A new study finds evidence from the DNA methylome that the biological age – different from the chronological age – of Brodmann area 9 cells of the prefrontal cortex may be higher in people with disorders related to cocaine use. This suggests that cocaine abuse causes these cells to age faster according to the “epigenetic clock.” The authors also find methylation differences in 20 genes, primarily involved in regulating neuron activity and connectivity. This post-mortem study is one of the first to directly examine brain cell methylome in human subjects with cocaine use disorder, rather than in rodents.
Scientists tend to think of drug addiction as a disease of the brain. When we enjoy sex, food, music, or entertainment, regions of our brain in 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 aren’t at the mercy of such dopamine surges: there, the prefrontal cortex is weighing options and can decide to forego pleasurable activities when it’s not the time or place. In contrast, such “inhibitory control” is impaired in the addicted brain, making it difficult to resist. But what are the biochemical changes in the prefrontal cortex that cause this deficiency?
Today, German and Canadian scientists have shown in Frontiers in Psychiatry that in humans, cocaine use disorder (CUD) leads to changes in the ‘methylome’ of a subregion of the prefrontal cortex, Brodmann’s area 9, thought to be important for self-awareness and control inhibitor. Typically, a higher degree of DNA methylation leads to “down dialing” of neighboring genes.
“As DNA methylation is an important regulatory mechanism for gene expression, the identified alterations in DNA methylation could contribute to functional changes in the human brain and thus to behavioral aspects associated with addiction. “said first author Eric Poisel, a doctoral student at the Central Institute for Mental Health in Mannheim, Germany.
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Because the study of brain methylome is invasive, the study was performed on the cryopreserved brains of 42 deceased male donors, half of whom had had CUD while the other half had not. This is important because most previous studies in this area have been done on rat brains.
Brain cells may age faster in cocaine addicts
Researchers found evidence that Brodmann area 9 cells appear biologically ‘older’ in people with CUD, suggesting that these cells age faster than in people without substance use disorders . Here they used DNA methylation patterns as a measure of the biological age of cells in Brodmann’s area 9. The biological age of cells, tissues, and organs can be greater or less than their chronological age, depending on diet, lifestyle, and exposure. disease or harmful environmental factors. Scientists can thus estimate biological age from methylome data with established mathematical algorithms.
“We detected a trend towards stronger biological aging of the brain in people with cocaine use disorder compared to people without cocaine use disorder. This could be caused by pathological processes related to cocaine in the brain, such as inflammation or cell death,” said lead author Dr. Stephanie Witt, a researcher at the same institute.
“As biological age estimation is a very new concept in addiction research and is influenced by many factors, further studies are needed to investigate this phenomenon, with larger sample sizes than was possible. here.”
Poisel and his 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 each donor’s life. They corrected for differences in donor age, time since death, brain pH, and other illnesses such as depressive disorder and alcohol use disorder.
They 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 particularly important among genes that regulate neuron activity and connectivity between them. Interestingly, differential DNA methylation was linked to several transcription factors and proteins with DNA-binding domains, implying direct effects of these DNA methylation changes on gene expression. . This needs to be followed up in further studies,” Poisel said.
“Furthermore, it was fascinating that among the genes that showed the greatest changes in DNA methylation levels in our study, two genes were previously reported to regulate behavioral aspects of cocaine use in rodent experiments,” Witt said.