Abstract
Background
Opiate abuse and overdose reached epidemic levels in the United States. However, despite
significant advances in animal and in vitro models, little knowledge has been directly
accrued regarding the neurobiology of the opiate-addicted human brain.
Methods
We used postmortem human brain specimens from a homogeneous European Caucasian population
of heroin users for transcriptional and epigenetic profiling, as well as direct assessment
of chromatin accessibility in the striatum, a brain region central to reward and emotion.
A rat heroin self-administration model was used to obtain translational molecular
and behavioral insights.
Results
Our transcriptome approach revealed marked impairments related to glutamatergic neurotransmission
and chromatin remodeling in the human striatum. A series of biochemical experiments
tracked the specific location of the epigenetic disturbances to hyperacetylation of
lysine 27 of histone H3, showing dynamic correlations with heroin use history and
acute opiate toxicology. Targeted investigation of GRIA1, a glutamatergic gene implicated in drug-seeking behavior, verified the increased
enrichment of lysine-27 acetylated histone H3 at discrete loci, accompanied by enhanced
chromatin accessibility at hyperacetylated regions in the gene body. Analogous epigenetic
impairments were detected in the striatum of heroin self-administering rats. Using
this translational model, we showed that bromodomain inhibitor JQ1, which blocks the
functional readout of acetylated lysines, reduced heroin self-administration and cue-induced
drug-seeking behavior.
Conclusions
Overall, our data suggest that heroin-related histone H3 hyperacetylation contributes
to glutamatergic transcriptional changes that underlie addiction behavior and identify
JQ1 as a promising candidate for targeted clinical interventions in heroin use disorder.
Keywords
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Article info
Publication history
Published online: September 28, 2016
Accepted:
September 12,
2016
Received in revised form:
September 12,
2016
Received:
July 1,
2016
Identification
Copyright
© 2016 Published by Elsevier Inc. All rights reserved.
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- Opioid Use Disorder: A Desperate Need for Novel TreatmentsBiological PsychiatryVol. 81Issue 7
