Differential regulation of tyrosine hydroxylase in the basal ganglia of mice lacking the dopamine transporter

Mice lacking the dopamine transporter (DAT) display biochemical and behavio ural dopaminergic hyperactivity despite dramatic alteration in dopamine hom eostasis. In order to determine the anatomical and functional integrity of the dopaminergic system, we examined the expression of tyrosine hydroxylase (TH), the rate-limiting enzyme of dopamine synthesis as well as DOPA decar boxylase and vesicular monoamine transporter. TH-positive neurons in the su bstantia nigra were only slightly decreased (-27.6+/-4.5%), which can not a ccount for the dramatic decreases in the levels of TH and dopamine that we previously observed in the striatum. TH mRNA levels were decreased by 25% i n the ventral midbrain with no modification in the ratio of TH mRNA levels per cell. However, TH protein levels were decreased by 90% in the striatum and 35% in the ventral midbrain. In the striatum, many dopaminergic project ions had no detectable TH, while few projections maintained regular labelli ng as demonstrated using electron microscopy. DOPA decarboxylase levels wer e not modified an vesicular transporter levels were decreased by only 28.7% which suggests that the loss of TH labelling in the striatum is not due to loss of TH projections. Interestingly, we also observed sporadic TH-positi ve cell bodies using immunohistochemistry and in situ hybridization in the striatum of homozygote mice, and to some extent that of wild-type animals, which raises interesting possibilities as to their potential contribution t o the dopamine hyperactivity and volume transmission previously reported in these animal. In conjunction with out previous findings, these results hig hlight the complex regulatory mechanisms controlling TH expression at the l evel of mRNA, protein, activity and distribution. The paradoxical hyperdopa minergia in the DAT KO mice despite a marked decrease in TH and dopamine le vels suggests a parallel to Parkinson's disease implying that blockade of D AT may be beneficial in this condition.