Knockout of the Vesicular Monoamine Transporter 2 Gene Results in Neonatal Death and Supersensitivity to Cocaine and Amphetamine

Wang, Yan Min; Gainetdinov, Raul R.; Fumagalli, Fabio; Xu, Fei; Jones, Sara R.; Bock, Cheryl B.; Miller, Gary W.; Wightman, R. Mark; Caron, Marc G.

doi:10.1016/s0896-6273(00)80419-5

Cited by 344 publications

(318 citation statements)

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“…As shown in Figure 1A, the monoclonal antibody detected in human striatal samples only the two larger forms (I and IIa) of VMAT2, with the relative intensity of the two bands also similar to that observed with the polyclonal antibody. Therefore, our observations with two antibodies against different epitopes of VMAT2 provide some support for the notion that the minor VMAT2-immunoreactive species at 45 and 35 kDa might be N-terminally truncated forms (Wang et al, 1997;Gainetdinov et al, 1998;Miller et al, 1999;Jassen et al, 2005).…”

Section: Characterization Of Vesicular Monoamine Transporter 2-immunosupporting

confidence: 78%

Distribution of Vesicular Monoamine Transporter 2 Protein in Human Brain: Implications for Brain Imaging Studies

Tong

Boileau

Furukawa

et al. 2011

J Cereb Blood Flow Metab

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The choice of reference region in positron emission tomography (PET) human brain imaging of the vesicular monoamine transporter 2 (VMAT2), a marker of striatal dopamine innervation, has been arbitrary, with cerebellar, whole cerebral, frontal, or occipital cortices used. To establish whether levels of VMAT2 are in fact low in these cortical areas, we measured VMAT2 protein distribution by quantitative immunoblotting in autopsied normal human brain (n = 6). Four or five species of VMAT2 immunoreactivity (75, 55, 52, 45, 35 kDa) were detected, which were all markedly reduced in intensity in nigrostriatal regions of patients with parkinsonian conditions versus matched controls (n = 9 to 10 each). Using the intact VMAT2 immunoreactivity, cerebellar and cerebral neocortices had levels of the transporter > 100-fold lower than the VMAT2-rich striatum and with no significant differences among the cortical regions. We conclude that human cerebellar and cerebral cortices contain negligible VMAT2 protein versus the striatum and, in this respect, all satisfy a criterion for a useful reference region for VMAT2 imaging. The slightly lower PET signal for VMAT2 binding in occipital (the currently preferred reference region) versus cerebellar cortex might not therefore be explained by differences in VMAT2 protein itself but possibly by other imaging variables, for example, partial volume effects.

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Section: Characterization Of Vesicular Monoamine Transporter 2-immunosupporting

confidence: 78%

Distribution of Vesicular Monoamine Transporter 2 Protein in Human Brain: Implications for Brain Imaging Studies

Tong

Boileau

Furukawa

et al. 2011

J Cereb Blood Flow Metab

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“…The high level of metab olites suggests an increase of both the time spent in the cytoplasm and the exposure to enzymes, such as monoamine oxidase (MAO), 29 as demonstrated by the increased 5-HT levels observed following MAO-A inhibition in VMAT2-KO mice. 11 The deletion of VMAT2 in DA neurons is solely responsible for postnatal death Whereas the constitutive deletion of VMAT2 is lethal 2-3 days after birth, [11][12][13] only its specific deletion in DA neurons reproduces this phenotype. Mice with a conditional deletion of VMAT2 in NE or 5-HT neurons are viable and reach adulthood, although retarded growth has previously been observed in VMAT2 SERTcre -KO mice.…”

Section: Discussionmentioning

confidence: 99%

“…This increased locomotor response to drugs is associated with a decreased sensitization to cocaine and a reduction in amphetamine-conditioned place preference (CPP). 12,13 The behavioural characterization of VMAT2-HET and WT animals did not indicate any difference in anxiety levels, although a sucrose preference test revealed that HET mice are less responsive to sucrose. 14 In conjunction with the decreased CPP in HET mice, these data suggest the presence of anhedonia in VMAT2-HET mice.…”

Section: J Psychiatry Neurosci 2016;41(3)mentioning

confidence: 97%

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Selective genetic disruption of dopaminergic, serotonergic and noradrenergic neurotransmission: insights into motor, emotional and addictive behaviour

