Essential Role of Histone Methyltransferase G9a in Rapid Tolerance to the Anxiolytic Effects of Ethanol

Berkel, Tiffani D.M.; Zhang, Huaibo; Teppen, Tara; Sakharkar, Amul J.; Pandey, Subhash C.

doi:10.1093/ijnp/pyy102

Cited by 24 publications

(24 citation statements)

References 64 publications

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“…On the other hand, more recent insight into the developmental effects of THC directly refers to epigenetic alterations. Besides enduring alterations in the expression of the proenkephalin and DA receptor 2 genes in the NAc of subjects exposed to THC during either prenatal or adolescent developmental periods (DiNieri et al, 2011; Tomasiewicz et al, 2012), increased levels of dimethylation of lysine 9 on histone H3, a transcriptionally repressive mark that controls npy gene expression in limbic brain regions (Berkel et al, 2019), have also been described following prenatal THC exposure (DiNieri et al, 2011), providing a putative epigenetic substrate for the modifications in NPY expression observed in this study.…”

Section: Discussionmentioning

confidence: 99%

In utero Δ9-tetrahydrocannabinol exposure confers vulnerability towards cognitive impairments and alcohol drinking in the adolescent offspring: Is there a role for neuropeptide Y?

et al. 2020

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Background: Cannabinoid consumption during pregnancy has been increasing on the wave of the broad-based legalisation of cannabis in Western countries, raising concern about the putative detrimental outcomes on foetal neurodevelopment. Indeed, since the endocannabinoid system regulates synaptic plasticity, emotional and cognitive processes from early stages of life interfering with it and other excitability endogenous modulators, such as neuropeptide Y (NPY), might contribute to the occurrence of a vulnerable phenotype later in life. Aims: This research investigated whether in utero exposure to Δ9-tetrahydrocannabinol (THC) may induce deficits in emotional/cognitive processes and alcohol vulnerability in adolescent offspring. NPY and excitatory postsynaptic density (PSD) machinery were measured as markers of neurobiological vulnerability. Methods: Following in utero THC exposure (2 mg/kg delivered subcutaneously), preadolescent male rat offspring were assessed for: behavioural reactivity in the open field test, neutral declarative memory and aversive limbic memory in the Novel Object and Emotional Object Recognition tests, immunofluorescence for NPY neurons and the PSD proteins Homer-1, 1b/c and 2 in the prefrontal cortex, amygdala and nucleus accumbens at adolescence (cohort 1); and instrumental learning, alcohol taking, relapse and conflict behaviour in the operant chamber throughout adolescence until early adulthood (cohort 2). Results: In utero THC-exposed adolescent rats showed: (a) increased locomotor activity; (b) no alteration in neutral declarative memory; (c) impaired aversive limbic memory; (d) decreased NPY-positive neurons in limbic regions; (e) region-specific variations in Homer-1, 1b/c and 2 immunoreactivity; (f) decreased instrumental learning and increased alcohol drinking, relapse and conflict behaviour in the operant chamber. Conclusion: Gestational THC impaired the formation of memory traces when integration between environmental encoding and emotional/motivational processing was required and promoted the development of alcohol-addictive behaviours. The abnormalities in NPY signalling and PSD make-up may represent the common neurobiological background, suggesting new targets for future research.

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Section: Discussionmentioning

confidence: 99%

In utero Δ9-tetrahydrocannabinol exposure confers vulnerability towards cognitive impairments and alcohol drinking in the adolescent offspring: Is there a role for neuropeptide Y?

et al. 2020

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“…Then, the proteins in each sample were separated on 8 and 10% SDS-PAGE gels and subsequently transferred onto a 0.22 or 0.45 μm polyvinylidene fluoride (PVDF) membrane. Then, after blocking the membrane with 5% skim milk for 2 h, the primary antibody against BDNF (CY5577, Abways Biotechnology Co., Ltd., Shanghai, China) or against H3K9me2 (ab1220, Abcam, Cambridge, United Kingdom) was added and the membrane was incubated overnight at 4°C ( Berkel et al, 2019 ). Subsequently, after washing the membrane three times with tris-buffered saline Tween 20 (TBST) for 10 min each time, the secondary antibody was added, and incubated for 1 h at room temperature.…”

Section: Methodsmentioning

confidence: 99%

“…Un0642 was dissolved in dimethyl sulfoxide (DMSO), polyethylene glycol (PEG) 300 and double-distilled water (DDW). The injection (i.p) (2.5 mg/kg/d) was administered 30 min after each shock (Berkel et al, 2019;Griñán-Ferré et al, 2019;Wang et al, 2019).…”

Section: Animals and Drug Treatmentmentioning

confidence: 99%

Long-Term Effect of Post-traumatic Stress in Adolescence on Dendrite Development and H3K9me2/BDNF Expression in Male Rat Hippocampus and Prefrontal Cortex

Zhao

Wang

Jiang

et al. 2020

Front. Cell Dev. Biol.

