Vesicular Monoamine Transporter Research Articles

MicroPET imaging of vesicular monoamine transporter 2 revealed the potentiation of (+)-dihydrotetrabenazine on MPTP-induced degeneration of dopaminergic neurons

IntroductionVesicular monoamine transporter 2 (VMAT2) has been associated with the risk of PD. Genetic reduction of VMAT2 level is reported to increase the vulnerability for dopaminergic neurodegeneration. In this study, by using in vivo microPET imaging with a VMAT2 radioligand [18F]fluoropropyl-(+)-dihydrotetrabenazine ([18F]FP-(+)-DTBZ), we investigated the enhanced role of inhibiting VMAT2 in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced loss of dopaminergic neurons. MethodsThe (+)-α-dihydrotetrabenazine ((+)-DTBZ, an inhibitor of VMAT2, 5 mg/kg), or MPTP (low dose (ld): 10 mg/kg, high dose (hd): 30 mg/kg) or both of them were intraperitoneally injected into C57BL/6 mice for 5 or 10 consecutive days. MicroPET imaging with [18F]FP-(+)-DTBZ was performed to test the dopaminergic neuronal integrity. [18F]FP-(+)-DTBZ uptake in striatum was quantified as standardized uptake value (SUV). The pathological changes in the striata and substantia nigra were confirmed by measuring the DA contents and immunohistochemical staining of tyrosine hydroxylase (TH). ResultsIn vivo imaging results showed that the striatal SUVs of both DTBZ&MPTPld and MPTPhd groups were substantially declined compared to the baseline. Moreover, the striatal uptakes of [18F]FP-(+)-DTBZ in DTBZ&MPTPld and MPTPhd groups were obviously lower than the control, DTBZ group and MPTPld group. Notably, the decrease of the striatal uptake in the DTBZ&MPTPld/10d group was more serious than the DTBZ&MPTPld/5d group and comparable to the MPTPhd group. Consistently, the ratios of DA metabolites to DA in DTBZ&MPTPld/10d and MPTPhd mice were significantly increased. The correlation analysis showed that SUVs were highly correlated to the striatal dopaminergic fiber density and TH-positive dopaminergic neuron number in the substantia nigra. ConclusionsMicroPET brain imaging with [18F]FP-(+)-DTBZ noninvasively revealed that (+)-DTBZ co-administration significantly aggravated the neurotoxicity of MPTP to dopaminergic neurons, suggesting that inhibition of VMAT2 may be related to the pathogenesis of PD and tracing VMAT2 activity with PET imaging is of potential value in monitoring PD progression.

Gastric enterochromaffin-like cell changes in multiple endocrine neoplasia type 1.

Gastric enterochromaffin-like cell (ECL) tumours can occur in patients with multiple endocrine neoplasia type 1 (MEN1), especially in those affected by Zollinger Ellison syndrome (ZES). Since the prevalence of ECL lesions is not well defined yet, the present study evaluated the presence and extent of ECL lesions in MEN1 patients with and without ZES. Multiple endocrine neoplasia type 1 patients being part of a regular screening program (2014-2018) underwent gastroduodenoscopies with biopsies of the stomach and determination of serum gastrin and chromogranin A levels. Haematoxylin- and immunostaining with chromogranin A, gastrin and VMAT I and II (vesicular monoamine transporter I and II) of the biopsies were performed. Thirty-eight MEN1 patients, of whom 16 (42%) were diagnosed and treated earlier for ZES, were analysed. In ten of 16 (62.5%) ZES patients, a locally scattered, mixed image of diffuse, linear and micronodular mild hyperplasia was present. In addition, two of these patients (13%) showed small (max 1.5mm in size) intramucosal ECL tumours. Neither ECL changes, nor tumours were found in MEN1 patients without ZES (n=22). In MEN1/ZES patients, the median serum gastrin level was significantly elevated compared to MEN1 patients without ZES (206pg/ml vs. 30.5pg/ml, p<.001). A subgroup analysis of the serum gastrin and chromogranin A levels of MEN1/ZES patients with or without ECL hyperplasia did not show significant differences (gastrin level: p=.302, chromogranin A: p=.464). Enterochromaffin-like cell hyperplasia and gastric carcinoids occur only in MEN1 patients with ZES, but less frequently than reported.

