Valproate increases dopamine transporter expression through histone acetylation and enhanced promoter binding of Nurr1

Green, Ashley L.; Zhan, Lin; Eid, Aseel; Zarbl, Helmut; Guo, Grace L.; Richardson, Jason R.

doi:10.1016/j.neuropharm.2017.07.020

Cited by 26 publications

(23 citation statements)

References 68 publications

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“…Using HDAC inhibitors, Green et al. () observed increases of DAT mRNA expression in rat N27 mesencephalic cells, accompanied by significant increases in Nurr1 and Pitx3 mRNA expression. A detailed description is provided in Table .…”

Section: Mechanisms Underlying the Effects Of Social Defeat Stress Onmentioning

confidence: 99%

Social defeat stress: Mechanisms underlying the increase in rewarding effects of drugs of abuse

Montagud‐Romero

Blanco-Gandía

Reguilón

et al. 2018

Eur J of Neuroscience

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Social interaction is known to be the main source of stress in human beings, which explains the translational importance of this research in animals. Evidence reported over the last decade has revealed that, when exposed to social defeat experiences (brief episodes of social confrontations during adolescence and adulthood), the rodent brain undergoes remodeling and functional modifications, which in turn lead to an increase in the rewarding and reinstating effects of different drugs of abuse. The mechanisms by which social stress cause changes in the brain and behavior are unknown, and so the objective of this review is to contemplate how social defeat stress induces long-lasting consequences that modify the reward system. First of all, we will describe the most characteristic results of the short- and long-term consequences of social defeat stress on the rewarding effects of drugs of abuse such as psychostimulants and alcohol. Secondly, and throughout the review, we will carefully assess the neurobiological mechanisms underlying these effects, including changes in the dopaminergic system, corticotrophin releasing factor signaling, epigenetic modifications and the neuroinflammatory response. To conclude, we will consider the advantages and disadvantages and the translational value of the social defeat stress model, and will discuss challenges and future directions.

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Section: Mechanisms Underlying the Effects Of Social Defeat Stress Onmentioning

confidence: 99%

Social defeat stress: Mechanisms underlying the increase in rewarding effects of drugs of abuse

Montagud‐Romero

Blanco-Gandía

Reguilón

et al. 2018

Eur J of Neuroscience

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“…Inhibition of histone deacetylases (HDACs) and glycogen synthase kinase 3 (Gsk3α and β) are the most prominent mechanisms suspected to be involved in the mood-stabilizing effects of VPA [16][17][18][19] .VPA has been demonstrated to be an inhibitor of HDACs both in vitro and in vivo 20,21 . Chromatin remodeling mediated through HDAC inhibition may lead to transcriptional control of target genes related to neuronal differentiation, protection, and the regulation of behavioral dimensions such as mood and cognitive states 16,17,22 .In conclusion, our findings uncovered an effect of chronic VPA treatment on Ncs-1 expression that is mediated through inhibition of Gsk3. These data support a potential contribution of Ncs-1 to the behavioral effects of mood stabilizers and provide a mechanism by which inhibition of Gsk3 affects mood-related behavioral response.…”

mentioning

confidence: 63%

“…Previous studies showed that VPA can increase gene expression through the inhibition of histone deacetylases (HDACs) 22,53,54 , however it is unlikely that VPA mediates Ncs-1 upregulation through this pathway since both in vitro and in vivo treatments with HDAC inhibitors did not induce Ncs-1 expression ( Fig. 2).…”

Section: Discussionmentioning

confidence: 98%

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Contribution of neuronal calcium sensor 1 (Ncs-1) to anxiolytic-like and social behavior mediated by valproate and Gsk3 inhibition

