Tetrabenazine inhibition of monoamine uptake and methamphetamine behavioral effects: Locomotor activity, drug discrimination and self-administration

Meyer, Andrew; Horton, David B.; Neugebauer, Nicole; Wooters, Thomas E.; Nickell, Justin R.; Dwoskin, Linda P.; Bardo, Michael T.

doi:10.1016/j.neuropharm.2011.05.033

Cited by 26 publications

(17 citation statements)

References 34 publications

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“…This is consistent with uptake experiments performed in synaptosomes (Meyer et al, 2011). However, the authors concluded that the ability of TBZ to inhibit uptake in synaptosomes is due to action at DAT.…”

Section: Discussionsupporting

confidence: 92%

A fluorescent-based assay for live cell, spatially resolved assessment of vesicular monoamine transporter 2-mediated neurotransmitter transport

Bernstein

Stout

Miller

2012

Journal of Neuroscience Methods

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The vesicular monoamine transporter 2 (VMAT2; Slc18a2) packages monoamines into synaptic vesicles. Monoamine homeostasis is highly regulated and dysfunction may play a role in Parkinson’s disease, Huntington’s disease, drug addiction, and neuropsychiatric disorders. The primary function of VMAT2 is to sequester monoamine neurotransmitters into vesicles for subsequent release; it also sequesters toxicants away from cytosolic sites of action. Identification of compounds that modify the action of VMAT2 may be useful as therapeutic agents for preventing or reversing monoamine-related toxicity. Current methods for measuring VMAT2 function are unable to assess uptake in intact cells. Here, we adapted the Neurotransmitter Uptake Assay (Molecular Devices) to develop a measure of VMAT2 function in live whole cells. This assay contains a fluorescent compound, which is transported into cells by the plasma membrane monoamine transporters and has been marketed as a rapid, high-throughput, plate reader based assay for function of these plasma membrane transporters. We demonstrate a modified version of this assay that can be used to visualize and measure transport into vesicles by VMAT2. HEK293 cell lines stably expressing the dopamine transporter and a mCherry-VMAT2 fusion protein were generated. Confocal microscopy confirmed that the fluorescent compound is transported into mCherry-positive compartments. Furthermore, the VMAT2-specific inhibitor tetrabenazine (TBZ) blocks uptake into the mCherry-positive compartment. Confocal images can be analyzed to generate a measure of VMAT2 activity. In summary, we demonstrate a method for spatially resolved analysis of VMAT2-mediated uptake in live intact cells.

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Section: Discussionsupporting

confidence: 92%

A fluorescent-based assay for live cell, spatially resolved assessment of vesicular monoamine transporter 2-mediated neurotransmitter transport

Bernstein

Stout

Miller

2012

Journal of Neuroscience Methods

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“…Considerable attention has been given to positive rewarding effects associated with MA addiction (Beckmann et al, 2010;Horton et al, 2011;Kamens et al, 2005;Mahler et al, 2013;Meyer et al, 2011;Mizoguchi et al, 2004;Shabani et al, 2011Shabani et al, , 2012aWheeler et al, 2009), whereas aversive effects that could limit intake have been given less consideration (Harrod et al, 2010;Pringle et al, 2008;Shabani et al, 2011Shabani et al, , 2012bWheeler et al, 2009). Greater Figure 3 (a) Methamphetamine (MA) consumption differs by Taar1 genotype.…”

Section: Discussionmentioning

confidence: 99%

Trace Amine-Associated Receptor 1 Regulation of Methamphetamine Intake and Related Traits

