Early onset torsion dystonia, the most common form of hereditary
primary dystonia, is caused by a mutation in the TOR1A gene, which codes for the
protein torsinA. This form of
dystonia is referred to as
DYT1. We have used a transgenic mouse model of
DYT1 dystonia [human mutant-type (hMT)1 mice] to examine the effect of the mutant human torsinA
protein on striatal dopaminergic function. Analysis of striatal tissue
dopamine (DA) and metabolites using HPLC revealed no difference between hMT1 mice and their non-transgenic littermates. Pre-synaptic DA transporters were studied using in vitro autoradiography with [(3)H]
mazindol, a
ligand for the membrane DA transporter, and [(3)H]
dihydrotetrabenazine, a
ligand for the
vesicular monoamine transporter. No difference in the density of striatal DA transporter or
vesicular monoamine transporter binding sites was observed. Post-
synaptic receptors were studied using [(3)H]
SCH-23390, a
ligand for D(1) class receptors, [(3)H]
YM-09151-2 and a
ligand for D(2) class receptors. There were again no differences in the density of striatal binding sites for these
ligands. Using in vivo microdialysis in awake animals, we studied basal as well as
amphetamine-stimulated striatal extracellular DA levels. Basal extracellular DA levels were similar, but the response to
amphetamine was markedly attenuated in the hMT1 mice compared with their non-transgenic littermates (253 +/- 71% vs. 561 +/- 132%, p < 0.05, two-way anova). These observations suggest that the mutation in the torsinA
protein responsible for
DYT1 dystonia may interfere with transport or release of DA, but does not alter pre-synaptic transporters or post-synaptic DA receptors. The defect in DA release as observed may contribute to the abnormalities in motor learning as previously documented in this transgenic mouse model, and may contribute to the clinical symptoms of the human disorder.