Magno

Tenza-Ferrer

Collodetti

et al. 2020

Sci Rep

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Peripheral biomarker and post-mortem brains studies have shown alterations of neuronal calcium sensor 1 (Ncs-1) expression in people with bipolar disorder or schizophrenia. However, its engagement by psychiatric medications and potential contribution to behavioral regulation remains elusive. We investigated the effect on Ncs-1 expression of valproic acid (VPA), a mood stabilizer used for the management of bipolar disorder. Treatment with VPA induced Ncs-1 gene expression in cell line while chronic administration of this drug to mice increased both Ncs-1 protein and mRNA levels in the mouse frontal cortex. Inhibition of histone deacetylases (HDACs), a known biochemical effect of VPA, did not alter the expression of Ncs-1. In contrast, pharmacological inhibition or genetic downregulation of glycogen synthase kinase 3β (Gsk3β) increased Ncs-1 expression, whereas overexpression of a constitutively active Gsk3β had the opposite effect. Moreover, adeno-associated virus-mediated Ncs-1 overexpression in mouse frontal cortex caused responses similar to those elicited by VPA or lithium in tests evaluating social and mood-related behaviors. These findings indicate that VPA increases frontal cortex Ncs-1 gene expression as a result of Gsk3 inhibition. Furthermore, behavioral changes induced by Ncs-1 overexpression support a contribution of this mechanism in the regulation of behavior by VPA and potentially other psychoactive medications inhibiting Gsk3 activity.The neuronal calcium sensor 1 (Ncs-1) is a Ca 2+ -binding protein that regulates neurotransmitter release 1 , dopamine D2 receptor (D2R) desensitization 2 and neuronal survival 3 , among other functions 4,5 . Alterations in Ncs-1 levels may contribute to psychiatric disorders. Indeed, the expression pattern of Ncs-1 is altered in schizophrenia and bipolar disorder patients 6,7 . In addition, inducible overexpression of Ncs-1 in the brain of rodents enhances exploration and spatial memory acquisition, and increases axonal sprouting 8,9 , whereas loss of Ncs-1 in knockout (KO) mice caused depressive-like, anxiety-like and impaired motivated behaviors 10,11 .Although evidence suggests that Ncs-1 is affected in schizophrenia and bipolar disorder, the effect of psychiatric medications on Ncs-1 remains unexplored. We investigated whether the mood-stabilizing drug valproate (VPA) could contribute to the regulation of brain Ncs-1. VPA is a first-line treatment for depressive and manic phases of bipolar disorder 12 . It alters gene expression and promotes neuroplasticity changes, which in recent years has been suggested to underlie malfunctioning of the neurocircuits related to the psychiatric symptoms [13][14][15] . Inhibition of histone deacetylases (HDACs) and glycogen synthase kinase 3 (Gsk3α and β) are the most prominent mechanisms suspected to be involved in the mood-stabilizing effects of VPA [16][17][18][19] .VPA has been demonstrated to be an inhibitor of HDACs both in vitro and in vivo 20,21 . Chromatin remodeling mediated through HDAC inhibition may lead to transcri...

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“…Neurotoxicity caused by transcriptional genes (BDNF, GDNE, HSP70, and TH+-IR), α-synuclein and MPP+ is inhibited by using HDAC inhibitors (Harrison and Dexter, 2013). A study of DAT promoter in the cultured rat N27 cell shows a significant role of valproate in regulating DAT expression via elevating the histone acetylation and proves to be neuroprotective (Green et al 2017).…”

Section: Parkinson's Diseasementioning

confidence: 99%

Histone Deacetylase Inhibitors As Potential Therapeutic Agents For Various Disorders

Thapa

Kumar

Sharma

et al. 2017

JPTRM

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Epigenetic modification acetylation or deacetylation of histone considered as an important element in various disorders. Histone acetyltransferases (HATs) and histone deacetylases (HDACs) are the enzymes which catalyse the acetylation and deacetylation of histone respectively. It helps in regulating the condensation of chromatin and transcription of genes. Lysine acetylation and deacetylation present on the nucleosomal array of histone is the key factor for gene expression and regulation in a normal working living cell. Modification in histone protein will lead to the development of cancer and can cause various neurodegenerative disorders. To safeguard the cells or histone proteins from these diseases histone deacetylase inhibitors are used. In this review, the main focus is upon the role of histone deacetylases inhibitors in various diseases.

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Valproate increases dopamine transporter expression through histone acetylation and enhanced promoter binding of Nurr1

Cited by 26 publications

References 68 publications

Social defeat stress: Mechanisms underlying the increase in rewarding effects of drugs of abuse

Social defeat stress: Mechanisms underlying the increase in rewarding effects of drugs of abuse

Contribution of neuronal calcium sensor 1 (Ncs-1) to anxiolytic-like and social behavior mediated by valproate and Gsk3 inhibition

Histone Deacetylase Inhibitors As Potential Therapeutic Agents For Various Disorders

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