In Vivo Measurement of the Vesicular Monoamine Transporter in Schizophrenia

We have identified four neurons (VC4, VC5, HSNL, HSNR) in Caenorhabditis elegans adult hermaphrodites that express both the vesicular acetylcholine transporter and the vesicular monoamine transporter. All four of these cells are motor neurons that innervate the egg-laying muscles of the vulva. In addition, they all express choline acetyltransferase, the synthetic enzyme for acetylcholine. The distributions of the vesicular acetylcholine transporter and the vesicular monoamine transporter are not identical within the individual cells. In mutants deficient for either of these transporters, there is no apparent compensatory change in the expression of the remaining transporter. This is the first report of neurons that express two different vesicular neurotransmitter transporters in vivo.

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Increased vesicular monoamine transporter enhances dopamine release and opposes Parkinson disease-related neurodegeneration in vivo

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1402134111 ◽

2014 ◽

Vol 111 (27) ◽

pp. 9977-9982 ◽

Cited By ~ 100

Author(s):

Kelly M. Lohr ◽

Alison I. Bernstein ◽

Kristen A. Stout ◽

Amy R. Dunn ◽

Carlos R. Lazo ◽

...

Keyword(s):

Parkinson Disease ◽

Dopamine Release ◽

Vesicular Monoamine Transporter ◽

Monoamine Transporter

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Assessment of Extrastriatal Vesicular Monoamine Transporter Binding Site Density Using Stereoisomers of [11C]Dihydrotetrabenazine

Journal of Cerebral Blood Flow & Metabolism ◽

10.1097/00004647-199912000-00011 ◽

1999 ◽

Vol 19 (12) ◽

pp. 1376-1384 ◽

Cited By ~ 51

Author(s):

Robert A. Koeppe ◽

Kirk A. Frey ◽

David E. Kuhl ◽

Michael R. Kilbourn

Keyword(s):

Binding Site ◽

Specific Binding ◽

Three Dimensional ◽

Precise Determination ◽

Tracer Uptake ◽

Vesicular Monoamine Transporter ◽

Reference Region ◽

Monoamine Transporter

Previous studies have demonstrated the utility of [nC]dihydrotetrabenazine ([11C]DTBZ) as a ligand for in vivo imaging of the vesicular monoamine transporter system. The (+)-isomer has a high affinity (approximately 1 nmol/L) for the vesicular monoamine transporter (VMAT2) binding site, whereas the (–)-isomer has an extremely low affinity (approximately 2 μmol/L). Efforts to model dynamic (+)-[11C]DTBZ data demonstrate the difficulty in separating the specific binding component from the free plus nonspecific component of the total positron emission tomography (PET) measure. The authors' previous*** PET work, as well as in vitro studies, indicate that there is little specific VMAT2 binding in neocortical regions. However, precise determination of in vivo binding levels have not been made, leaving important questions unanswered. At one extreme, is there sufficient specific binding in cortex or other extrastriate regions to be estimated reliably with PET? At the other extreme, is there sufficiently little binding in cortex so that it can be used as a reference region representing nonsaturable tracer uptake? The authors address these questions using paired studies with both active (+) and inactive (–) stereoisomers of [11C]DTBZ. Six normal control subjects were scanned twice, 2 hours apart, after injections of 16 mCi of (+)- and (–)-[11C]DTBZ (order counter-balanced). Three-dimensional PET acquisition consisted of 15 frames over 60 minutes for each scan. Arterial samples were acquired throughout, plasma counted, and corrected for radiolabeled metabolites. Analysis of specific binding was assessed by comparison of total distribution volume measures from the (+)- and (–)-[11C]DTBZ scans. The authors' findings indicate that only approximately 5% of the cortical signal in (+)-[11C]DTBZ scans results from binding to VMAT2 sites. The strongest extrastriatal signal comes from the midbrain regions where approximately 30% of the PET measure results from specific binding. The authors conclude that (1) the density of VMAT2 binding sites in cortical regions is not high enough to be quantified reliably with DTBZ PET, and (2) binding does appear to be low enough so that cortex can be used as a free plus nonspecific reference region for striatum.

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Role of vesicular monoamine transporter type 2 in rodent insulin secretion and glucose metabolism revealed by its specific antagonist tetrabenazine

Journal of Endocrinology ◽

10.1677/joe-07-0632 ◽

2008 ◽

Vol 198 (1) ◽

pp. 41-49 ◽

Cited By ~ 27

Author(s):

Anthony Raffo ◽

Kolbe Hancock ◽

Teresa Polito ◽

Yuli Xie ◽

Gordon Andan ◽

...

Keyword(s):

Insulin Secretion ◽

Glucose Metabolism ◽

Glucose Homeostasis ◽

Vesicular Monoamine Transporter ◽

Β Cells ◽

Monoamine Transporter ◽

Specific Antagonist

AbstractDespite different embryological origins, islet β-cells and neurons share the expression of many genes and display multiple functional similarities. One shared gene product, vesicular monoamine transporter type 2 (VMAT2, also known as SLC18A2), is highly expressed in human β-cells relative to other cells in the endocrine and exocrine pancreas. Recent reports suggest that the monoamine dopamine is an important paracrine and/or autocrine regulator of insulin release by β-cells. Given the important role of VMAT2 in the economy of monoamines such as dopamine, we investigated the possible role of VMAT2 in insulin secretion and glucose metabolism. Using a VMAT2-specific antagonist, tetrabenazine (TBZ), we studied glucose homeostasis, insulin secretion both in vivo and ex vivo in cultures of purified rodent islets. During intraperitoneal glucose tolerance tests, control rats showed increased serum insulin concentrations and smaller glucose excursions relative to controls after a single intravenous dose of TBZ. One hour following TBZ administration we observed a significant depletion of total pancreas dopamine. Correspondingly, exogenous l-3,4-dihydroxyphenylalanine reversed the effects of TBZ on glucose clearance in vivo. In in vitro studies of rat islets, a significantly enhanced glucose-dependent insulin secretion was observed in the presence of dihydrotetrabenazine, the active metabolite of TBZ. Together, these data suggest that VMAT2 regulates in vivo glucose homeostasis and insulin production, most likely via its role in vesicular transport and storage of monoamines in β-cells.

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