Lmo4 in the nucleus accumbens regulates cocaine sensitivity.
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ABSTRACT:
SUBMITTER: Lasek AW
PROVIDER: S-EPMC3130015 | biostudies-literature | 2010 Oct
REPOSITORIES: biostudies-literature
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Lmo4 in the nucleus accumbens regulates cocaine sensitivity.
Lasek A W AW Kapfhamer D D Kharazia V V Gesch J J Giorgetti F F Heberlein U U
Genes, brain, and behavior 20100812 7
An estimated 2 million Americans use cocaine, resulting in large personal and societal costs. Discovery of the genetic factors that contribute to cocaine abuse is important for understanding this complex disease. Previously, mutations in the Drosophila LIM-only (dLmo) gene were identified because of their increased behavioral sensitivity to cocaine. Here we show that the mammalian homolog Lmo4, which is highly expressed in brain regions implicated in drug addiction, plays a similar role in cocai ...[more]
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Project description:BackgroundDrug addiction is defined as a chronic disease characterized by compulsive drug seeking and episodes of relapse despite prolonged periods of drug abstinence. Neurobiological adaptations, including transcriptional and epigenetic alterations in the nucleus accumbens, are thought to contribute to this life-long disease state. We previously demonstrated that the transcription factor SMAD3 is increased after 7 days of withdrawal from cocaine self-administration. However, it is still unknown which additional factors participate in the process of chromatin remodeling and facilitate the binding of SMAD3 to promoter regions of target genes. Here, we examined the possible interaction of BRG1-also known as SMARCA4, an adenosine triphosphatase-containing chromatin remodeler-and SMAD3 in response to cocaine exposure.MethodsThe expression of BRG1, as well as its binding to SMAD3 and target gene promoter regions, was evaluated in the nucleus accumbens and dorsal striatum of rats using western blotting, co-immunoprecipitation, and chromatin immunoprecipitation following abstinence from cocaine self-administration. Rats were assessed for cocaine-seeking behaviors after either intra-accumbal injections of the BRG1 inhibitor PFI3 or viral-mediated overexpression of BRG1.ResultsAfter withdrawal from cocaine self-administration, BRG1 expression and complex formation with SMAD3 are increased in the nucleus accumbens, resulting in increased binding of BRG1 to the promoter regions of Ctnnb1, Mef2d, and Dbn1. Intra-accumbal infusion of PFI3 attenuated, whereas viral overexpression of Brg1 enhanced, cocaine-reinstatement behavior.ConclusionsBRG1 is a key mediator of the SMAD3-dependent regulation of cellular and behavioral plasticity that mediates cocaine seeking after a period of withdrawal.
| S-EPMC5050080 | biostudies-literature
Project description:Repeated cocaine exposure induces persistent alterations in genome-wide transcriptional regulatory networks, chromatin remodeling activity and, ultimately, gene expression profiles in the brain's reward circuitry. Virtually all previous investigations have centered on drug-mediated effects occurring throughout active euchromatic regions of the genome, with very little known concerning the impact of cocaine exposure on the regulation and maintenance of heterochromatin in adult brain. Here, we report that cocaine dramatically and dynamically alters heterochromatic histone H3 lysine 9 trimethylation (H3K9me3) in the nucleus accumbens (NAc), a key brain reward region. Furthermore, we demonstrate that repeated cocaine exposure causes persistent decreases in heterochromatization in this brain region, suggesting a potential role for heterochromatic regulation in the long-term actions of cocaine. To identify precise genomic loci affected by these alterations, chromatin immunoprecipitation followed by massively parallel DNA sequencing (ChIP-Seq) was performed on NAc. ChIP-Seq analyses confirmed the existence of the H3K9me3 mark mainly within intergenic regions of the genome and identified specific patterns of cocaine-induced H3K9me3 regulation at repetitive genomic sequences. Cocaine-mediated decreases in H3K9me3 enrichment at specific genomic repeats [e.g., long interspersed nuclear element (LINE)-1 repeats] were further confirmed by the increased expression of LINE-1 retrotransposon-associated repetitive elements in NAc. Such increases likely reflect global patterns of genomic destabilization in this brain region after repeated cocaine administration and open the door for future investigations into the epigenetic and genetic basis of drug addiction.
| S-EPMC3041122 | biostudies-literature
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.