Isingrini¹,

Perret²,

Rainer³

et al. 2016

jpn

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IntroductionMonoaminergic neurotransmitters, namely dopamine (DA), noradrenaline (NE) and serotonin (5-HT), extensively modulate cognitive, affective, neuroendocrine and motor functions in the brain. 1 The role of the monoaminergic systems in psychi atric pathology has been clearly established based on the observation that effective psychotropic drugs primarily target these systems. [2][3][4] However, the functional subdivision of the monoamine systems indicates a disparity in cerebral distribution, receptor subtypes and mechanisms of action. Unravelling the independent roles of the monoaminergic systems in patients with neuropsychiatric disorders remains a challenge that is complicated by their large anatomic, pharmacological and functional overlaps.At the molecular level, the monoaminergic systems share common properties. The intra-and extracellular concentrations of monoamines are primarily controlled by 2 types of transporters. The plasma membrane transporters (norepinephrine transporter [NET], serotonin transporter [SERT] and dopamine transporter [DAT]) play an essential role in the clearance and recycling of monoamines via uptake from the extracellular space, and the vesicular monoamine transporter (VMAT) accumulates monoamines in synaptic vesicles and is essential for their release. 5 Two VMAT genes have been cloned, 6,7 and although the proteins encoded by these genes are structurally related, they fulfill distinct roles. VMAT1 is primarily expressed in the peripheral nervous system; VMAT2 is primarily expressed in the neurons of the central nervous system. 8,9 The functions of VMAT2 include storage of monoamines, protection of monoamines from cytoplasmic oxi dation and regulation of stimulated monoamine quantal release. 10 Thus, VMAT2 deficiency contributes to a decrease in the synaptic release of monoamines and an increase in the degradation of intracellular monoamines.To better understand the physiologic and behavioural roles of monoaminergic signalling, several investigators have created VMAT2-knockout (KO) mice by disrupting the gene that Background:The monoaminergic transmitters dopamine (DA), noradrenaline (NE) and serotonin (5-HT) modulate cerebral functions via their extensive effects in the brain. Investigating their roles has led to the creation of vesicular monoaminergic transporter-2 (VMAT2) knockout (KO) mice. While this mutation results in postnatal death, VMAT2-heterozygous (HET) mice are viable and show a complex behavioural phenotype. However, the simultaneous alteration of the 3 systems prevents investigations into their individual functions. Methods: To assess the specific role of NE, 5-HT and DA, we genetically disrupted their neurotransmission by creating conditional VMAT2-KO mice with targeted recombination. These specific recombinations were obtained by breeding VMAT2 lox/lox mice with DBHcre, SERTcre and DATcre mice, respectively. We conducted a complete neurochemical and behavioural characterization of VMAT2-HET animals in each system. Results: Conditional VMAT2-KO mice reveale...

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“…Mice lacking both copies of the VMAT2 gene die during development, but heterozygotes survive and show reduced amphetamineconditioned reward, enhanced amphetamine and cocaineinduced locomotion, and enhanced MPTP toxicity (Takahashi et al, 1997;Wang et al, 1997). We hypothesized that sequence variants in the regions of the mouse genes encoding VMAT2, the alpha 2A adrenergic receptor, and/or beta-1 adrenergic receptor might explain the QTL and thus the differential effects of citalopram in the parental strains.…”

Section: Discussionmentioning

confidence: 99%

Pharmacogenomic Evaluation of the Antidepressant Citalopram in the Mouse Tail Suspension Test

Crowley

Brodkin

Blendy

et al. 2006

Neuropsychopharmacol

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The identification of genetic variants regulating antidepressant response in human patients would allow for more individualized, rational, and successful drug treatments. We have previously identified the BALB/cJ inbred mouse strain as highly responsive to the selective serotonin reuptake inhibitor (SSRI) citalopram in the tail suspension test (TST), a widely used and well-established screening paradigm for detecting compounds with antidepressant activity. In contrast, A/J mice did not show a significant response to citalopram in this test despite exposure to equivalent plasma levels of the drug. To identify genetic determinants of this differential response, 506 F 2 mice from an intercross between BALB/cJ and A/J mice were phenotyped. Composite interval mapping of 92 mice from the phenotypic extremes revealed three loci on chromosomes 7, 12, and 19 affecting citalopram response in the TST. The quantitative trait locus (QTL) at the telomeric end of chromosome 19 showed the greatest level of significance. Three candidate genes residing in this locus include those for vesicular monoamine transporter 2 (VMAT2, slc18a2), alpha 2A adrenergic receptor (adra2a), and beta 1 adrenergic receptor (adrb1). The protein coding regions of these three genes in BALB/cJ and A/J mice were sequenced and two polymorphisms were found in VMAT2 (Leu117Pro and Ser505Pro), while the transcribed regions of adra2a and adrb1 were of identical sequence between strains. Follow-up studies are needed to determine if the VMAT2 polymorphisms are functional and if they could explain the chromosome 19 QTL. The present quantitative trait study suggests possible candidate genes for human pharmacogenetic studies of therapeutic responses to SSRIs such as citalopram.

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Knockout of the Vesicular Monoamine Transporter 2 Gene Results in Neonatal Death and Supersensitivity to Cocaine and Amphetamine

Cited by 344 publications

References 54 publications

Distribution of Vesicular Monoamine Transporter 2 Protein in Human Brain: Implications for Brain Imaging Studies

Distribution of Vesicular Monoamine Transporter 2 Protein in Human Brain: Implications for Brain Imaging Studies

Selective genetic disruption of dopaminergic, serotonergic and noradrenergic neurotransmission: insights into motor, emotional and addictive behaviour

Pharmacogenomic Evaluation of the Antidepressant Citalopram in the Mouse Tail Suspension Test

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