Scientists from the Icahn School of Medicine at Mount Sinai have discovered a new role for the brain chemical dopamine, which is independent of the classic neurotransmission. The new role appears to be crucial for changes in gene expression associated with chronic exposure to or abuse of cocaine. This is the result of a study published in the journal Science on Friday, April 10th.
"Our study provides the first evidence of how dopamine can directly influence drug-induced gene expression disorders and subsequent relapse behavior," said Ian Maze, PhD, associate professor of neuroscience and pharmacological sciences at the Icahn School of Medicine in Berg Sinai and lead author the study. "In addition to transmitting signals between neurons in the brain, we found that dopamine can be chemically bound to histone proteins, causing cells to turn different genes on and off and affect regions of the brain that are involved in motivation and reward behavior. The biochemical process significantly affects the susceptibility and relapse of cocaine when it is disrupted by drug abuse. "
The study is about DNA and how it works to build each person's individual biological map. Each cell in the body contains two meters of DNA, the blueprint for all the functions of all cells in the body. This DNA is wrapped around coils of histone proteins (proteins that package DNA in the cell nucleus and are highly susceptible to chemical modifications that help regulate gene expression) in structures called nucleosomes. If DNA encoding a particular gene is tightly wound in the coil, that gene is less likely to be expressed. If the gene is not so tightly wrapped, it is more likely to be expressed. This can affect many functions of a particular cell.
Dopamine, known as a feel-good neurotransmitter, is a chemical that carries information between neurons. The brain is released when we eat food we crave or when we have sex, which contributes to feelings of joy and contentment as part of the natural reward system. This important neurochemical substance promotes mood, motivation and attention and helps regulate movement, learning and emotional reactions. Dopamine also enables us not only to see rewards, but to take action to approach them.
It is believed that the susceptibility to relapse during periods of cocaine withdrawal is due to functional rewiring of the brain's reward circuits, particularly in regions of the middle brain such as the ventral segmental region (VTA). The research team discovered that a protein called transglutaminase can bind 2 dopamine molecules directly to histone proteins (a process called histone dopaminylation, or H3Q5dop), which in turn affects the histone DNA coil to enable environmentally regulated changes in gene expression. They found that histone dopaminylation plays a crucial role in increasing the increased susceptibility to relapse over a longer period of time. In particular, the accumulation of H3Q5dop in the VTA can hijack the reward circuit, making it difficult to distinguish between good and badly adapted behavior. However, the study found that reducing H3Q5dop in rats programmed for cocaine withdrawal significantly reversed the changes in gene expression mediated by cocaine and reduced behavior when searching for cocaine.
"The question that has always challenged neuroscientists is which molecular phenomena increase the increased susceptibility to drug relapse in humans," says Dr. Ashley Lepack, researcher at the Friedman Brain Institute's Neuroscience Institute in Dr. Maze & # 39; s laboratory on Mount Sinai and lead author of the study. "Our research sheds valuable light on this area by identifying histone dopaminylation as a new neurotransmission-independent role for dopamine that has not previously been considered in brain pathology."
"We believe that these results represent a paradigm shift in our attitude to dopamine, not only in connection with drug abuse, but possibly also in other reward-related behaviors and disorders, and in neurodegenerative diseases such as Parkinson's dopamine neurons," says Dr. Maze. "In this case, the question arises whether this neuronal death is due in part to faulty dopaminylation of histone proteins." "
In a study published last year, Dr. Maze and his team found that another neurotransmitter, serotonin, a chemical that helps regulate mood, works in a similar way to dopamine on gene expression in brain cells.
"When we observed this unique signaling mechanism with serotonin, we decided to investigate other neurotransmitters, especially dopamine, and found that it could experience this type of chemical modification on the same histone protein," explains Dr. Maze.
Early work with human autopsy tissues made Dr. Maze demonstrated that there may be strong parallels, but fundamental questions about biochemical function are still open before human experiments can begin. "From a therapeutic perspective, we started using rodent models to identify the mechanisms that can actually reverse aberrant and addictive behaviors," says Dr. Maze, "and that knowledge could be critical to bringing this novel research to the clinic."
Researchers at Buffalo New York State University, Rockefeller University, McGill University, and Vanderbilt University School of Medicine have contributed to this research.
The study was supported by grants from the National Institute on Drug Abuse and the National Institute on Mental Health.
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