Cocaine Addiction Accelerates Brain Aging

Scientists find that differences in DNA methylation within brain region are important for inhibitory control in people with cocaine use disorder

Scientists tend to view substance addiction primarily as a disease of the brain. 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 stronger. However, healthy brains are not at the mercy of such dopamine rushes: there, the prefrontal cortex weighs the options and can decide to forego pleasurable activities when it is not the time or place. On the contrary, 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 deterioration?

Now, scientists from Germany and Canada have shown in Frontiers in Psychiatry that in humans, cocaine use disorder (CUD) leads to changes in the ’methylome’ of a subregion within the prefrontal cortex, Brodmann’s Area 9, which is believed to be important for self-control. awareness and inhibitory control. Typically, a higher degree of DNA methylation leads to the “decrease” of nearby genes.

"Given that DNA methylation is an important regulatory mechanism for gene expression, the identified DNA methylation alterations could contribute to functional changes in the human brain and, therefore, to the behavioral aspects associated with addiction," said first author Eric Poisel, a doctoral student at the Center Institute for Mental Health in Mannheim, Germany.

Because studying brain methylome is invasive, the study was performed on the cryopreserved brains of 42 deceased male donors, half of whom had had CUD and half had not. This is important, because most previous studies in this field were conducted in rat brains.

Brain cells may age faster in people addicted to cocaine

The researchers found evidence that cells in Brodmann Area 9 appear biologically "older" in people with CUD, evidence 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 Area 9. The biological age of cells, tissues, and organs may be older or younger than their chronological age, depending on diet, lifestyle, and exposure. to diseases 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 cocaine-related disease processes in the brain, such as inflammation or cell death,” said lead author Dr. Stephanie Witt, a researcher at the same institute.

“Given that biological age estimation is a very recent concept in addiction research and is influenced by many factors, more studies are required to investigate this phenomenon, with larger sample sizes than possible here.”

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 each donor’s lifetime. They corrected for differences in donor age, time since death, brain pH, and other conditions 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 especially prominent among genes that regulate the activity of neurons and the connectivity between them. Interestingly, differential DNA methylation was associated with several transcription factors and proteins with DNA-binding domains, implying direct effects of these DNA methylation changes on gene expression. This should be followed up in additional studies,” Poisel said.

"Furthermore, it was fascinating that among the 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," Witt said.