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 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 postsynaptic 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.

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SummaryMethylphenidate is a frequently prescribed stimulant for the treatment of attention deficit hyperactivity disorder (ADHD). An important assumption in the animal models that have been employed to study methylphenidate's effects on the brain and behavior is that bioavailability of methylphenidate in the animal models reflects that in human subjects. From this perspective, the dose and route of administration of methylphenidate assume critical importance because both these factors likely influence rate of uptake, plasma and brain concentrations of the drug. In the present study, plasma and brain concentrations of D-and L-methylphenidate and D-and L-ritalinic acid were measured in 2-month old mice (equivalent to young adulthood in humans) following a single oral administration of a racemic mixture. Our data show that oral administration of 0.75 mg/kg dose produced within 15 min, plasma levels of D-methylphenidate that correspond to the clinically effective plasma levels in human subjects (estimated to be 6-10 ng/ml). Brain concentrations of Dand L-methylphenidate tended to exceed their plasma concentrations, while the plasma concentrations of D-and L-ritalinic acid exceeded their brain concentrations. A single oral administration at 0.75 mg/kg dose increased dopamine content of the frontal cortex within 1 hr, without producing statistically significant changes in serotonin or noradrenaline contents. Striatal monoamine levels remained unaltered. These data highlight disparities between plasma and brain concentrations of methylphenidate and its metabolites following oral administration and illustrate brain region-and monoamine-specific changes produced by the low oral dose of methylphenidate.