of the synaptosomal DA uptake in vitro and of the bin ding characteristics of mazindol in brain slices by autoradiography, o ne has the advantage of combining the anatomical resolution of uptake site visualization with a dynamic indicator of function for DA uptake in the nerve terminal.