Individuals
with cocaine use disorder exhibit gene expression changes in two brain
regions: the nucleus accumbens, a region associated with reward, and the
caudate nucleus, a region mediating habit formation, according to the
research published in Science Advances.
These changes, which contribute importantly to the persistent behavioral
abnormalities seen in addiction to drugs, occur because cocaine use
sets off a series of chemical reactions that lead to increases in the
amount of messenger RNA being produced from some of the affected genes
in these two brain regions, whereas the activity of other genes
decreases. Changes in the amount of messenger RNA produced—a process
also known as “expression” of the underlying genes—lead to changes in
the amount of proteins that are produced and that subsequently carry out
chemical reactions in the brain.
The research team found a significant overlap between the RNAs expressed
in these two brain regions, suggesting that these molecular changes may
be key to the development and maintenance of cocaine use disorder.
Cocaine use disorder is a chronic, relapsing brain disorder for which
there are currently no FDA-approved medication treatments. While it is
hypothesized that regulation of gene expression in the brain’s reward
and motivational centers plays a critical role in the persistent
behavioral changes that define addiction, knowledge remains limited of
the maladaptive gene activity that chronic cocaine use causes in these
circuits in humans and that underlies cocaine use disorder.
To address the knowledge gap, the research team performed RNA sequencing
in both the nucleus accumbens and caudate nucleus from the postmortem
brain tissue of persons with cocaine use disorder and matched controls.
Using the largest and most diverse cohort examined to date, they found
that neuroinflammatory processes are suppressed and that synaptic
transmembrane transporters and ionotropic receptors – proteins that
control how nerve cells communicate with one another in the brain—are
enriched in the striatum of people with cocaine use disorder.
Cocaine increases the amount of the neurotransmitter dopamine at
synapses, or junctions between two brain cells where electrical signals
are converted into chemical signals. By doing so, the research team
found, cocaine sets off a cascade of events that activate a chemical
messenger in the brain called cyclic AMP, which then triggers changes in
gene expression.
“In addition to the new insights into the molecular changes that cocaine
use confers, we found that people with cocaine use disorder have
dysregulated genes associated with schizophrenia and major depressive
disorder, which indicates that these disorders may share some underlying
gene regulatory and neural circuit systems,” said the first author of
the paper.
“Importantly, the transcriptional abnormalities—in particular, the
neuroinflammatory responses that are suppressed in the nucleus accumbens
of people with cocaine use disorder—are directionally opposite of the
proinflammatory cascade responses conferred by opioid use disorder. The
observation that there are distinct molecular changes conferred by each
of the two substance use disorders could be valuable for the development
of targeted, effective treatments specific to cocaine use disorder.”
Because it is difficult to directly study how drugs like cocaine affect
the human brain, researchers often use animal models to study their
effects. However, a key question is whether what they learn from these
animal models is similar to what happens in the brains of humans who use
cocaine.
“Our research team looked at studies performed in mice that were given
the opportunity to self-administer cocaine and compared the resulting
molecular changes to those seen in postmortem brain tissue of people
with cocaine use disorder. Our analysis revealed strikingly similar
changes in the brain’s gene expression profiles in both the mice and
humans, validating the use of mouse models to study the
pathophysiological basis of cocaine use disorder,” said the senior
author of the paper.
“It is also important to emphasize that our human brain cohort includes a
significant number of Black individuals, who have not been well
represented in prior transcriptional studies of cocaine use disorder,
despite longstanding evidence that the highest rate of overdose deaths
involving cocaine is among Black individuals. Together, these findings
represent a considerable advance in our understanding of the molecular
abnormalities in cocaine use disorder and provide a highly valuable
resource for future investigations.”
https://www.science.org/doi/10.1126/sciadv.add8946
http://sciencemission.com/site/index.php?page=news&type=view&id=publications%2Fconvergent-abnormalities&filter=22