Behavioral Sensitization Induced by Methamphetamine Causes Differential Alterations in Gene Expression and Histone Acetylation of the Prefrontal Cortex in Rats

Li, Jin; Chen, Jing-An; Ding, Qiao; Lu, Guan-Yi; Wu, Ning; Su, Rui‐Bin; Li, Fēi

doi:10.21203/rs.2.20165/v4

Cited by 2 publications

(4 citation statements)

References 26 publications

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“…Additionally, we have conducted some experiments to analyze possible methamphetamine-induced epigenetic changes, and results indicated that methamphetamine intake was correlated with an increased amount of DNA methylation and associated gene repression. Similar results have been documented for methamphetamine-induced addiction studies in other animal models (27,28). While hypermethylation could possibly be associated with the upregulation of ion channel genes and the subsequent dysregulation of cardiac rhythm, the exact mechanism linking these epigenetic and physiological changes remains unknown.…”

Section: Discussionsupporting

confidence: 81%

Cardiotoxic effects of methamphetamine associated with electrophysiological and epigenetic aberrations in zebrafish

Zhang

Nguyen

Schmiess-Heine

et al. 2021

Preprint

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Long-term methamphetamine abuse damages functional and molecular changes in the brain that causes chronic and relapsing disease. In this study, we sought to investigate a relationship between cardiotoxicity and arrhythmia with associated methamphetamine abuse in zebrafish to identify and to understand the adverse cardiac symptoms associated with methamphetamine as well as to assess the applicability of zebrafish as an appropriate model for cardiac-related drug screening studies. Over a two-week duration, zebrafish were first treated with various concentrations of methamphetamine, ranging from 0 to 50 μM. Immediately after treatment, zebrafish underwent electrocardiogram (ECG) measurement for electrophysiological analysis. Results show that a higher incidence of increased heart rate over the duration of the experiment, corroborating with results from previous human case studies involving methamphetamine users. However, abnormalities commonly cited in those same case studies, such as prolongation of QTc, were not significantly presented in obtained ECG recordings. We have also conducted genetic, epigenetic, and histochemical analysis in an attempt to understand the cardiotoxic effects of methamphetamine on zebrafish cardiac function. These results suggested myocardial damage and decrease in gene expression associated with normal physiological function. Finally, this manuscript provides an analysis into potential reasons for the apparent discrepancies in our data with prior research as well as a future outlook of zebrafish cardiotoxic drug screening studies.

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Section: Discussionsupporting

confidence: 81%

Cardiotoxic effects of methamphetamine associated with electrophysiological and epigenetic aberrations in zebrafish

Zhang

Nguyen

Schmiess-Heine

et al. 2021

Preprint

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“…Consistent with previous studies, we found that subthreshold dose of METH (METH F1 ), which is insufficient to induce CPP in naï ve mice, effectively induced METH-preferred behaviors in METH-sired male F1 and not in SAL-sired male F1, indicating an enhanced sensitivities to drugs in F1 of sires exposed to METH. The mPFC has been implicated in the vulnerability to drug abuse [6][7][8].…”

Section: Discussionmentioning

confidence: 99%

“…One recent study found that METH-sired rats exhibit more sensitized behaviors in response to acute drug use [3], indicating that paternal METH use may enhance susceptibility to drugs in offspring. The medial prefrontal cortex (mPFC) is critically implicated in the processes of METH addiction [4,5] and susceptibility to drugs [6][7][8]. Human imaging studies show that prenatal METH exposure significantly affect the volume, cortical thickness and connection of offspring brains, especially the prefrontal cortex (PFC) [7,9,10].…”

Section: Introductionmentioning

confidence: 99%

“…The medial prefrontal cortex (mPFC) is critically implicated in the processes of METH addiction [4,5] and susceptibility to drugs [6–8]. Human imaging studies show that prenatal METH exposure significantly affect the volume, cortical thickness and connection of offspring brains, especially the prefrontal cortex (PFC) [7,9,10]. Previously, we found that mPFC were blunted to stimulants in METH-sired mice during adulthood [11].…”

Section: Introductionmentioning

confidence: 99%

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Paternal methamphetamine exposure induces higher sensitivity to methamphetamine in male offspring through driving ADRB1 on CaMKII-positive neurons in mPFC

Zheng

Wen

et al. 2022

Preprint

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As a highly addictive psychostimulant drug, paternal methamphetamine (METH) exposure enhances the risk of developing addiction to drugs in descendants, however the underlying mechanism remains unclear. Medial prefrontal cortex (mPFC) is a key brain region that implicated in susceptibility to drugs. Here, male adult mice were exposed to METH for 30 days, followed by mating with naive female mice to create the first-generation (F1) mice. In METH-sired mice, baseline levels of c-Fos were decreased but β1-adrenergic receptor (ADRB1) were increased in mPFC by paternal METH exposure. Trained with subthreshold-dosed administration of METH, METH-sired mice exhibited significant METH-preferred behaviors, accompanied with higher levels of c-Fos, ADRB1 and dendritic spines density in mPFC. Importantly, local blocking ADRB1 activity or specific knockdown of ADRB1 on excitatory neurons of mPFC, both efficiently inhibited METH-preferred behaviors in METH-sired mice. In parallel, levels of p-ERK1/2 and ΔFosB, as well as dendritic spine density were reduced by knocking-down mPFC ADRB1 in METH-sired mice. Collectively, these findings suggested that targeting ADRB1 signals in mPFC may represent a promising therapeutic strategy for preventing drug addiction, particularly in progeny with a history of paternal drugs exposure.

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Behavioral Sensitization Induced by Methamphetamine Causes Differential Alterations in Gene Expression and Histone Acetylation of the Prefrontal Cortex in Rats

Cited by 2 publications

References 26 publications

Cardiotoxic effects of methamphetamine associated with electrophysiological and epigenetic aberrations in zebrafish

Cardiotoxic effects of methamphetamine associated with electrophysiological and epigenetic aberrations in zebrafish

Paternal methamphetamine exposure induces higher sensitivity to methamphetamine in male offspring through driving ADRB1 on CaMKII-positive neurons in mPFC

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