Researchers at the University of California San Diego have completed a massive genetic study that identifies key biological drivers of cocaine addiction, uncovering a potential new target for treatment that resides in the liver rather than the brain. The study, published in Nature Communications, used a genetically diverse group of nearly 900 rats to map the genetic markers associated with compulsive drug use.
"Finding a liver-based enzyme that shapes cocaine-taking behavior was a real ‘aha’ moment for us,” said co-corresponding author Olivier George, PhD, a professor of psychiatry at UC San Diego School of Medicine, whose lab led the addiction behavioral studies that provided the foundation for the research. “It reminds us that addiction isn’t only in the brain. It’s a complex puzzle involving how the entire body processes the drug.”
While it is well-known that cocaine use disorder has a strong genetic component, scientists have struggled to pinpoint the specific genes that make certain individuals more vulnerable to addiction.
“Identifying those genes in 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 author Abraham A. Palmer, PhD, professor of psychiatry at UC San Diego School of Medicine, who led the project's intensive genetic modeling and analysis.
Current research in this area often focuses on the brain, but the UC San Diego team’s findings suggest that how the body breaks down — or metabolizes — cocaine may be just as critical in determining whether somebody develops an addiction.
The researchers identified a specific group of genes, known as Ces1, which are responsible for creating the enzyme that metabolizes cocaine. The study found that variations in these genes are closely linked to how frequently and compulsively rats self-administered the drug. By utilizing heterogeneous stock rats — a model system capable of mimicking the vast genetic diversity found in human populations — the team was able to capture the critical differences between individuals who are genetically susceptible to addiction and those who are naturally more resistant.
Analyzing millions of genetic markers in each animal, the team was able to identify six major genetic regions linked to addiction-like behaviors, such as the escalation of drug intake and the time elapsed between doses. Their findings suggest that by targeting the enzymes that metabolize cocaine with medicines, scientists might be able to alter how the drug affects the body, potentially reducing its addictive impact.
“This work showcases the power of long-term, team-science collaboration that pairs experts in rodent behavior with quantitative geneticists,” said Palmer. “A decade of coordinated effort across multiple cohorts and federal partners made possible a discovery that no single lab could achieve alone.”
The findings also replicated a known genetic link found in humans (Trak2), providing a vital translational bridge between animal research and human medicine. This replication strengthens the argument that the biological pathways identified in the lab could eventually lead to real-world therapies.
“Seeing the Ces1 signal validate a hypothesis that has been circulating for decades is incredibly exciting,” said first author Montana Kay Lara, PhD, a postdoctoral researcher at UC San Diego School of Medicine, who helped bridge the gap between the study's behavioral and genetic components. “It gives us a concrete target to test whether changing how cocaine is metabolized can blunt the drive toward compulsive use.”
The research team is now moving into the next phase of the project, which involves investigating exactly how these genetic mutations change the function of the enzyme. They also hope to use the study’s extensive Preclinical Addiction Biobanks — collections of blood, urine, brain and other tissue samples — to identify biological markers that could one day help predict an individual's risk of developing a substance use disorder.
The researchers hope that by leveraging this resource, they and other scientists working in this space will be able to translate genetic discoveries into diagnostic tools and new treatments that can help stabilize individuals struggling with addiction.
Read the full study.
Additional coauthors on the study include: Lieselot L.G. Carrette, Thiago Missfeld Sanches, Oksana Polesskaya, Alicia Avelar, Angela Beeson, Hassiba Beldjoud, Brent Boomhower, Molly Brennan, Denghui Chen, Riyan Cheng, Lindsay China, Apurva S. Chitre, Dana Elizabeth Conlisk, Mackenzie Fannon, Benjamin B. Johnson, Elaine Keung, Adam Kimbrough, Jenni Kononoff, Angelica Renee Martinez, Lisa Maturin, Khai-Minh Nguyen, Alex Morgan, Joseph Mosquera, Dyar Othman, Sonja L. Plasil, Jarryd Ramborger, Paul Schweitzer, Sharona Sedighim, Osborne Seshie, Kokil Shankar, Benjamin Sichel, Sierra Simpson, Lauren Cassandra Smith, Elizabeth A. Sneddon, Lan Tieu, Nathan Velarde, Selene Zahedi, Marisa Kallupi, and Giordan de Guglielmo at UC San Diego and The Scripps Research Institute, and Leah C. Solberg Woods at Wake Forest University School of Medicine.
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