Targeting barrel field spiny stellate cells using a vesicular monoaminergic transporter 2-Cre mouse line

Rodent primary somatosensory cortex (S1) is organized in defined layers, where layer IV serves as the main target for thalamocortical projections. Serotoninergic signaling is important for the organization of thalamocortical projections and consequently proper barrel field development in rodents, and the vesicular monoamine transporter 2 (VMAT2) can be detected locally in layer IV S1 cortical neurons in mice as old as P10, but the identity of the Vmat2-expressing neurons is unknown. We here show that Vmat2 mRNA and also Vmat2-Cre recombinase are still expressed in adult mice in a sub-population of the S1 cortical neurons in the barrel field. The Vmat2-Cre cells showed a homogenous intrinsically bursting firing pattern determined by whole-cell patch-clamp, localized radial densely spinous basal dendritic trees and almost exclusively lack of apical dendrite, indicative of layer IV spiny stellate cells. Single cell mRNA sequencing analysis showed that S1 cortical Vmat2-Cre;tdTomato cells express the layer IV marker Rorb and mainly cluster with layer IV neurons, and RNAscope analysis revealed that adult Vmat2-Cre neurons express Vmat2 and vesicular glutamate transporter 1 (Vglut1) and Vglut2 mRNA to a high extent. In conclusion, our analysis shows that cortical Vmat2 expression is mainly confined to layer IV neurons with morphological, electrophysiological and transcriptional characteristics indicative of spiny stellate cells.

Genetic or Toxicant-Induced Disruption of Vesicular Monoamine Storage and Global Metabolic Profiling in Caenorhabditis elegans.

The proper storage and release of monoamines contributes to a wide range of neuronal activity. Here, we examine the effects of altered vesicular monoamine transport in the nematode Caenorhabditis elegans. The gene cat-1 is responsible for the encoding of the vesicular monoamine transporter (VMAT) in C. elegans and is analogous to the mammalian vesicular monoamine transporter 2 (VMAT2). Our laboratory has previously shown that reduced VMAT2 activity confers vulnerability on catecholamine neurons in mice. The purpose of this article was to determine whether this function is conserved and to determine the impact of reduced VMAT activity in C. elegans. Here we show that deletion of cat-1/VMAT increases sensitivity to the neurotoxicant 1-methyl-4-phenylpyridinium (MPP+) as measured by enhanced degeneration of dopamine neurons. Reduced cat-1/VMAT also induces changes in dopamine-mediated behaviors. High-resolution mass spectrometry-based metabolomics in the whole organism reveals changes in amino acid metabolism, including tyrosine metabolism in the cat-1/VMAT mutants. Treatment with MPP+ disrupted tryptophan metabolism. Both conditions altered glycerophospholipid metabolism, suggesting a convergent pathway of neuronal dysfunction. Our results demonstrate the evolutionarily conserved nature of monoamine function in C. elegans and further suggest that high-resolution mass spectrometry-based metabolomics can be used in this model to study environmental and genetic contributors to complex human disease.

Tyramine synthesis, vesicular packaging, and the SNARE complex function coordinately in astrocytes to regulate Drosophila alcohol sedation.

Identifying mechanisms underlying alcohol-related behaviors could provide important insights regarding the etiology of alcohol use disorder. To date, most genetic studies on alcohol-related behavior in model organisms have focused on neurons, leaving the causal roles of glial mechanisms less comprehensively investigated. Here, we report our studies on the role of Tyrosine decarboxylase 2 (Tdc2), which converts tyrosine to the catecholamine tyramine, in glial cells in Drosophila alcohol sedation. Using genetic approaches that drove transgene expression constitutively in all glia, constitutively in astrocytes and conditionally in glia during adulthood, we found that knockdown and overexpression of Tdc2, respectively, increased and decreased the sensitivity to alcohol sedation in flies. Manipulation of the genes tyramine β-hydroxylase and tyrosine hydroxylase, which respectively synthesize octopamine and dopamine from tyramine and tyrosine, had no discernable effect on alcohol sedation, suggesting that Tdc2 affects alcohol sedation by regulating tyramine production. We also found that knockdown of the vesicular monoamine transporter (VMAT) and disruption of the SNARE complex in all glia or selectively in astrocytes increased sensitivity to alcohol sedation and that both VMAT and the SNARE complex functioned downstream of Tdc2. Our studies support a model in which the synthesis of tyramine and vesicle-mediated release of tyramine from adult astrocytes regulates alcohol sedation in Drosophila. Considering that tyramine is functionally orthologous to norepinephrine in mammals, our results raise the possibility that gliotransmitter synthesis release could be a conserved mechanism influencing behavioral responses to alcohol as well as alcohol use disorder.

