Elsevier

Biological Psychiatry

Volume 74, Issue 7, 1 October 2013, Pages 511-519
Biological Psychiatry

Archival Report
ELK1 Transcription Factor Linked to Dysregulated Striatal Mu Opioid Receptor Signaling Network and OPRM1 Polymorphism in Human Heroin Abusers

https://doi.org/10.1016/j.biopsych.2013.04.012Get rights and content

Background

Abuse of heroin and prescription opiate medications has grown to disturbing levels. Opioids mediate their effects through mu opioid receptors (MOR), but minimal information exists regarding MOR-related striatal signaling relevant to the human condition. The striatum is a structure central to reward and habitual behavior and neurobiological changes in this region are thought to underlie the pathophysiology of addiction disorders.

Methods

We examined molecular mechanisms related to MOR in postmortem human brain striatal specimens from a homogenous European Caucasian population of heroin abusers and control subjects and in an animal model of heroin self-administration. Expression of ets-like kinase 1 (ELK1) was examined in relation to polymorphism of the MOR gene OPRM1 and drug history.

Results

A characteristic feature of heroin abusers was decreased expression of MOR and extracellular regulated kinase signaling networks, concomitant with dysregulation of the downstream transcription factor ELK1. Striatal ELK1 in heroin abusers associated with the polymorphism rs2075572 in OPRM1 in a genotype dose-dependent manner and correlated with documented history of heroin use, an effect reproduced in an animal model that emphasizes a direct relationship between repeated heroin exposure and ELK1 dysregulation. A central role of ELK1 was evidenced by an unbiased whole transcriptome microarray that revealed ~20% of downregulated genes in human heroin abusers are ELK1 targets. Using chromatin immune precipitation, we confirmed decreased ELK1 promoter occupancy of the target gene Use1.

Conclusions

ELK1 is a potential key transcriptional regulatory factor in striatal disturbances associated with heroin abuse and relevant to genetic mutation of OPRM1.

Section snippets

Human Brain Specimens

Postmortem brain samples from heroin abusers and control subjects were collected at the Department of Forensic Medicine at Semmelweis University, Hungary, and the National Institute of Forensic Medicine at Karolinska Institutet, Stockholm, Sweden under the ethics guidelines approved by each institution. Heroin subjects died from heroin intoxication, were predominantly heroin users not receiving methadone or buprenorphine treatment, and were negative for human immunodeficiency virus infection.

Dysregulation of MOR Signaling Molecules in the Putamen of Human Heroin Abusers

Protein expression levels of MOR (89.55 ± 3.42%, p < .005; F2,43 = 6.73) and β-arrestin2 (87.11 ± 4.26%, p < .05; F3,41 = 8.1), which regulates MOR desensitization and internalization (43), were significantly reduced in heroin abusers compared with control subjects (Figure 1A,B), indicating that the tone of MOR signaling cascades may be altered. One of the key intracellular pathways activated upon MOR stimulation is the MAPK pathway, depicted in Figure 1C. We focused on the core components of

Discussion

The current study provides convergent lines of evidence identifying ELK1 disturbances in association with heroin use history and variants of the OPRM1 gene. The findings suggest that repeated activation of MOR, and subsequently the ERK pathway, efficiently controls the availability of ELK1 to regulate striatal transcriptional machinery in a dose-dependent manner. The ELK1 transcription factor has been generally overlooked in the context of addiction, but the current results implicate it as a

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