Abstract
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.
Highlights
The dopaminergic (DA) system plays important roles in addiction
We examined expression of the dopamine transporter (DAT) gene in hDA neurons differentiated from inducible pluripotent stem cells (iPSCs) lines that carry either 9 or 10 repeats of the Human DAT (hDAT) 30 variable number tandem repeats (VNTR)
Our goal was to explore the potential utility of human iPSCs as a model to examine the effect of polymorphisms on gene expression comparing cells from opioid-dependent versus control subjects and to examine the response of individually derived human dopaminergic neurons to addictive drugs and clinically relevant medications
Summary
The dopaminergic (DA) system plays important roles in addiction. human DA neurons from drug-dependent subjects were not available for study until recent development in inducible pluripotent stem cells (iPSCs) technology. 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, Nurr, and TH; this might partly explain its action in regulating addictive behaviors. Drugs of abuse are chemically divergent molecules with very different initial activities, one of the common downstream actions is the activation of the mesolimbic dopamine system. This includes increased firing of dopamine neurons in the VTA and a subsequent increase in synaptic dopamine concentration in target brain areas including the NAc and prefrontal cortex (Nestler 2001). It would be of great importance to be able to directly assay the molecular and cellular mechanisms that regulate the mesolimbic dopamine system in individual patients
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