VMAT2 binding is elevated in dopa‐responsive dystonia: Visualizing empty vesicles by PET

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 (±)‐α‐[11C]dihydrotetrabenazine ([11C]DTBZ) binding potential of untreated DRD patients and normal controls. Two other PET markers of presynaptic nigrostriatal function, d‐threo‐[11C]methylphenidate ([11C]MP) and 6‐[18F]fluoro‐L‐dopa ([18F]‐dopa), and [11C]raclopride were also used in the study. We found increased [11C]DTBZ binding potential in the striatum of DRD patients. By contrast, no significant changes were detected in either [11C]MP binding potential or [18F]‐dopa uptake rate constant. In addition, we found evidence for increased dopamine turnover in one DRD patient by examining changes in [11C]raclopride binding potential in relation to levodopa treatment. We propose that the increase in [11C]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 [11C]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. Synapse 49:20–28, 2003. © 2003 Wiley‐Liss, Inc.

[1]  V. Sossi,et al.  In vivo positron emission tomographic evidence for compensatory changes in presynaptic dopaminergic nerve terminals in Parkinson's disease , 2000, Annals of neurology.

[2]  B. K. Krueger,et al.  Kinetics and Block of Dopamine Uptake in Synaptosomes from Rat Caudate Nucleus , 1990, Journal of neurochemistry.

[3]  J. Haycock,et al.  Striatal 3,4‐dihydroxyphenylalanine decarboxylase in aging: Disparity between postmortem and positron emission tomography studies? , 1995, Annals of neurology.

[4]  M Schulzer,et al.  Biochemical variations in the synaptic level of dopamine precede motor fluctuations in Parkinson's disease: PET evidence of increased dopamine turnover. , 2001, Annals of neurology.

[5]  R. Kessler,et al.  Analysis of emission tomographic scan data: limitations imposed by resolution and background. , 1984, Journal of computer assisted tomography.

[6]  K. Frey,et al.  The vesicular monoamine transporter is not regulated by dopaminergic drug treatments. , 1995, European journal of pharmacology.

[7]  D. Scherman,et al.  Characterization of the vesicular monoamine transporter in cultured rat sympathetic neurons: persistence upon induction of cholinergic phenotypic traits. , 1987, Developmental biology.

[8]  N. Neff,et al.  Aromatic L-amino acid decarboxylase modulation and Parkinson's disease. , 1995, Progress in brain research.

[9]  Douglas G. Altman,et al.  Practical statistics for medical research , 1990 .

[10]  R. Weizman,et al.  Modulatory effect of agents active in the presynaptic dopaminergic system on the striatal dopamine transporter. , 1996, European journal of pharmacology.

[11]  D. Scherman,et al.  Radioligands of the vesicular monoamine transporter and their use as markers of monoamine storage vesicles. , 1989, Biochemical pharmacology.

[12]  C. Patlak,et al.  Graphical Evaluation of Blood-to-Brain Transfer Constants from Multiple-Time Uptake Data. Generalizations , 1985, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[13]  Svante B. Ross,et al.  Synaptic Concentration of Dopamine in the Mouse Striatum in Relationship to the Kinetic Properties of the Dopamine Receptors and Uptake Mechanism , 1991, Journal of neurochemistry.

[14]  D. Calne,et al.  The long-term response to levodopa in dopa-responsive dystonia. , 2001, Parkinsonism & related disorders.

[15]  V. P. Whittaker,et al.  The Synaptic Vesicle , 1984 .

[16]  A. Levey,et al.  Differential changes in neurochemical markers of striatal dopamine nerve terminals in idiopathic Parkinson's disease , 1996, Neurology.

[17]  J S Fowler,et al.  Cocaine abusers do not show loss of dopamine transporters with age. , 1997, Life sciences.

[18]  J. Nutt,et al.  Response to levodopa treatment in dopa-responsive dystonia. , 2001, Archives of neurology.

[19]  J S Fowler,et al.  Binding of d-threo-[11C]methylphenidate to the dopamine transporter in vivo: insensitivity to synaptic dopamine. , 1995, European Journal of Pharmacology.

[20]  Vesna Sossi,et al.  Biochemical variations in the synaptic level of dopamine precede motor fluctuations in Parkinson's disease: PET evidence of increased dopamine turnover , 2001 .

