Histone 3 lysine 9 acetylation of BRG1 in the medial prefrontal cortex is associated with heroin self‑administration in rats

Abstract

Heroin addiction is a chronic relapsing brain disorder with negative social consequences. Histone acetylation serves a role in drug-induced behavior and neuroplasticity impairment. Brahma/SWi2-related gene-1 (BRG1) participates in cerebellar development, embryogenesis and transcriptional regulation of neuronal genes concurrent with histone modifications. However, little is known about the relationship between histone H3 lysine 9 acetylation (H3K9ac) and BRG1 in response to heroin. The present study aimed to assess the contribution of histone 3 lysine 9 acetylation of BRG1 to heroin self-administration. The present study established a Sprague-dawley rat model of heroin self-administration under a fixed-ratio-1 paradigm. chromatin immunoprecipitation followed by reverse transcription-quantitative Pcr (rT-qPcr) was used to detect the accumulation of H3K9ac on BRG1 in the medial prefrontal cortex (mPFC) and nucleus accumbens (NAc) following heroin self-administration. The relative expression levels of BRG1 were analyzed by rT-qPcr. H3K9ac at the promoter region of BRG1 was significantly elevated (P=0.002), and the expression of BRG1 in the mPFC increased 1.47-fold in the heroin self-administration group compared with the control group. No significant difference in H3K9ac at the BRG1 locus was observed in the NAc (P= 0.323), with the expression of BRG1 decreasing 1.38-fold in the heroin self-administering rats compared with the control group. H3K9ac is associated with transcriptional activation, and the increased BRG1 expression suggested an essential and novel role for BRG1 and its H3K9ac-mediated regulation in the mPFC after heroin self-administration; and this may function through epigenetically modulating the activation of neuroplasticity-associated genes. This association may provide a novel therapeutic target for the treatment of heroin addiction.

Role of GABRD Gene Methylation in the Nucleus Accumbens in Heroin-Seeking Behavior in Rats

“…Firstly, in order to explore the potential changes of DNA methylation in heroin self-administration rats in the NAc, animal behavioral training was initiated after recovery as previously described (Hong et al, 2020). In brief, the rats were trained to self-administer heroin under a fixed ratio paradigm for 4 h daily in operant chambers which equipped with two nose pokes: an active nose-poke hole and an inactive one Med Associates,St.…”

“…Once all testing was completed, rats were anesthetized using sodium pentobarbital (50 mg/kg, intramuscular) and rapidly decapitated. Brain tissues were dissected from the bregma using a rat brain matrix [2.2-0.8 mm according to coordinates from Paxinos and Watson (1998) rat brain atlas] (1.4 ± 0.1 mm thickness), and serial 1 mm brain sections were cut (Hong et al, 2020). The NAc were harvested bilaterally using a stainless-steel cannula (1.5 mm in diameter).…”

“…Total RNA was extracted and reverse-transcripted into singlestrand cDNA according to the method described previously (Hong et al, 2020). RT-PCR was used to analyze the mRNA levels of GABRD and GABRP with glyceraldehyde 3-phosphate dehydrogenase (GAPDH) for normalization; the nucleotide sequences of the primers are shown in Table 1.…”

Epigenetic Alterations in Prescription Opioid Misuse: New Strategies for Precision Pain Management

“…Novel therapeutic targets were also proposed among histone tail modifications [75,76]. For example, H3K9ac, which is associated with transcriptional activation, was found significantly elevated in the Brahma/SWI2-related gene-1 (BRG1) with related higher expression of this gene in the mPFC after heroin self-administration [77]. The activation of histone acetylation has already been proposed as a pharmacological strategy for treating heroin-seeking behavior.…”