Harkness

Shi

Janowsky

et al. 2015

Neuropsychopharmacol

149

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Continued methamphetamine (MA) use is dependent on a positive MA experience and is likely attenuated by sensitivity to the aversive effects of MA. Bidirectional selective breeding of mice for high (MAHDR) or low (MALDR) voluntary consumption of MA demonstrates a genetic influence on MA intake. Quantitative trait locus (QTL) mapping identified a QTL on mouse chromosome 10 that accounts for greater than 50% of the genetically-determined differences in MA intake in the MAHDR and MALDR lines. The trace amine-associated receptor 1 gene (Taar1) is within the confidence interval of the QTL and encodes a receptor (TAAR1) that modulates monoamine neurotransmission and at which MA serves as an agonist. We demonstrate the existence of a non-functional allele of Taar1 in the DBA/2J mouse strain, one of the founder strains of the selected lines, and show that this non-functional allele co-segregates with high MA drinking and with reduced sensitivity to MA-induced conditioned taste aversion (CTA) and hypothermia. The functional Taar1 allele, derived from the other founder strain, C57BL/6J, segregates with low MA drinking and heightened sensitivity to MA-induced CTA and hypothermia. A role for TAAR1 in these phenotypes is corroborated in Taar1 transgenic mice: Taar1 knockout mice consume more MA and exhibit insensitivity to MA-induced CTA and hypothermia, compared with Taar1 wild-type mice. These are the first data to show that voluntary MA consumption is, in part, regulated by TAAR1 function. Behavioral and physiological studies indicate that TAAR1 function increases sensitivity to aversive effects of MA, and may thereby protect against MA use.

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“…Also, acute administration of GZ-793A had no effect on locomotor activity when administered alone or in conjunction with METH. This finding was surprising given that VMAT2 inhibitors lobelineand tetrabenazine are able to inhibit amphetamine- and methamphetamine-induced hyperactivity (Miller et al 2001; Meyer et al 2011). Also, GZ-793A reduces striatal extracellular DA release (Horton et al 2011) which is assumed to underlie the psychomotor activating effects of psychostimulants (Wise and Bozarth 1987).…”

Section: Discussionmentioning

confidence: 99%

The effect of VMAT2 inhibitor GZ-793A on the reinstatement of methamphetamine-seeking in rats

et al. 2012

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Rationale The vesicular monoamine transporter 2 (VMAT2) has been identified as a potential target for the treatment of methamphetamine (METH) abuse. GZ-793A is a potent and selective VMAT2 inhibitor that has been shown to block the primary and conditioned rewarding effects of METH, while demonstrating no abuse liability when given alone. Objectives The aim of the current study was to determine if GZ-793A attenuates METH- or cue-induced reinstatement of METH-seeking after a period of extinction. The effect of acute GZ-793A on locomotor activity also was assessed. Methods After a period of extinction, rats were administered GZ-793A (15 mg/kg, s.c.) 15 min prior to a priming injection of METH or re-exposure to cues associated with METH infusions. GZ-793A also was administered 20 min prior to an injection of METH (0.5 mg/kg, s.c.) or saline to determine its effect on locomotor behavior. Results Pretreatment with GZ-793A (15 mg/kg) decreased cue-induced reinstatement, without demonstrating any response suppressive effects when administered in the absence of reinstating stimuli. GZ-793A also decreased methamphetamine-induced reinstatement; however, response suppressant effects of GZ-793A were obtained when the compound was presented alone. In this latter experiment, GZ-793A may have reduced responding for the conditioned reinforcing effects of the contingently available cues rather than having non-specific effects on baseline responding. GZ-793A had no effect on locomotor activity when administered alone or with METH. Conclusions GZ-793A and related VMAT2 inhibitors may be promising leads for reducing the risk of relapse to METH use following exposure to drug-associated cues.

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Tetrabenazine inhibition of monoamine uptake and methamphetamine behavioral effects: Locomotor activity, drug discrimination and self-administration

Cited by 26 publications

References 34 publications

A fluorescent-based assay for live cell, spatially resolved assessment of vesicular monoamine transporter 2-mediated neurotransmitter transport

A fluorescent-based assay for live cell, spatially resolved assessment of vesicular monoamine transporter 2-mediated neurotransmitter transport

Trace Amine-Associated Receptor 1 Regulation of Methamphetamine Intake and Related Traits

The effect of VMAT2 inhibitor GZ-793A on the reinstatement of methamphetamine-seeking in rats

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