An Acute Methamphetamine Injection Downregulates the Expression of Several Histone Deacetylases (HDACs) in the Mouse Nucleus Accumbens: Potential Regulatory Role of HDAC2 Expression

Torres, Oscar V.; Ladenheim, Bruce; Jayanthi, Subramaniam; McCoy, Michael T.; Krasnova, Irina N.; Vautier, Francois; Cadet, Jean Lud

doi:10.1007/s12640-015-9591-3

Cited by 21 publications

(19 citation statements)

References 63 publications

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“…The mice were treated with four s.c injections of 10 mg/kg MA with each injection 2 hour apart. This dose of MA was chosen based on previously published reports, where 10-40 mg/kg of MA was found to be neurotoxic via various mechanisms [13, 44, 45]. The brains of mice were collected after 24 hours from the last MA injection and protein lysates were prepared from PFC, PC, hippocampus, EC, and cerebellum (Figure 6A-6E).…”

Section: Resultsmentioning

confidence: 99%

Methamphetamine-mediated endoplasmic reticulum (ER) stress induces type-1 programmed cell death in astrocytes via ATF6, IRE1α and PERK pathways

Shah

Kumar

2016

Oncotarget

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Methamphetamine (MA), a psychostimulant drug has been associated with a variety of neurotoxic effects which are thought to be mediated by induction of pro-inflammatory cytokines/chemokines, oxidative stress and damage to blood-brain-barrier. Conversely, the ER stress-mediated apoptosis has been implicated in several neurodegenerative diseases. However, its involvement in MA-mediated neurodegenerative effects remains largely unexplored. The present study was undertaken to assess the effect of MA on ER stress and its possible involvement in apoptosis. For this purpose, SVGA astrocytes were treated with MA, which induced the expressions of BiP and CHOP at both, mRNA and protein levels. This phenomenon was also confirmed in HFA and various regions of mouse brain. Assessment of IRE1α, ATF6 and PERK pathways further elucidated the mechanistic details underlying MA-mediated ER stress. Knockdown of various intermediate molecules in ER stress pathways using siRNA demonstrated reduction in MA-mediated CHOP. Finally, MA-mediated apoptosis was demonstrated via MTT assay and TUNEL staining. The involvement of ER stress in the apoptosis was demonstrated with the help of MTT and TUNEL assays in the presence of siRNA against various ER stress proteins. The apoptosis also involved activation of caspase-3 and caspase-9, which was reversed by knockdown with various siRNAs. Altogether, this is the first report demonstrating mechanistic details responsible for MA-mediated ER stress and its role in apoptosis. This study provides a novel group of targets that can be explored in future for management of MA-mediated cell death and MA-associated neurodegenerative disorders.

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Section: Resultsmentioning

confidence: 99%

Methamphetamine-mediated endoplasmic reticulum (ER) stress induces type-1 programmed cell death in astrocytes via ATF6, IRE1α and PERK pathways

Shah

Kumar

2016

Oncotarget

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“…This idea will need to be tested further by using specific inhibitor of this enzyme and/or by manipulation of NAc HDAC3 mRNA levels via virus-mediated gene expression. It is important to note that the changes in the expression of these enzymes were not due solely to METH exposure since injection of the drug in a binge pattern [25] or in single large doses [26] did not impact their expression in the rodent brain.…”

Section: Discussionmentioning

confidence: 99%

Differential Expression of mRNAs Coding for Histone Deacetylases (HDACs) in the Nucleus Accumbens of Compulsive Methamphetamine Takers and Abstinent Rats

Cadet¹,

Ladenheim²,

Krasnova³

et al. 2016

J Drug Alcohol Res

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Methamphetamine (METH) addiction is a common neuropsychiatric disorder that is associated with loss of control over drug use. The long-term manifestations of METH addiction may be related to epigenetic neuroadaptations in the brain. To test this idea, we used rats of divergent phenotypes triggered by footshocks that helped to distinguish rats that continue to take METH compulsively (shockresistant, SR) from those that become abstinent (shock-sensitive, SS). Male Sprague-Dawley rats were trained to self-administer METH (0.1 mg/kg/injection, IV) or saline during twenty 9-hour sessions. During training, all rats escalated their intake of METH. Following the training phase, rats were subjected to progressive increases in footshock intensity. This approach led to a split of the rats into the SR and SS phenotypes. Two hours after the last shock sessions the nucleus accumbens (NAc) was dissected and processed to measure mRNA levels. We found significant differences in the expression of HDAC1, HDAC3, HDAC6, and HDAC8 between the SR and SS rats. There was also increased expression of HDAC11 in the SS group in comparison to the SR and control groups. There were also significant differences in the mRNA expression of Sirt1, Sirt2, Sirt3, Sirt5, Sirt6, and Sirt7, with Sirt2 showing the greatest increase in the SS phenotype. Because these HDACs are differentially located in the cytoplasm, mitochondria, and the nucleus, these results suggest that METH self-administration may have impacted signaling pathways in various cellular compartments. Further dissection of these pathways should help us to elucidate molecular events that are involved in the maintenance of abstinence.

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“…The function of the class IIb HDAC6 and HDAC10 in SUD-related behaviors has not been reported. However, class IIb HDACs are expressed in dopaminergic neurons (Takase et al, 2013;Fukada et al, 2016), and their expression is regulated by methamphetamine exposure (Omonijo et al, 2014;Torres et al, 2016), leaving open the possible involvement in addiction-related behavior.…”

Section: Histone Acetylation and Deacetylation In Substance Use Disormentioning

confidence: 99%

It is a complex issue: emerging connections between epigenetic regulators in drug addiction

Anderson

Penrod

Barry

et al. 2018

Eur J of Neuroscience

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Drug use leads to addiction in some individuals, but the underlying brain mechanisms that control the transition from casual drug use to an intractable substance use disorder (SUD) are not well understood. Gene x environment interactions such as the frequency of drug use and the type of substance used likely to promote maladaptive plastic changes in brain regions that are critical for controlling addiction‐related behavior. Epigenetics encompasses a broad spectrum of mechanisms important for regulating gene transcription that are not dependent on changes in DNA base pair sequences. This review focuses on the proteins and complexes contributing to epigenetic modifications in the nucleus accumbens (NAc) following drug experience. We discuss in detail the three major mechanisms: histone acetylation and deacetylation, histone methylation, and DNA methylation. We discuss how drug use alters the regulation of the associated proteins regulating these processes and highlight how experimental manipulations of these proteins in the NAc can alter drug‐related behaviors. Finally, we discuss the ways that histone modifications and DNA methylation coordinate actions by recruiting large epigenetic enzyme complexes to aid in transcriptional repression. Targeting these multiprotein epigenetic enzyme complexes – and the individual proteins that comprise them – might lead to effective therapeutics to reverse or treat SUDs in patients.

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An Acute Methamphetamine Injection Downregulates the Expression of Several Histone Deacetylases (HDACs) in the Mouse Nucleus Accumbens: Potential Regulatory Role of HDAC2 Expression

Cited by 21 publications

References 63 publications

Methamphetamine-mediated endoplasmic reticulum (ER) stress induces type-1 programmed cell death in astrocytes via ATF6, IRE1α and PERK pathways

Methamphetamine-mediated endoplasmic reticulum (ER) stress induces type-1 programmed cell death in astrocytes via ATF6, IRE1α and PERK pathways

Differential Expression of mRNAs Coding for Histone Deacetylases (HDACs) in the Nucleus Accumbens of Compulsive Methamphetamine Takers and Abstinent Rats

It is a complex issue: emerging connections between epigenetic regulators in drug addiction

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