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Exposure to a harsh environment in early life increases in the risk of post-traumatic stress disorder (PTSD) of an individual. Brain derived neurotrophic factor (BDNF) plays an important role in neurodevelopment in developmental stages. Both chronic and traumatic stresses induce a decrease in the level of BDNF and reduce neural plasticity, which is linked to the pathogenesis of PTSD. Also, studies have shown that stress alters the epigenetic marker H3K9me2, which can bind to the promoter region of the Bdnf gene and reduce BDNF protein level. However, the long-term effects of traumatic stress during adolescence on H3K9me2, BDNF expression and dendrite development are not well-known. The present study established a model of PTSD in adolescent rats using an inescapable foot shock (IFS) procedure. Anxiety-like behaviors, social interaction behavior and memory function were assessed by the open field test, elevated plus maze test, three-chamber sociability test and Morris water maze test. In addition, neuronal development and H3K9me2/BDNF expression in hippocampus (HIP) and prefrontal cortex (PFC) were evaluated by Golgi staining, western blotting, qRT-PCR analysis and CHIP-qPCR analysis. Additionally, the Unc0642, a small molecule inhibitor of histone methyltransferase (EHMT2) was used for intervention. The results showed that the IFS procedure induced the PTSD-like behaviors in rats, resulted in fewer dendrite branches and shorter dendrite length in CA1 of HIP and PFC, increased H3K9me2 level and decreased BDNF expression in HIP and PFC. Also, although all the changes can persist to adulthood, Unc0642 administration relieved most of alterations. Our study suggests that traumatic stress in adolescence leads to immediate and long-term mental disorders, neuronal morphological changes, lower BDNF level and increased H3K9me2 level in the HIP and PFC, indicating that H3K9me2/BDNF dysfunction plays a key role in pathogenesis of PTSD.

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“…7,8 In addition, prior research suggested a potential relationship between G9a in the amygdala and alcohol-induced changes in anxiety-like behavior. 9 Because anxiety disorders in humans are often comorbid with an AUD diagnosis, 10,11 possibly as a cause or consequence of escalated alcohol drinking and development of AUD, regulation of G9a following alcohol intake in anxiety-and addiction-relevant brain regions, like amygdala and NAc, positions this epigenetic factor at the intersection of AUD and anxiety. However, analysis of the potential role of NAc G9a as it relates to AUD-associated behavior is unexplored.…”

Section: [Ehmt2]mentioning

confidence: 99%

The histone methyltransferase G9a mediates stress‐regulated alcohol drinking

et al. 2021

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The epigenetic enzyme G9a is a histone methyltransferase that dimethylates lysine 9 on histone H3 (H3K9me2), and in the adult nucleus accumbens (NAc), G9a regulates multiple behaviors associated with substance use disorder. We show here that chronic intermittent ethanol (CIE) exposure in male mice reduced both G9a and H3K9me2 levels in the adult NAc, but not dorsal striatum. Viral-mediated reduction of G9a in the NAc had no effects on baseline volitional ethanol drinking or escalated alcohol drinking produced by CIE exposure; however, NAc G9a was required for stress-regulated changes in ethanol drinking, including potentiated alcohol drinking produced by activation of the kappa-opioid receptor. In addition, we observed that chronic systemic administration of a G9a inhibitor, UNC0642, also blocked stresspotentiated alcohol drinking. Together, our findings suggest that chronic alcohol use, similar to other abused substances, produces a NAc-selective reduction in G9a levels that serves to limit stress-regulated alcohol drinking. Moreover, our findings suggest that pharmacological inhibition of G9a might provide a novel therapeutic approach to treat stress-induced alcohol drinking, which is a major trigger of relapse in individuals suffering from AUD.

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Essential Role of Histone Methyltransferase G9a in Rapid Tolerance to the Anxiolytic Effects of Ethanol

Cited by 24 publications

References 64 publications

In utero Δ9-tetrahydrocannabinol exposure confers vulnerability towards cognitive impairments and alcohol drinking in the adolescent offspring: Is there a role for neuropeptide Y?

In utero Δ9-tetrahydrocannabinol exposure confers vulnerability towards cognitive impairments and alcohol drinking in the adolescent offspring: Is there a role for neuropeptide Y?

Long-Term Effect of Post-traumatic Stress in Adolescence on Dendrite Development and H3K9me2/BDNF Expression in Male Rat Hippocampus and Prefrontal Cortex

The histone methyltransferase G9a mediates stress‐regulated alcohol drinking

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