Vortioxetine attenuates the effects of early-life stress on depression-like behaviors and monoamine transporters in female mice

Major depressive disorder is a major psychiatric disorder and a leading cause of disability around the world. Females have about twice as high an incidence of depression as males. However, preclinical animal models of depression have seldom investigated the molecular alterations associated with higher depression risk in females. In this study, adopting the early-life stress (ELS) paradigm of limited bedding and nesting material, we found that ELS induced depression-like behaviors only in adult female mice, as evaluated by sucrose preference and tail suspension tests. We then examined the ELS effects on monoamine neurotransmission (transporters for monoamine reuptake and release) in depression-related brain regions in female mice. We found that ELS resulted in widespread changes of the expression levels of these transporters in four brain regions. Moreover, systemic 21-day treatment with vortioxetine, a novel multimodal antidepressant, successfully reversed depression-like behaviors and normalized some molecular changes, including that of the norepinephrine transporter in the medial prefrontal cortex, vesicular monoamine transporter 2 in nucleus accumbens core, and serotonin transporter in amygdala. Collectively, these results provide evidence for the validity of using the limited bedding and nesting material paradigm to investigate sex differences in depression and demonstrate that the region-specific alterations of monoamine neurotransmission may be associated with depression-like behaviors in female mice.This article is part of the special issue on ‘Stress, Addiction and Plasticity’.

Deletion of VGLUT2 in midbrain dopamine neurons attenuates dopamine and glutamate responses to methamphetamine in mice

Methamphetamine (METH) is a highly addictive psychostimulant. The continuous use of METH may lead to its abuse and neurotoxicity that have been associated with METH-induced increases in release of dopamine (DA) and glutamate in the brain. METH action in DA has been shown to be mediated by redistribution of DA from vesicles into cytoplasm via vesicular monoamine transporter 2 (VMAT2) and the subsequent reversal of membrane DA transporter (DAT), while little is known about the mechanisms underlying METH-induced glutamate release. Recent studies indicate that a subpopulation of midbrain DA neurons co-expresses VMAT2 and vesicular glutamate transporter 2 (VGLUT2). Therefore, we hypothesized that METH-induced glutamate release may in part originate from such a dual phenotype of DA neurons. To test this hypothesis, we used Cre-LoxP techniques to selectively delete VGLUT2 from midbrain DA neurons, and then examined nucleus accumbens (NAc) DA and glutamate responses to METH using in vivo brain microdialysis between DA-VGLUT2-KO mice and their VGLUT2-HET littermates. We found that selective deletion of VGLUT2 from DA neurons did not significantly alter basal levels of extracellular DA and glutamate, but attenuated METH-induced increases in extracellular levels of DA and glutamate. In addition, DA-VGLUT2-KO mice also displayed lower locomotor response to METH than VGLUT2-HET control mice. These findings, for the first time, suggest that cell-type specific VGLUT2 expression in DA neurons plays an important role in the behavioral and neurochemical effects of METH. Glutamate corelease from DA neurons may in part contributes to METH-induced increase in NAc glutamate release.

Identification of oxygen-sensitive neuroepithelial cells through an endogenous reporter gene in larval and adult transgenic zebrafish.