| S-EPMC6795199 | biostudies-literature
Project description:Cocaine exposure induces plasticity of glutamatergic synapses of medium spiny neurons (MSNs) in the nucleus accumbens (NAc), which has been proposed to contribute to its addictive behavior. The mechanisms underlying cocaine-induced plasticity are not fully understood. The orphan glutamate delta-1 (GluD1) receptor is a member of the ionotropic glutamate receptor family but does not function as a typical ligand-gated ion channel. Instead it serves a synaptogenic function by interacting with presynaptic Neurexin protein. Recent neuroanatomical studies have demonstrated enriched expression of GluD1 in the NAc but its role in reward behavior, MSN function, and drug-induced plasticity remains unknown. Using a combination of constitutive and conditional GluD1 KO models, we evaluated the effect of GluD1 ablation on cocaine-conditioned place preference (CPP) and cocaine-induced structural and functional plasticity. GluD1 KO mice showed higher cocaine CPP. Selective ablation of GluD1 from striatal neurons but not cortico-limbic excitatory neurons reproduced higher CPP. Higher cocaine preference in GluD1 KO correlated with an increase in spine density, greater maturation of dendritic spines, and basally upregulated spine-regulating active cofilin. GluD1 loss did not affect basal excitatory neurotransmission or plasticity but masked the generation of cocaine-induced silent synapses. Finally, loss of GluD1 increased the GluN2B subunit contribution to NMDA receptor currents in MSNs and a partial agonist of GluN2B-containing NMDA receptors normalized the higher active cofilin and cocaine preference in GluD1 KO mice. Together, these findings demonstrate a critical role of GluD1 in controlling susceptibility to cocaine preference and cocaine-induced plasticity by modulating NMDA receptor subunit contribution.
| S-EPMC6185950 | biostudies-literature
Project description:Dysfunction of glutamate neurotransmission in the nucleus accumbens (NAc) has been implicated in the pathophysiology of alcohol use disorders (AUD). Neurogranin (Ng) is exclusively expressed in the brain and mediates N-methyl-d-aspartate receptor (NMDAR) hypo-function by regulating the intracellular calcium-calmodulin (Ca2+ -CaM) pathway. Ng null mice (Ng-/- mice) demonstrate increased alcohol drinking compared to wild-type mice, while also showing less tolerance to the effect of alcohol. To identify the molecular mechanism related to alcohol seeking, both in vivo microdialysis and label-free quantification proteomics comparing Ng genotype and effects of alcohol treatment on the NAc are utilized. There is significant difference in glutamate and gamma-aminobutyric acid (GABA) neurotransmission between genotypes; however, alcohol administration normalizes both glutamate and GABA levels in the NAc. Using label-free proteomics, 427 protein expression changes are identified against alcohol treatment in the NAc among 4347 total proteins detected. Bioinformatics analyses reveal significant molecular differences in Ng null mice in response to acute alcohol treatment. Ingenuity pathway analysis found that the AKT network is altered significantly between genotypes, which may increase the sensitivity of alcohol in Ng null mice. The pharmacoproteomics results presented here illustrate a possible molecular basis of the alcohol sensitivity through Ng signaling in the NAc.
| S-EPMC7038789 | biostudies-literature
Project description: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.
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Project description:The sex-steroid hormone estradiol (E2) enhances the psychoactive effects of cocaine, as evidenced by clinical and preclinical studies. The medial preoptic area (mPOA), a region in the hypothalamus, is a primary neural locus for neuroendocrine integration, containing one of the richest concentrations of estrogen receptors in the CNS and also has a key role in the regulation of naturally rewarding behaviors. However, whether estradiol enhances the neurochemical response to cocaine by acting in the mPOA is still unclear. Using neurotoxic lesions and microdialysis, we examined whether the mPOA modulates cocaine-induced neurochemical activity in the nucleus accumbens. Tract tracing and immunohistochemical staining were used to determine whether projections from the mPOA to the ventral tegmental area (VTA) are sensitive to estrogen signaling. Finally, estradiol microinjections followed by microdialysis were used to determine whether estrogenic signaling in the mPOA modulates cocaine-induced changes of dopamine in the nucleus accumbens. Results showed that lesions of the mPOA or microinjections of estradiol directly into the mPOA increased cocaine-induced release of dopamine in the nucleus accumbens. Immunohistochemical analyses revealed that the mPOA modulates cocaine responsiveness via projections to both dopaminergic and GABAergic neurons in the VTA, and that these projections are sensitive to estrogenic stimulation. Taken together, these findings point to a novel estradiol-dependent pathway that modulates cocaine-induced neurochemical activity in the mesolimbic system.
