DISTRIBUTION OF DOPAMINE TRANSPORTERS IN BASAL GANGLIA OF CEREBELLAR ATAXIC MICE BY [I-125] RTI-121 QUANTITATIVE AUTORADIOGRAPHY

Dopamine (DA) uptake sites, or transporters, were examined with [I-125 ]RTI-121 in mutant mice that exhibit motor control deficits, namely we aver, lurcher and dystonia musculorum. In lurcher mice, the distributi on of [I-125]RTI-121 binding was similar to controls, except for a dec rease in the subthalamic nucleus. For dystonia musculorum mice, the la belling presented no differences between controls and mutants, except for decreases in the dorsal half of caudal neostriatum and in the vent ral tegmental area. Moreover, in this mutant the left rostral neostria tum DA transporters were reduced, when compared to the right counterpa rt. In weaver heterozygote (wv/+) mice, the distribution and density g radients of [I-125]RTI-121 labelling were similar as in their controls , except in caudal neostriatum, where binding was slightly higher. In contrast, the weaver homozygote (wv/wv) showed important decreases in labelling of the dorsal quadrant of rostral neostriatum as well as of the dorsal half of caudal neostriatum, where the reductions of binding densities were of 65% to 70%, respectively. There were also slight de creases in [I-125]RTI-121 binding in olfactory tubercles as well as in subthalamic nucleus, but only in wv/wv mice. In substantia nigra pars compacta and ventral tegmental area of wv/wv mice the labelling was l ower; however, while the 60% decrease in labelling in substantia nigra was highly significant, the 30% reduction in ventral tegmental area d id not attain statistical significance. In summary, in the ataxic neur ological mutant mice studied, important reductions of DA transporters were documented only for the weaver mice, the cerebellar mutant presen ting, besides its cerebellar pathology, a known degeneration of mesenc ephalic dopaminergic neurons. The results rule out major alterations o f the central DA systems in lurcher and dystonia musculorum, and are c ompatible with the hypothesis that the dopaminergic abnormalities of w eaver mutants are not secondary to cerebellar atrophy, but may be a di rect consequence of the abnormal weaver gene expressed by DA neurons l eading to their apoptotic death. (C) 1998 Elsevier Science Ltd. All ri ghts reserved.