In teleost fish, specialized oxygen (O2) chemoreceptors, called neuroepithelial cells (NECs), are found in the gill epithelium in adults. During development, NECs are present in the skin before the formation of functional gills. NECs are known for retaining the monoamine neurotransmitter, serotonin (5-HT) and are conventionally identified through immunoreactivity with antibodies against 5-HT or synaptic vesicle protein (SV2). However, identification of NECs in live tissue and isolated cell preparations has been challenging due to the lack of a specific marker. The present study explored the use of the transgenic zebrafish, ETvmat2:GFP, which expresses green fluorescent protein (GFP) under the control of the vesicular monoamine transporter 2 (vmat2) regulatory element, to identify NECs. Using immunohistochemistry and confocal microscopy, we confirmed that the endogenous GFP in ETvmat2:GFP labelled serotonergic NECs in the skin of larvae and in the gills of adults. NECs of the gill filaments expressed a higher level of endogenous GFP compared with other cells. The endogenous GFP also labelled intrabranchial neurons of the gill filaments. Flow cytometric analysis demonstrated that filamental NECs could be distinguished from other dissociated gill cells based on high GFP expression alone. Acclimation to 2weeks of severe hypoxia (PO2=35mmHg) induced an increase in filamental NEC frequency, size and GFP gene expression. Here we present for the first time a transgenic tool that labels O2 chemoreceptors in an aquatic vertebrate and its use in high-throughput experimentation.

Mixed exposure to As, Mn, and Pb and dopamine neurotransmission in the striatum ‎

Mixed exposure to arsenic (As), manganese (Mn), and lead (Pb) occur frequently in the general population; however, there are few studies on the neurotoxic effects, including those on dopaminergic neurotransmission in the striatum. This study investigated tyrosine hydroxylase (TH), dopamine transporter (DAT), and vesicular monoamine transporter 2 (VMAT2) expression in the mouse striatum after exposure to As, Mn, and Pb. Mixed exposure to these metals through drinking water for 4 weeks resulted in

A Brief Review on the Role of Vesicular Monoamine Transporter2 Inhibitors in Hyperkinetic Movement Disorders.

Hyperkinetic movement disorders are a common group of movement abnormalities in children, characterized with repetitive unintended involuntary movements. Major hyperkinetic movements include tremor, tic, dystonia, myoclonus, and chorea. Although a number of drugs have been proven to be beneficial for these abnormalities, some patients may become resistant to conventional treatments. Vesicular monoamine transporter2 (VMAT2) inhibitors (Tetrabenazine, Deutetrabenazine, and Valbenazine) are new agents introduced in the last decade for treating some of movement disorders, in particular tardive dyskinesia, Huntington chorea, and Tourette syndrome. In this brief review, we discussed the role of these drugs in managing hyperkinetic movement disorders.

Tardive Dyskinesia: Spotlight on Current Approaches to Treatment

Tardive dyskinesia (TD) is a debilitating, iatrogenic, and potentially severe movement disorder characterized by involuntary, repetitive, purposeless movements that are present throughout the body. The authors present a review of studies of past, current, and possible future treatment approaches to the management of TD; consider the phenomenology, assessment, and putative pathophysiological mechanisms of TD, early pharmacological trials, a focus on the newer vesicular monoamine transporter 2 inhibitors, and other evidence-based approaches, such as clozapine; and present preliminary evidence for newer approaches, such as deep brain stimulation and repetitive transcranial magnetic stimulation. On the basis of the evidence presented here, the authors highlight the importance of early recognition and assessment of TD, as well as how to best approach management of these often incapacitating symptoms.

Expression of VAT1 in hepatocellular carcinoma and its clinical significance

The objective of this study was to investigate the expression of vesicular amine transporter 1 (VAT1) in hepatocellular carcinoma (HCC) and its prognostic value and to analyze the relationship between VAT1 expression and clinicopathological features of HCC. First, several public databases, including Ualcan, GEPIA, and Oncomine, were used to analyze the expression of VAT1 in HCC and normal liver tissue. Next, 330 HCC and 190 normal liver samples were stained by immunohistochemistry and scored. Finally, we evaluated the clinical significance of VAT1 as a prognostic factor according to the clinicopathological characteristics. We observed that the expression level of VAT1 in HCC samples was significantly higher than that in normal liver tissues, and the high expression of VAT1 protein in HCC was significantly correlated with patient age, tumor size, number of tumors, and vascular metastasis (p<0.05). The average survival time of HCC patients with high expression of VAT1 was significantly lower than that of patients with low expression of VAT1. Further analysis demonstrated that VAT1 expression was significantly correlated with the length of overall survival in HCC patients. In conclusion, VAT1 may have an essential function in the progression of HCC, and the level of its expression may effectively predict the invasion and prognosis of HCC. Moreover, the combination of information contained in public databases and the results of the analysis of clinical samples can help us to understand better the mechanism of action of molecular oncogenes in HCC.

