Dopamine And Dystonia

Investigators have reported data supporting the hypothesis that abnormalities in dopamine transmission play a role in the pathophysiology of DYT1 dystonia. The mRNA for torsinA is strongly expressed in dopamine neurons in normal adult human brain (24, 25). TorsinA immunoreactivity is found within axons and presynaptic terminals in adult human and nonhuman primate striatum (26). Morphologically, some of the torsinA immunoreactive terminals resemble dopamine terminals, and within the terminals torsinA immunoreactivity is found in association with vesicles (26) (26). Additional studies analyzed dopamine, its metabolites, dopamine transporters, and dopamine receptors in four postmortem DYT1 brains (27). During life, three of the individuals had carried a clinical diagnosis of dystonia and one had carried a clinical diagnosis of Parkinsonism. The tissue content of dopamine and its metabolites 3,4-dihydrox-yphenylacetic acid (DOPAC) and homovanillic acid (HVA) were measured by HPLC from these cases as well as a group of controls (n = 6) matched for age and postmortem interval. In the DYT1 brains, striatal dopamine was low and DOPAC was elevated, which resulted in a significant increase in the DOPAC/dopamine ratio. The densities of the presynaptic high affinity dopamine transporter (DAT: [H3]-mazindol), the vesicular transporter (VMAT2: [H3]-dihydrotetrabenazine), and both the postsynaptic dopamine D1 ([H3]-SCH23390) and D2 receptor ([H3]-YM-09151-2) sites were measured by quantitative autoradiography. No significant differences were found in the density of DAT or VMAT2 binding; however, there was a trend towards a reduction in D1 receptor (-15%) and D2 receptor (-40%) binding. Collectively, these data are consistent with an intact nigrostriatal pathway in those with an abnormal neurological phenotype and carrying the DYT1 mutation, yet the data suggest an increase in striatal dopamine turnover coupled with a reduction in postsynaptic dopamine D1 and D2 receptor binding. A weakness of this study is the small number of cases, which reflects the very limited number of DYT1 cases currently available from brain banks and other sources. In addition, data on neurotransmitter levels from postmortem human DYT1 are limited in their ability to shed light on the pathogenesis of DYT1 dystonia in a living organism.

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