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Estrogen Receptor ? in the Nucleus Accumbens Regulates the Rewarding Properties of Cocaine in Female Mice.

ABSTRACT: Background:Females are more vulnerable to developing cocaine addiction compared with males, a phenomenon that may be regulated by the steroid hormone 17?-estradiol. 17?-Estradiol enhances cocaine reward as measured by the conditioned place preference test. It is currently not known which estrogen receptor is involved or the neuroanatomical locations in which estrogen receptors act to enhance cocaine responses. The purpose of this study was to determine if the estrogen receptors ER? and ER? regulate cocaine conditioned place preference in mice and whether they act in the nucleus accumbens, a brain region critically involved in the development of cocaine abuse. Methods:Ovariectomized mice were treated with 17?-estradiol or agonists selective for ER? or ER? and tested for cocaine conditioned place preference and for c-fos expression in the nucleus accumbens. Female mice with intact ovaries were also tested for cocaine conditioned place preference after RNA interference-mediated knockdown of ER? or ER? in the nucleus accumbens. Results:We found that mice treated with 17?-estradiol or an ER? agonist exhibited increased cocaine conditioned place preference, while knockdown of ER?, but not ER?, in the nucleus accumbens of females with intact ovaries abrogated cocaine conditioned place preference. Acute treatment with 17?-estradiol or an ER? agonist induced expression of the immediate-early gene c-fos in the nucleus accumbens, whereas the ER? agonist did not. Conclusions:These data indicate that ER? in the nucleus accumbens regulates the development of cocaine conditioned place preference in female mice. 17?-Estradiol may activate neurons in the nucleus accumbens via ER?. We speculate that this might increase the saliency of cocaine cues that predict drug reward.

SUBMITTER: Satta R

PROVIDER: S-EPMC5887286 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature

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Estrogen Receptor β in the Nucleus Accumbens Regulates the Rewarding Properties of Cocaine in Female Mice.

Satta Rosalba R Certa Briana B He Donghong D Lasek Amy W AW

The international journal of neuropsychopharmacology 20180401 4

<h4>Background</h4>Females are more vulnerable to developing cocaine addiction compared with males, a phenomenon that may be regulated by the steroid hormone 17β-estradiol. 17β-Estradiol enhances cocaine reward as measured by the conditioned place preference test. It is currently not known which estrogen receptor is involved or the neuroanatomical locations in which estrogen receptors act to enhance cocaine responses. The purpose of this study was to determine if the estrogen receptors ERα and E ...[more]

PMID: 29294029

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Project description:UNLABELLED: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 STATEMENT:This 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

Estrogen Receptor ? in the Nucleus Accumbens Regulates the Rewarding Properties of Cocaine in Female Mice.

Publications

Estrogen Receptor β in the Nucleus Accumbens Regulates the Rewarding Properties of Cocaine in Female Mice.

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