Sex-Dependent Modulation of Ethanol Consumption in Vesicular Monoamine Transporter 2 (VMAT2) and Dopamine Transporter (DAT) Knockout Mice

Hall, F. Scott; Sora, Ichiro; Uhl, George R.

doi:10.1038/sj.npp.1300070

Cited by 59 publications

(12 citation statements)

References 109 publications

(115 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Consistently, animal studies have also shown that reduced DAT expression is a risk factor. For example, mice carrying a reduction in DAT expression display liability for drug addiction [25–28]. Both clinical and pre-clinical findings suggest that up-regulation of hDAT , perhaps via modulation of the 121-bp, may alleviate related brain disorders such as substance abuse in humans.…”

Section: Resultsmentioning

confidence: 99%

Identification of an intronic cis-acting element in the human dopamine transporter gene

et al. 2011

View full text Add to dashboard Cite

The human dopamine transporter gene (hDAT) encodes the dopamine transporter in dopamine (DA) neurons to regulate DA transmission. hDAT expression varies significantly from neuron to neuron, and from individual to individual so that dysregulation of hDAT is related to many neuropsychiatric disorders. It is critical to identify hDAT-specific cis-acting elements that regulate the hDAT expression. Previous studies showed that hDAT Intron 1 displayed inhibitory activity for reporter gene expression. Here we report that the hDAT Intron 1 contains a 121-bp fragment that down-regulated both SV40 and hDAT promoter activities by 80% in vitro. Subfragments of 121-bp still down-regulated the SV40 promoter but not the hDAT promoter, as supported by nuclear protein-binding activities. Collectively, 121-bp is a silencer in vitro that might coordinate with transcriptional activities both inside and outside 121-bp in regulation of hDAT.

show abstract

Section: Resultsmentioning

confidence: 99%

Identification of an intronic cis-acting element in the human dopamine transporter gene

et al. 2011

View full text Add to dashboard Cite

show abstract

“…Rodent studies have demonstrated that DAT and VMAT2 play important roles in reinforcing behaviors (Hall et al. 2003; Thomsen et al. 2009).…”

Section: Introductionmentioning

confidence: 99%

Using iPSC‐derived human DA neurons from opioid‐dependent subjects to study dopamine dynamics

et al. 2016

View full text Add to dashboard Cite

IntroductionThe dopaminergic (DA) system plays important roles in addiction. However, human DA neurons from drug‐dependent subjects were not available for study until recent development in inducible pluripotent stem cells (iPSCs) technology.MethodsIn this study, we produced DA neurons differentiated using iPSCs derived from opioid‐dependent and control subjects carrying different 3′ VNTR (variable number tandem repeat) polymorphism in the human dopamine transporter (DAT or SLC6A3). In addition, the effects of valproic acid (VPA) exposures on iPSC‐derived human DA neurons are also examined.ResultsWe present the first evidence suggesting that the 3′ VNTR polymorphism in the hDAT gene affects DAT expression level in iPSC‐derived human DA neurons. In human DA neurons, which provide an appropriate cellular milieu, VPA treatment alters the expression of several genes important for dopaminergic neuron function including DAT, Nurr1, and TH; this might partly explain its action in regulating addictive behaviors. VPA treatment also significantly increased DA D2 receptor (Drd2) expression, especially in the opioid‐dependent iPSC cell lines.ConclusionsOur data suggest that human iPSC‐derived DA neurons may be useful in in vitro experimental model to examine the effects of genetic variation in gene regulation, to examine the underlying mechanisms in neurological disorders including drug addiction, and to serve as a platform for therapeutic development.

show abstract

“…Studies of mice lacking VMAT2 show that the homozygote animals die within a few days of birth and heterozygotes have significantly decreased monoamine levels and increased neurotoxicity as well as depressive-like phenotypes (Fon et al, 1997, Takahashi et al, 1997, Wang et al, 1997, Fumagalli et al, 1999, Narboux-Neme et al, 2011). Numerous other preclinical studies have shown that drugs of abuse have robust effects on VMAT2 function/expression, including increased neurotoxicity after methamphetamine exposure (Fumagalli et al, 1999, Uhl et al, 2000, Hall et al, 2003, Savelieva et al, 2006, Fleckenstein et al, 2007, Vergo et al, 2007, Yamamoto et al, 2007, Tong et al, 2008, Fleckenstein et al, 2009, Eiden and Weihe, 2011, Ellis et al, 2011, McFadden et al, 2011a, McFadden et al, 2011b, Vieira-Brock et al, 2011). Caudle et al (2007) observed that mice expressing approximately 5% of normal VMAT2 (VMAT2 LO) display age-associated nigrostriatal dopamine dysfunction accompanied by increased oxidative stress and decreased expression of the dopamine transporter and tyrosine hydroxylase, ultimately leading to neurodegeneration (Caudle et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

VMAT1 deletion causes neuronal loss in the hippocampus and neurocognitive deficits in spatial discrimination

et al. 2013

View full text Add to dashboard Cite

Vesicular monoamine transporters (VMAT) are involved in presynaptic storage and release of neurotransmitters. While it was thought initially that only VMAT2 is brain expressed and VMAT1 is present only in the periphery, recent data has challenged the exclusive expression of VMAT2 in brain. To further elucidate the role of VMAT1 brain expression and its potential role in neuropsychiatric disorders, we have investigated mice lacking VMAT1. Comparison of wildtype and knock-out (KO) mice using qPCR and immunohistochemistry documents the expression of VMAT1 in the brain. Deletion of VMAT1 leads to increased hippocampal apoptosis and reduced neurogenesis as assessed by caspase-3-labeling and BrdU-labeling. Behavioral data show that mice lacking VMAT1 have neurocognitive deficits. VMAT2 expression is not altered in VMAT1 KO mice, suggesting a distinct role of VMAT1. Our data support VMAT1 brain expression and suggest that VMAT1 plays a key role in survival of hippocampal neurons and thus might contribute to neurocognitive deficits observed in neuropsychiatric disorders.

show abstract

Sex-Dependent Modulation of Ethanol Consumption in Vesicular Monoamine Transporter 2 (VMAT2) and Dopamine Transporter (DAT) Knockout Mice

Cited by 59 publications

References 109 publications

Identification of an intronic cis-acting element in the human dopamine transporter gene

Identification of an intronic cis-acting element in the human dopamine transporter gene

Using iPSC‐derived human DA neurons from opioid‐dependent subjects to study dopamine dynamics

VMAT1 deletion causes neuronal loss in the hippocampus and neurocognitive deficits in spatial discrimination

Contact Info

Product

Resources

About