Assessing Vesicular Monoamine Transport and Toxicity Using Fluorescent False Neurotransmitters.

Impairments in the vesicular packaging of dopamine result in an accumulation of dopamine in the cytosol. Cytosolic dopamine is vulnerable to two metabolic processes-enzymatic catabolism and enzymatic- or auto-oxidation-that form toxic metabolites and generate reactive oxygen species. Alterations in the expression or activity of the vesicular monoamine transporter 2 (VMAT2), which transports monoamines such as dopamine from the cytosol into the synaptic vesicle, result in dysregulated dopamine packaging. Here, we developed a series of assays using the fluorescent false neurotransmitter 206 (FFN206) to visualize VMAT2-mediated vesicular packaging at baseline and following pharmacological and toxicological manipulations. As a proof of principle, we observed a significant reduction in vesicular FFN206 packaging after treatment with the VMAT2 inhibitors reserpine (IC50: 73.1 nM), tetrabenazine (IC50: 30.4 nM), methamphetamine (IC50: 2.4 μM), and methylphenidate (IC50: 94.3 μM). We then applied the assay to investigate the consequences on vesicular packaging by environmental toxicants including the pesticides paraquat, rotenone, and chlorpyrifos, as well as the halogenated compounds unichlor, perfluorooctanesulfonic acid, Paroil, Aroclor 1260, and hexabromocyclododecane. Several of the environmental toxicants showed minor impairment of the vesicular FFN206 loading, suggesting that the toxicants are weak VMAT2 inhibitors at the concentrations tested. The assay presented here can be applied to investigate the effect of additional pharmacological compounds and environmental toxicants on vesicular function, which will provide insight into how exposures to such factors are involved in the pathogenesis of monoaminergic diseases such as Parkinson's disease, and the assay can be used to identify pharmacological agents that influence VMAT2 activity.

Recent Advances in the Pharmacology of Tardive Dyskinesia.

Tardive dyskinesia (TD) is a syndrome of abnormal involuntary movements that follows treatment with dopamine D2-receptor antagonists. Recent approval of vesicular monoamine transporter-2 (VMAT2) inhibitors offers hope for reducing the impact of TD. Although these drugs represent a significant advance in patient care and a practical step forward in providing relief for patients with TD, understanding of the pharmacology of TD that could inform future research to prevent and reverse TD remains incomplete. This review surveys evidence for the effectiveness of VMAT2 inhibitors and other agents in the context of theories of pathogenesis of TD. In patients for whom VMAT2 inhibitors are ineffective or intolerable, as well as for extending therapeutic options and insights regarding underlying mechanisms, a review of clinical trial results examined as experimental tests of etiologic hypotheses is worthwhile. There are still compelling reasons for further investigations of the pharmacology of TD, which could generate alternative preventive and potentially curative treatments. Finally, benefits from novel drugs are best realized within an overall treatment strategy addressing the condition and needs of individual patients.

Deutetrabenazine for treatment of involuntary movements in patients with tardive dyskinesia

ABSTRACT Introduction: Tardive dyskinesia (TD) is a hyperkinetic movement disorder that arises as a complication of exposure to dopamine receptor blocking agents. Vesicular monoamine transporter type 2 (VMAT2) inhibitors reduce dyskinesia by decreasing transport of monoamines, including dopamine, into presynaptic vesicles, leaving unpackaged dopamine to be metabolized by monoamine oxidase. Deutetrabenazine was adapted from an earlier VMAT2 inhibitor, tetrabenazine, by substituting three deuterium isotopes in place of three hydrogen isotopes at the site of metabolic degradation to improve upon the pharmacokinetics of the parent compound. Areas covered: The authors reviewed the pivotal trials examining the safety and efficacy of deutetrabenazine, as well as long-term data from an open-label extension. Also reviewed were posters and oral presentations, as well as information from the product label and the United States Food and Drug Administration. Expert opinion: Deutetrabenazine is effective at decreasing dyskinesia in TD, but drug selection and cost-effectiveness between existing VMAT2 inhibitors are evolving areas of study. Other areas of investigation include novel anti-dyskinetic agents and use of deep brain stimulation.

