raclopride and Dystonic-Disorders

Writer's cramp is a task-specific focal hand dystonia characterized by involuntary excessive muscle contractions during writing. Although abnormal striatal dopamine receptor binding has been implicated in the pathophysiology of writer's cramp and other primary dystonias, endogenous dopamine release during task performance has not been previously investigated in writer's cramp. Using positron emission tomography imaging with the D2/D3 antagonist 11C-raclopride, we analysed striatal D2/D3 availability at rest and endogenous dopamine release during sequential finger tapping and speech production tasks in 15 patients with writer's cramp and 15 matched healthy control subjects. Compared with control subjects, patients had reduced 11C-raclopride binding to D2/D3 receptors at rest in the bilateral striatum, consistent with findings in previous studies. During the tapping task, patients had decreased dopamine release in the left striatum as assessed by reduced change in 11C-raclopride binding compared with control subjects. One cluster of reduced dopamine release in the left putamen during tapping overlapped with a region of reduced 11C-raclopride binding to D2/D3 receptors at rest. During the sentence production task, patients showed increased dopamine release in the left striatum. No overlap between altered dopamine release during speech production and reduced 11C-raclopride binding to D2/D3 receptors at rest was seen. Striatal regions where D2/D3 availability at rest positively correlated with disease duration were lateral and non-overlapping with striatal regions showing reduced D2/D3 receptor availability, except for a cluster in the left nucleus accumbens, which showed a negative correlation with disease duration and overlapped with striatal regions showing reduced D2/D3 availability. Our findings suggest that patients with writer's cramp may have divergent responses in striatal dopamine release during an asymptomatic motor task involving the dystonic hand and an unrelated asymptomatic task, sentence production. Our voxel-based results also suggest that writer's cramp may be associated with reduced striatal dopamine release occuring in the setting of reduced D2/D3 receptor availability and raise the possibility that basal ganglia circuits associated with premotor cortices and those associated with primary motor cortex are differentially affected in primary focal dystonias.

Topics: Adult; Aged; Brain Mapping; Case-Control Studies; Corpus Striatum; Dopamine; Dopamine Antagonists; Dystonic Disorders; Female; Functional Laterality; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Positron-Emission Tomography; Psychomotor Performance; Raclopride; Rest; Statistics as Topic

Functional neuroimaging, such as positron emission tomography (PET) and functional magnetic resonance imaging (fMRI), provides a valuable technique for detecting regional changes in brain metabolic activity associated with human disease. These techniques have been applied in different dystonic disorders including primary generalized dystonia and dopa-responsive dystonia (DRD), as well as focal dystonic syndromes such as torticollis, writer's cramp, and blepharospasm. A common finding is abnormality of the basal ganglia and associated outflow pathways to sensorimotor cortex and other regions involved with motor performance. Other recent imaging research has utilized diffusion-based MRI techniques to localize distinct microstructural abnormalities in dystonia patients and gene carriers. This presentation will focus on an integrated approach to understanding the pathophysiology of this genetic and biochemically diverse disorder.

Topics: Anisotropy; Basal Ganglia; Blepharospasm; Carbon Radioisotopes; Case-Control Studies; Dihydroxyphenylalanine; Dopamine Antagonists; Dystonia; Dystonic Disorders; Globus Pallidus; Heterozygote; Humans; Magnetic Resonance Imaging; Molecular Chaperones; Motor Cortex; Positron-Emission Tomography; Prospective Studies; Putamen; Raclopride; Receptors, Dopamine; Torticollis

Dopa-responsive dystonia (DRD) is a lifelong disorder in which dopamine deficiency is not associated with neuronal loss and therefore it is an ideal human model for investigating the compensatory changes that occur in response to this biochemical abnormality. Using positron emission tomography (PET), we examined the (+/-)-alpha-[(11)C]dihydrotetrabenazine ([(11)C]DTBZ) binding potential of untreated DRD patients and normal controls. Two other PET markers of presynaptic nigrostriatal function, d-threo-[(11)C]methylphenidate ([(11)C]MP) and 6-[(18)F]fluoro-L-dopa ([(18)F]-dopa), and [(11)C]raclopride were also used in the study. We found increased [(11)C]DTBZ binding potential in the striatum of DRD patients. By contrast, no significant changes were detected in either [(11)C]MP binding potential or [(18)F]-dopa uptake rate constant. In addition, we found evidence for increased dopamine turnover in one DRD patient by examining changes in [(11)C]raclopride binding potential in relation to levodopa treatment. We propose that the increase in [(11)C]DTBZ binding likely reflects the dramatic decrease in the intravesicular concentration of dopamine that occurs in DRD; upregulation of vesicular monoamine transporter type 2 (VMAT2) expression may also contribute. Our findings suggest that the striatal expression of VMAT2 (as estimated by [(11)C]DTBZ binding) is not coregulated with dopamine synthesis. This is in keeping with a role for VMAT2 in other cellular processes (i.e., sequestration and release from the cell of potential toxic products), in addition to its importance for the quantal release of monoamines.

Topics: Adolescent; Adult; Carbon Radioisotopes; Corpus Striatum; Cytoplasmic Vesicles; Dopamine; Dopamine Agents; Dystonic Disorders; Female; Fluorine Radioisotopes; Humans; Levodopa; Male; Membrane Glycoproteins; Membrane Transport Proteins; Methylphenidate; Middle Aged; Neuropeptides; Parkinson Disease; Raclopride; Tetrabenazine; Tomography, Emission-Computed; Vesicular Biogenic Amine Transport Proteins; Vesicular Monoamine Transport Proteins