Epigenetic Alteration a Promising New Drug Target for Heroin Use Disorder
Heroin use is associated with excessive histone acetylation, an epigenetic process that regulates gene expression, and more years of drug use correlate with higher levels of hyperacetylation, according to research conducted at The Icahn School of Medicine at Mount Sinai and published April 1 in the journal Biological Psychiatry. The study provides the first direct evidence of opiate-related epigenetic alterations in the human brain, indicating that the drug alters accessibility to portions of DNA to be either open or closed, thereby controlling whether genes implicated in addiction are switched on or off.
The Mount Sinai study focuses on epigenetics, the study of changes in the action of human genes caused, not by changes in DNA code we inherit from our parents, but instead by molecules that regulate when, where, and to what degree our genetic material is turned on and off. Histone acetylation of DNA-linked proteins is an essential process for gene regulation by which an acetyl functional group is transferred from one molecule to another, thereby activating gene expression.
To uncover the molecular underpinnings of heroin addiction, the Mount Sinai study team focused on the striatum, a brain region implicated in drug addiction because of its central role in habit formation and goal-directed behavior. Studying postmortem human tissue from 48 heroin users and 37 controls, they found acetylation changes at genes that regulate the function of glutamate, a neurotransmitter that regulates the drug reward system and controls drug-seeking behavior. Specifically, changes were identified at the glutamate receptor gene GRIA1, which has previously been implicated in drug use.
“We hypothesized that the epigenetic impairments uncovered in our study reflect changes that would increase accessibility to DNA that is required to enhance gene transcription that subsequently plays an important role in addiction behavior,” says Yasmin Hurd, PhD, Professor of Psychiatry and Neuroscience at the Icahn School of Medicine at Mount Sinai and Director of The Center for Addictive Disorders at the Mount Sinai Behavioral Health System, who led the study. “Because epigenetic impairments are physical alterations to the DNA that do not change the sequence of a gene, they have the potential to be reversed, so our next step was to address this possibility.”
Using a rat model of heroin addiction, researchers allowed rats to self-administer heroin and observed the same hyperacetylation alterations that were found in the postmortem human brains. The study team then treated the heroin-addicted rats with JQ1, a compound originally developed against cancer pathology, which inhibits the readout of acetylated epigenetic proteins thereby reducing accessibility to the DNA that was previously induced by heroin. The drug reduced heroin self-administration among study rats. Importantly, JQ1 also reduced drug-seeking behavior after abstinence from heroin, suggesting it might be beneficial for long-term heroin users.
“Our findings suggest that JQ1 and similar compounds might be promising therapeutic tools for heroin use disorder,” says Dr. Hurd. “Furthermore, the animal model we created that displayed analogous epigenetic impairments related to heroin use will be useful for future studies looking to identify addiction-related changes that translate to the human brain.”
Researchers from Semmelweis University in Budapest, Hungary, contributed to this study.
About the Mount Sinai Health System
The Mount Sinai Health System is New York City's largest integrated delivery system, encompassing eight hospitals, a leading medical school, and a vast network of ambulatory practices throughout the greater New York region. Mount Sinai's vision is to produce the safest care, the highest quality, the highest satisfaction, the best access and the best value of any health system in the nation. The Health System includes approximately 7,480 primary and specialty care physicians; 11 joint-venture ambulatory surgery centers; more than 410 ambulatory practices throughout the five boroughs of New York City, Westchester, Long Island, and Florida; and 31 affiliated community health centers. The Icahn School of Medicine is one of three medical schools that have earned distinction by multiple indicators: ranked in the top 20 by U.S. News & World Report's "Best Medical Schools", aligned with a U.S. News & World Report's "Honor Roll" Hospital, No. 12 in the nation for National Institutes of Health funding, and among the top 10 most innovative research institutions as ranked by the journal Nature in its Nature Innovation Index. This reflects a special level of excellence in education, clinical practice, and research. The Mount Sinai Hospital is ranked No. 14 on U.S. News & World Report's "Honor Roll" of top U.S. hospitals; it is one of the nation's top 20 hospitals in Cardiology/Heart Surgery, Diabetes/Endocrinology, Gastroenterology/GI Surgery, Geriatrics, Gynecology, Nephrology, Neurology/Neurosurgery, and Orthopedics in the 2019-2020 "Best Hospitals" issue. Mount Sinai's Kravis Children's Hospital also is ranked nationally in five out of ten pediatric specialties by U.S. News & World Report. The New York Eye and Ear Infirmary of Mount Sinai is ranked 12th nationally for Ophthalmology and the South Nassau Communities Hospital is ranked 35th nationally for Urology. Mount Sinai Beth Israel, Mount Sinai St. Luke's, Mount Sinai West, and South Nassau Communities Hospital are ranked regionally.