Isolongifolene mitigates rotenone-induced dopamine depletion and motor deficits through anti-oxidative and anti-apoptotic effects in a rat model of Parkinson's disease

Isolongifolene (ILF), a novel tricyclic sesquiterpene compound isolated from the Indian herb Murraya koenigii (M. koenigii), has been previously demonstrated to have a neuroprotective effect against rotenone-induced oxidative stress, mitochondrial dysfunction, and apoptosis in in vitro model. However, these neuroprotective and anti-apoptotic effects of ILF are not well understood and must be further investigated to elucidate the underlying molecular mechanism of ILF in animal experiments. The objective of this study was to evaluate the neuroprotective effect of ILF on motor impediments, neurochemical variables, anti-oxidative indices, and apoptotic protein expression in a rotenone-induced rat model of Parkinson's disease (PD). PD was induced in male albino Wistar rats via injection of 2.5 mg/kg rotenone for 4 weeks. Rotenone produces PD-like effects by promoting mitochondrial complex I inhibition and microglial activation properties. The protective effect of three different doses of ILF 5, 10 and 20 mg/kg were evaluated for spontaneous locomotion, rotarod performance, and striatal dopamine (DA) content. The results showed that ILF dose-dependently ameliorated the rotenone-induced striatal DA loss and motor impairment from 10 mg/kg. Therefore, we selected 10 mg/kg as the ILF dose for further investigation. Chronic administration of rotenone caused PD-related pathological processes like oxidative stress, and produced a significant decrease in tyrosine hydroxylase (TH), DA transporter (DAT), Vesicular monoamine transporter 2 (VMAT2), and a significant upregulated in α-synuclein and apoptotic protein expression of Bax, Cyt-C and caspases -3, -8 and −9 as well as by decreasing Bcl2 expression. Treatment with ILF 10 mg/kg mitigated oxidative stress in rotenone-treated rats. Furthermore, ILF dramatically alleviated rotenone-induced toxicity and cell death by increasing TH, DAT and VMAT2 expression and reducing the upregulation of α-synuclein, Bax, Cyt-C, caspases -3, -8 and -9. Together, our results confirm that ILF’s protective effect against rotenone-induced PD is mediated through anti-oxidant and anti-apoptotic properties. However, further in-depth investigations on ILF’s anti-inflammatory and mitochondrial protective abilities are needed to establish ILF as a potential drug candidate for the treatment of Parkinson’s disease.

Acquired dysregulation of dopamine homeostasis reproduces features of Parkinson\u2019s disease

The catecholamine neurotransmitter dopamine has the potential to act as an endogenous neurotoxin when its vesicular sequestration is dysregulated. Despite postmortem analyses from patients with Parkinson’s disease that demonstrate decreased vesicular sequestration of dopamine with a corresponding increase in dopamine metabolism, dopamine’s contribution to nigrostriatal dopaminergic degeneration in Parkinson’s disease has been debated. Here, we present a new in vivo model demonstrating the induction of Parkinson’s disease-associated pathogenic mechanisms of degeneration resulting from acquired dysregulation of dopamine sequestration in nigrostriatal dopaminergic neurons in adult rats. Utilizing adeno-associated virus (serotype 2), viral-mediated small-hairpin RNA interference of endogenous vesicular monoamine transporter 2 (VMAT2) expression resulted in a loss of VMAT2 protein expression in transduced dopaminergic cell bodies in the substantia nigra with a corresponding loss of VMAT2 protein within the striatal terminals. The loss of VMAT2 resulted in an accumulation of cytosolic dopamine and subsequent increased dopamine metabolism, deficits in dopamine-mediated behaviors, and degeneration of nigrostriatal dopaminergic neurons that was rescued through reintroduction of exogenous VMAT2, demonstrating that the toxicity was specific to the loss of VMAT2. Analysis of parkinsonian pathogenic mechanisms of degeneration identified oxidative damage, activation of Parkinson’s disease-associated kinase LRRK2, and the formation of aberrant α-synuclein. This model demonstrates that a progressive acquired loss of VMAT2 expression in adulthood is sufficient to induce Parkinson’s disease-associated pathogenic mechanisms of degeneration and provides a new model to further investigate the consequences of cytosolic dopamine.