| S-EPMC4869059 | biostudies-literature
Project description:BackgroundIncreasing evidence supports a role for altered gene expression in mediating the lasting effects of cocaine on the brain, and recent work has demonstrated the involvement of chromatin modifications in these alterations. However, all such studies to date have been restricted by their reliance on microarray technologies that have intrinsic limitations.ResultsWe use next generation sequencing methods, RNA-seq and ChIP-seq for RNA polymerase II and several histone methylation marks, to obtain a more complete view of cocaine-induced changes in gene expression and associated adaptations in numerous modes of chromatin regulation in the mouse nucleus accumbens, a key brain reward region. We demonstrate an unexpectedly large number of pre-mRNA splicing alterations in response to repeated cocaine treatment. In addition, we identify combinations of chromatin changes, or signatures, that correlate with cocaine-dependent regulation of gene expression, including those involving pre-mRNA alternative splicing. Through bioinformatic prediction and biological validation, we identify one particular splicing factor, A2BP1(Rbfox1/Fox-1), which is enriched at genes that display certain chromatin signatures and contributes to drug-induced behavioral abnormalities. Together, this delineation of the cocaine-induced epigenome in the nucleus accumbens reveals several novel modes of regulation by which cocaine alters the brain.ConclusionsWe establish combinatorial chromatin and transcriptional profiles in mouse nucleus accumbens after repeated cocaine treatment. These results serve as an important resource for the field and provide a template for the analysis of other systems to reveal new transcriptional and epigenetic mechanisms of neuronal regulation.
| S-EPMC4073058 | biostudies-literature
Project description:Repeated cocaine exposure regulates transcriptional regulation within the nucleus accumbens (NAc), and epigenetic mechanisms-such as histone acetylation and methylation on Lys residues-have been linked to these lasting actions of cocaine. In contrast to Lys methylation, the role of histone Arg (R) methylation remains underexplored in addiction models. Here we show that protein-R-methyltransferase-6 (PRMT6) and its associated histone mark, asymmetric dimethylation of R2 on histone H3 (H3R2me2a), are decreased in the NAc of mice and rats after repeated cocaine exposure, including self-administration, and in the NAc of cocaine-addicted humans. Such PRMT6 down-regulation occurs selectively in NAc medium spiny neurons (MSNs) expressing dopamine D2 receptors (D2-MSNs), with opposite regulation occurring in D1-MSNs, and serves to protect against cocaine-induced addictive-like behavioral abnormalities. Using ChIP-seq, we identified Src kinase signaling inhibitor 1 (Srcin1; also referred to as p140Cap) as a key gene target for reduced H3R2me2a binding, and found that consequent Srcin1 induction in the NAc decreases Src signaling, cocaine reward, and the motivation to self-administer cocaine. Taken together, these findings suggest that suppression of Src signaling in NAc D2-MSNs, via PRMT6 and H3R2me2a down-regulation, functions as a homeostatic brake to restrain cocaine action, and provide novel candidates for the development of treatments for cocaine addiction.
| S-EPMC5003250 | biostudies-literature
Project description:Natural antisense transcripts (NATs) are an abundant class of long noncoding RNAs that have recently been shown to be key regulators of chromatin dynamics and gene expression in nervous system development and neurological disorders. However, it is currently unclear if NAT-based mechanisms also play a role in drug-induced neuroadaptations. Aberrant regulation of gene expression is one critical factor underlying the long-lasting behavioral abnormalities that characterize substance use disorder, and it is possible that some drug-induced transcriptional responses are mediated, in part, by perturbations in NAT activity. To test this hypothesis, we used an automated algorithm that mines the NCBI AceView transcriptomics database to identify NAT overlapping genes linked to addiction. We found that 22% of the genes examined contain NATs and that expression of Homer1 natural antisense transcript (Homer1-AS) was altered in the nucleus accumbens (NAc) of mice 2h and 10days following repeated cocaine administration. In in vitro studies, depletion of Homer1-AS lead to an increase in the corresponding sense gene expression, indicating a potential regulatory mechanisms of Homer1 expression by its corresponding antisense transcript. Future in vivo studies are needed to definitely determine a role for Homer1-AS in cocaine-induced behavioral and molecular adaptations.
| S-EPMC5698162 | biostudies-literature