To learn more about the biology underlying cocaine addiction, researchers analyzed almost 900 rats to map the genetic basis of behaviors associated with cocaine use, like taking the drug, taking increasing amounts of the drug, and compulsion. This work revealed several addiction-related genes, some of which have been found in previous studies of alcohol or tobacco use disorders. The research also identified a potential target for addiction treatment, which is a liver-related gene involved in cocaine metabolism. The findings have been reported in Nature Communications.
“Finding a liver-based enzyme that shapes cocaine-taking behavior was a real ‘aha moment’ for us. It reminds us that addiction isn’t only in the brain. It’s a complex puzzle involving how the entire body processes the drug,” said co-corresponding study author Olivier George, Ph.D., a professor of psychiatry at the University of California San Diego (UCSD) School of Medicine.
Genetics are known to influence cocaine use disorder, but the specific genes that are related to it have been largely unknown.
“Identifying those genes is an important goal, because drugs could then be developed to target those genes, shifting genetically susceptible people to become more like genetically resistant people,” said co-corresponding study author Abraham A. Palmer, Ph.D., a professor of psychiatry at UCSD School of Medicine.
A genetic region known as Ces1 was linked to cocaine use disorder in this work; the genes Ces1 contains encode for an enzyme that metabolizes cocaine. Variations in this genetic region were associated with the frequency and compulsion of cocaine self-administration in the rat model. The study authors suggested that cocaine metabolism in the liver could be just as relevant to addiction as genes in the brain.
The investigators used hundreds of rats that carried heterogeneous genetic backgrounds to identify small or rare genetic variations that made individuals more likely to become addicted to cocaine. Ultimately, the work found six genetic regions that are associated with addiction-related behaviors, although the findings remain to be confirmed in humans.
The work did, however, confirm a previously identified genetic link to addiction that has been found in people: Trak2. It bolsters the assertion that these findings are very relevant to human biology, and may be useful for creating addiction treatments.
“Seeing the Ces1 signal validate a hypothesis that has been circulating for decades is incredibly exciting,” noted first study author Montana Kay Lara, Ph.D., a postdoctoral researcher at UC San Diego School of Medicine. “It gives us a concrete target to test whether changing how cocaine is metabolized can blunt the drive toward compulsive use.”
Sources: University of California – San Diego, Nature Communications