Researchers have found evidence in humans that cells in Brodmann Area 9 in the brain, considered important for self-awareness and inhibitory control, appear biologically ‘older’ in people with cocaine use disorder (CUD), according to a new study.
The evidence suggested that these cells age faster in people with CUD than in those without substance use disorders, the study said.
The scientists from Germany and Canada have found that CUD results in changes in the ‘methylome’ of Brodmann Area 9, a subregion within the prefrontal cortex of the brain.
Typically, a greater degree of DNA methylation leads to the ‘dialing down’ of nearby genes, the study said.
The findings have been published in the journal Frontiers in Psychiatry.
In this study, the scientists used patterns of DNA methylation as a measure of the biological age of cells in Brodmann Area 9, it said.
The biological age of cells, tissues, and organs can be greater or less than their chronological age, depending on diet, lifestyle, and exposure to disease or harmful environmental factors, the study said.
Scientists can, thus, estimate the biological age from methylome data with established mathematical algorithms, the study said.
”We detected a trend towards stronger biological aging of the brain in individuals with cocaine use disorder compared to individuals without cocaine use disorder.
”This could be caused by cocaine-related disease processes in the brain, such as inflammation or cell death,” said lead author Stephanie Witt, a researcher at the Central Institute of Mental Health in Mannheim, Germany.
”As biological age estimation is a very recent concept in addiction research and is influenced by many factors, further studies are required to investigate this phenomenon, with larger sample sizes than were possible here,” said Witt.
Scientists tend to view substance addiction as primarily a disease of the brain, the study said.
When we enjoy sex, food, music, or hobbies, regions of our brain within the reward pathway are flooded with pleasure-inducing dopamine.
Drugs like cocaine copy this effect, except up to ten times more strongly.
However, healthy brains are not at the mercy of such dopamine rushes, because the prefrontal cortex weighs options and can decide to forego pleasurable activities when it is not the time or place.
In contrast, such ‘inhibitory control’ is impaired in the addicted brain, making it hard to resist.
But what are the biochemical changes in the prefrontal cortex that cause this impairment? ”As DNA methylation is an important regulatory mechanism for gene expression, the identified DNA methylation alterations might contribute to functional changes in the human brain and, thereby, to the associated behavioral aspects of addiction,” said first author Eric Poisel, a PhD student at the same institute.
Because the study of the brain methylome is invasive, the study was done on the cryo-preserved brains of 42 deceased male donors, of whom half had had CUD while the other half had not, the study said.
This is important, because most earlier studies in this field were done on the brains of rats, the study said.
According to the study, Poisel and colleagues also looked at differences in the degree of methylation at 654,448 sites in the human genome, and looked for associations with the presence or absence of CUD in the life of each donor.
They corrected for differences in the donor’s age, the time since death, the brain pH, and further diseases such as depressive disorder and alcohol use disorder, the study said.
The study found 17 genomic regions that were more methylated in donors with CUD than in donors without CUD, and three regions that were less methylated in donors with CUD than in donors without CUD.
”We were surprised that in our network analysis, changes in DNA methylation were especially prominent among genes that regulate the activity of neurons and the connectivity between them.
”Interestingly, differential DNA methylation was related to several transcription factors and proteins with DNA binding domains, which implies direct effects of these DNA methylation changes on gene expression. This needs to be followed up in further studies,” said Poisel.
”Also, it was fascinating that among those genes that showed the strongest changes in DNA methylation levels in our study, two genes were previously reported to regulate behavioral aspects of cocaine intake in rodent experiments,” said Witt.
