Switching genes to fight addiction
Drugs can change epigenetics, a finding that could inform drug discovery
NEW YORK—Drug use can change epigenetics, and other drugs can reverse the damage, according to research conducted at the Icahn School of Medicine at Mount Sinai and published April 1 in the journal Biological Psychiatry. The study reportedly offers 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, thus controlling whether genes implicated in addiction are switched on or off.
Heroin use is linked with excessive histone acetylation, an epigenetic process that regulates gene expression. More years of drug use correlate with higher levels of hyperacetylation.
The Mount Sinai study focuses on epigenetics, the study of changes in the action of human genes caused, not by changes in DNA code people inherit from parents, but instead by molecules that regulate when, where and to what degree 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, thus activating gene expression.
To find the molecular basis of heroin addiction, the Mount Sinai team focused on the striatum, a brain region linked with drug addiction because of its central role in habit formation and goal-directed behavior. In 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. Changes were identified at the glutamate receptor gene GRIA1, which has been cited in drug use.
According to study leader Dr. Yasmin Hurd, professor of psychiatry and neuroscience at the Icahn School of Medicine and director of the Center for Addictive Disorders at the Mount Sinai Behavioral Health System, “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. 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, researchers allowed rats to self-administer heroin and observed the same hyperacetylation alterations that were found in the postmortem human brains. Then the heroin-addicted rats were treated with JQ1, a compound originally developed against cancer pathology. The compound inhibits the readout of acetylated epigenetic proteins, 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.
As Hurd explained, “Our findings suggest that JQ1 and similar compounds might be promising therapeutic tools for heroin use disorder. 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.”
She added that JQ1 had been used unsuccessfully for cancer in animal studies, showing that it was safe. In the Mount Sinai study, conducted along with researchers from Semmelweis University in Budapest, Hungary, the drug showed promise when self-administered. She hopes to bring it to clinical trials within a year.
In other but unrelated substance use research, The Scripps Research Institute (TSRI) in La Jolla, Calif., has conducted a study that could help researchers to develop personalized treatments for alcoholism and alcohol use disorder. Supported by grants from the National Institutes of Health, the research shows an important difference between the brains of alcohol-dependent vs. nondependent rats. When given alcohol, both groups showed increased activity in the central amygdala region of the brain, but this activity was attributed to two completely different brain signaling pathways.
In an article in The Journal of Neuroscience, TSRI professor Marisa Roberto, senior author of the new study, said the findings could help researchers develop more personalized treatments for alcohol dependence, as they evaluate how a person’s brain responds to different therapeutics. The new research builds on the lab’s previous discovery that alcohol increases neuronal activity in the central amygdala. The researchers found increased activity in both nondependent, or naïve, and alcohol-dependent rats. The researchers were surprised to find that the mechanisms underlying this increased activity differed between the two groups.
By giving naïve rats a dose of alcohol, the researchers increased neuronal activity. Neurons fired as the specific calcium channels at play, called L-type voltage-gated calcium channels (LTCCs), boosted the release of a neurotransmitter called GABA. Blocking these LTCCs reduced voluntary alcohol consumption in naïve rats.
However, in alcohol-dependent rats, there was decreased abundance of LTCCs on neuronal cell membranes, disrupting their normal ability to drive a dose of alcohol’s effects on cerebral amygdala activity. Instead, increased neuronal activity was driven by a stress hormone called corticotropin-releasing factor (CRF) and its type 1 receptor (CRF1). By blocking the receptor, there is reduced voluntary alcohol consumption in the dependent rats.
Studying these two groups shed light on how alcohol functionally alters the brain, according to Roberto. She hopes the findings lead to better ways to treat alcohol dependence. The new findings suggest that doctors could analyze certain symptoms or genetic markers to determine which patients are likely to benefit from the development of a novel drug that blocks that activity.