Selective Knockout of the Vesicular Monoamine Transporter 2 (Vmat2) Gene in Calbindin2/Calretinin-Positive Neurons Results in Profound Changes in Behavior and Response to Drugs of Abuse.

The vesicular monoamine transporter 2 (VMAT2) has a range of functions in the central nervous system, from sequestering toxins to providing conditions for the quantal release of monoaminergic neurotransmitters. Monoamine signaling regulates diverse functions from arousal to mood, movement, and motivation, and dysregulation of VMAT2 function is implicated in various neuropsychiatric diseases. While all monoamine-releasing neurons express the Vmat2 gene, only a subset is positive for the calcium-binding protein Calbindin 2 (Calb2; aka Calretinin, 29 kDa Calbindin). We recently showed that about half of the dopamine neurons in the mouse midbrain are positive for Calb2 and that Calb2 is an early developmental marker of midbrain dopamine cells. Calb2-positive neurons have also been identified in other monoaminergic areas, yet the role of Calb2-positive monoaminergic neurons is poorly understood. To selectively address the impact of Calb2-positive monoaminergic neurons in behavioral regulation, we took advantage of the Cre-LoxP system to create a new conditional knockout (cKO) mouse line in which Vmat2 expression is deleted selectively in Calb2-Cre-positive neurons. In this Vmat2lox/lox;Calb2−Cre cKO mouse line, gene targeting of Vmat2 was observed in several distinct monoaminergic areas. By comparing control and cKO mice in a series of behavioral tests, specific dissimilarities were identified. In particular, cKO mice were smaller than control mice and showed heightened sensitivity to the stereotypy-inducing effects of amphetamine and slight reductions in preference toward sucrose and ethanol, as well as a blunted response in the elevated plus maze test. These data uncover new knowledge about the role of genetically defined subtypes of neurons in the brain’s monoaminergic systems.

How to Assess Tardive Dyskinesia Symptom Improvement With Measurement-Based Care.

​​​​​​ Clinicians now have 2 effective and well-tolerated vesicular monoamine transporter 2 (VMAT2) inhibitors-valbenazine and deutetrabenazine-for the treatment of patients with tardive dyskinesia (TD), a severe and potentially irreversible side effect associated with dopamine receptor blocking agents. Clinicians should use measurement-based care, eg, the Abnormal Involuntary Movement Scale with activation maneuvers, to assess and document TD symptoms and treatment progress. Each follow-up visit should be personalized with questions related to patients' functioning and level of distress regarding their specific TD symptoms. Family members, if available, can provide information on symptom changes and assistance with medication adherence. With continued treatment and measurement-based care, patients can experience improvement in their TD symptoms.

The Gene Polymorphism of VMAT2 Is Associated with Risk of Schizophrenia in Male Han Chinese.

ObjectiveTo investigate the association between gene polymorphism of vesicular monoamine transporter type 2(VMAT2) and schizophrenia in Han Chinese population. Methods430 patients with schizophrenia and 470 age-sex matched controls were recruited from four mental health centers. All patients were diagnosed by two psychiatrists based on the Structured Clinical Interview for DSM Disorders (SCID). The ligase detection reactions (LDR) method was used to assess the polymorphism of the two SNPs (rs363371 and rs363324) of VMAT2. ResultsNo associations of two SNPs with schizophrenia was found. When we stratified males and females for the analysis, we found that that in the recessive model of rs363371, there was an obvious significant association between rs363371 and schizophrenia in males (OR=0.564, 95% CI=0.357–0.892, p=0.014) but not females. For the association between rs363324 and schizophrenia, no association was found in either males or females. No association was found when stratifying early-onset schizophrenia and late-onset schizophrenia. ConclusionOur findings indicate that both rs363371 and rs363324 were not associated with schizophrenia, while it seemed that the AA genotype of rs363371 plays a protective effect in male Chinese in developing schizophrenia.