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

Abstract

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 (ERK) 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 immuneprecipitation, 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.

KAT2Bpolymorphism identified for drug abuse in African Americans with regulatory links to drug abuse pathways in human prefrontal cortex

“…The OPRM1 gene has long been suspected to influence susceptibility to drug addiction, given that the protein encoded by OPRM1 is a principal target of natural and synthetic opioids. Our observed pattern for OPRM1 expression is consistent with prior reports showing lower OPRM1 expression levels in putamen(Sillivan et al, 2013) and frontal cortex(Ferrer-Alcon et al, 2004) of heroin abusers compared to normal controls. Down-regulation of OPRM1 may play a role in increasing risk of heroin abuse, by depriving the opioid system of a key compensatory response to heroin exposure.…”

Striatal H3K27 Acetylation Linked to Glutamatergic Gene Dysregulation in Human Heroin Abusers Holds Promise as Therapeutic Target

“…In order to better understand the transcriptional impairments that underlie heroin-induced synaptic plasticity in the striatum, we first examined existing data (12) from transcriptional profiling of the ventral striatum (nucleus accumbens; NAc) of post-mortem human heroin users and matching control subjects (see Tables S1 and S2 in Supplement 1 for demographic information). Using the Affymetrix HG-U133A microarray, we identified 2132 differentially expressed genes (Table S3 in Supplement 1; the raw data has been deposited in GEO).…”

Heroin abuse exaggerates age-related deposition of hyperphosphorylated tau and p62-positive inclusions

“…Accordingly, it can be theorized that anatomical areas, which directly regulate cognitive function may be more prone to tau phosphorylation. The brain reward system, including the nucleus accumbens is the major target of the mesolimbic dopaminergic system, which shows molecular disturbances in heroin addicts (Albertson, et al, 2006; Sillivan, et al, 2013). Apart from the cortical pathologies, tau positive neurites appeared more frequently in the mesencephalon, including the VTA, which has been also implicated in the pathogenesis of heroin addiction (Horvath, et al, 2007).…”