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Investigating cocaine- and abstinence-induced effects on astrocyte gene expression in the nucleus accumbens.

ABSTRACT: In recent years, astrocytes have been increasingly implicated in cellular mechanisms of substance use disorders (SUD). Astrocytes are structurally altered following exposure to drugs of abuse; specifically, astrocytes within the nucleus accumbens (NAc) exhibit significantly decreased surface area, volume, and synaptic colocalization after operant self-administration of cocaine and extinction or protracted abstinence (45 days). However, the mechanisms that elicit these morphological modifications are unknown. The current study aims to elucidate the molecular modifications that lead to observed astrocyte structural changes in rats across cocaine abstinence using astrocyte-specific RiboTag and RNA-seq, as an unbiased, comprehensive approach to identify genes whose transcription or translation change within NAc astrocytes following cocaine self-administration and extended abstinence. Using this method, our data reveal cellular processes including cholesterol biosynthesis that are altered specifically by cocaine self-administration and abstinence, suggesting that astrocyte involvement in these processes is changed in cocaine-abstinent rats. Overall, the results of this study provide insight into astrocyte functional adaptations that occur due to cocaine exposure or during cocaine withdrawal, which may pinpoint further mechanisms that contribute to cocaine-seeking behavior.

SUBMITTER: Franklin JP

PROVIDER: S-EPMC11326167 | biostudies-literature | 2024 Aug

REPOSITORIES: biostudies-literature

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Investigating cocaine- and abstinence-induced effects on astrocyte gene expression in the nucleus accumbens.

Franklin Janay P JP Testen Anze A Mieczkowski Piotr A PA Hepperla Austin A Crynen Gogce G Simon Jeremy M JM Wood Jonathan D JD Harder Eden V EV Bellinger Tania J TJ Witt Emily A EA LaShae Powell N N VanRyzin Jonathan W JW Reissner Kathryn J KJ

bioRxiv : the preprint server for biology 20250729

In recent years, astrocytes have been increasingly implicated in cellular mechanisms of substance use disorders (SUD). Astrocytes are structurally altered following exposure to drugs of abuse; specifically, astrocytes within the nucleus accumbens (NAc) exhibit significantly decreased surface area, volume, and synaptic colocalization after operant self-administration of cocaine and extinction or protracted abstinence (45 days). However, the mechanisms that elicit these morphological modifications ...[more]

PMID: 39149305

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Project description:Recent evidence suggests that histone modifications play a role in the behavioral effects of cocaine in rodent models. Histone arginine is known to be methylated by protein arginine N-methyltransferases (PRMTs). Evidence shows that PRMT1 contributes to >90% of cellular PRMT activity, which regulates histone H4 arginine 3 asymmetric dimethylation (H4R3me2a). Though histone arginine methylation represents a chemical modification that is relatively stable compared with other histone alterations, it is less well studied in the setting of addiction. Here, we demonstrate that repeated noncontingent cocaine injections increase PRMT1 activity in the nucleus accumbens (NAc) of C57BL/6 mice. We, subsequently, identify a selective inhibitor of PRMT1, SKLB-639, and show that systemic injections of the drug decrease cocaine-induced conditioned place preference to levels observed with genetic knockdown of PRMT1. NAc-specific downregulation of PRMT1 leads to hypomethylation of H4R3me2a, and hypoacetylation of histone H3 lysine 9 and 14. We also found that H4R3me2a is upregulated in NAc after repeated cocaine administration, and that H4R3me2a upregulation in turn controls the expression of Cdk5 and CaMKII. Additionally, the suppression of PRMT1 in NAc with lentiviral-short hairpin PMRT1 decreases levels of CaMKII and Cdk5 in the cocaine-treated group, demonstrating that PRMT1 affects the ability of cocaine to induce CaMKII and Cdk5 in NAc. Notably, increased H4R3me2a by repeated cocaine injections is relatively long-lived, as increased expression was observed for up to 7 d after the last cocaine injection. These results show the role of PRMT1 in the behavioral effects of cocaine.Significance statementThis work demonstrated that repeated cocaine injections led to an increase of protein arginine N-methyltransferase (PRMT1) in nucleus accumbens (NAc). We then identified a selective inhibitor of PRMT1 (SKLB-639), which inhibited cocaine-induced conditioned place preference (CPP). Additionally, genetic downregulation of PRMT1 in NAc also attenuated cocaine-caused CPP and locomotion activity, which was associated with decreased expression of histone H4 arginine 3 asymmetric demethylation (H4R3me2a) and hypoacetylation of histone H3 lysine 9 and 14 (acH3K9/K14). This study also showed that H4R3me2a controlled transcriptions of Cdk5 and CaMKII, and that PRMT1 negatively affected the ability of cocaine to induce CaMKII and Cdk5 in NAc. Notably, increased H4R3me2a by repeated cocaine injection was relatively long-lived as increased expression was observed up to 7 d after withdrawal from cocaine. Together, this study suggests that PRMT1 inhibition may serve as a potential therapeutic strategy for cocaine addiction.

Dataset Information

Investigating cocaine- and abstinence-induced effects on astrocyte gene expression in the nucleus accumbens.

Publications

Investigating cocaine- and abstinence-induced effects on astrocyte gene expression in the nucleus accumbens.

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