[21]  A. Kishore,et al.  Striatal D2 receptors in symptomatic and asymptomatic carriers of dopa-responsive dystonia measured with [11C]-raclopride and positron-emission tomography , 1998, Neurology.

[22]  J. Jeong,et al.  Dopamine transporter density measured by [123I]β‐CIT single‐photon emission computed tomography is normal in dopa‐responsive dystonia , 1998 .

[23]  S. Gilman,et al.  Presynaptic monoaminergic vesicles in Parkinson's disease and normal aging , 1996, Annals of neurology.

[24]  S. Tsuji,et al.  Hereditary progressive dystonia with marked diurnal fluctuation caused by mutations in the GTP cyclohydrolase I gene , 1994, Nature Genetics.

[25]  R. Reimer,et al.  Vesicular neurotransmitter transport and the presynaptic regulation of quantal size , 1998, Current Opinion in Neurobiology.

[26]  D. Scherman,et al.  Regulation of the Chromaffin Granule Catecholamine Transporter in Cultured Bovine Adrenal Medullary Cells: Stimulus–Biosynthesis Coupling , 1992, Journal of neurochemistry.

[27]  W. Gibb,et al.  Dopa‐responsive dystonia: Pathological and biochemical observations in a case , 1994, Annals of neurology.

[28]  M Linial,et al.  Vesicular neurotransmitter transporters: from bacteria to humans. , 1995, Physiological reviews.

[29]  Irwin J. Kopin,et al.  The Biochemical Basis of Neuropharmacology , 1971, The Yale Journal of Biology and Medicine.

[30]  D. Scherman,et al.  Time required for transmitter accumulation inside monoaminergic storage vesicles differs in peripheral and in central systems , 1988, Neuroscience.

[31]  A. Malhotra,et al.  Schizophrenia is associated with elevated amphetamine-induced synaptic dopamine concentrations: evidence from a novel positron emission tomography method. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[32]  J. Hubble,et al.  Aromatic L‐Amino Acid Decarboxylase Activity of Mouse Striatum Is Modulated via Dopamine Receptors , 1993, Journal of neurochemistry.

[33]  P. Emson,et al.  Neuronal stem cells express vesicular monoamine transporter 2 immunoreactivity in the adult rat , 1996, Neuroscience.

[34]  Hirohide Takahashi,et al.  Positron emission tomographic studies of dopa‐responsive dystonia and early‐onset idiopathic parkinsonism , 1993, Annals of neurology.

[35]  A. Lang,et al.  Dopa‐responsive dystonia due to a large deletion in the GTP cyclohydrolase I gene , 2000, Annals of neurology.

[36]  S. Kish,et al.  The Vesicular Monoamine Transporter, in Contrast to the Dopamine Transporter, Is Not Altered by Chronic Cocaine Self-Administration in the Rat , 1996, The Journal of Neuroscience.

[37]  S. Schuldiner A Molecular Glimpse of Vesicular Monoamine Transporters , 1994, Journal of neurochemistry.

[38]  J. Henry,et al.  Expression and regulation of the bovine vesicular monoamine transporter gene , 1993, FEBS letters.

[39]  S J Kish,et al.  Striatal biopterin and tyrosine hydroxylase protein reduction in dopa-responsive dystonia , 1999, Neurology.

[40]  A. Horn Dopamine uptake: A review of progress in the last decade , 1990, Progress in Neurobiology.

[41]  R. Edwards,et al.  The role of vesicular transport proteins in synaptic transmission and neural degeneration. , 1997, Annual review of neuroscience.

[42]  R. Fremeau,et al.  Uptake of glutamate into synaptic vesicles by an inorganic phosphate transporter. , 2000, Science.

[43]  V. Sossi,et al.  Apomorphine-Induced Changes in Synaptic Dopamine Levels: Positron Emission Tomography Evidence for Presynaptic Inhibition , 2001, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[44]  N. Volkow,et al.  Distribution Volume Ratios without Blood Sampling from Graphical Analysis of PET Data , 1996, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[45]  J. Haycock,et al.  Synaptic Vesicle Transporter Expression Regulates Vesicle Phenotype and Quantal Size , 2000, The Journal of Neuroscience.