Ces1 Genes Linked to Compulsive Cocaine Addiction

Summary: A new study has expanded the biological map of substance use disorder, locating a primary genetic driver of cocaine addiction within the liver rather than the brain.

Utilizing a highly diverse cohort of nearly 900 heterogeneous stock rats to replicate human population genetics, the team mapped millions of genetic markers alongside years of compulsive drug-taking behavior. Their analysis isolated a crucial cluster of metabolic liver genes known as Ces1. Variations in this specific liver infrastructure dictate how rapidly an organism breaks down the substance, directly predicting whether an individual is naturally resistant to or highly susceptible to escalating into compulsive, addictive cycles.

Key Facts

Addiction Beyond the Blood-Brain Barrier : Traditional neuro-psychiatry has universally treated substance use disorders as purely neurocentric conditions, focusing entirely on brain rewards and synaptic dopamine loops. This study provides a powerful paradigm shift, showing that peripheral metabolic processes within the liver play a major role in shaping compulsive behavioral drives.

: Traditional neuro-psychiatry has universally treated substance use disorders as purely neurocentric conditions, focusing entirely on brain rewards and synaptic dopamine loops. This study provides a powerful paradigm shift, showing that peripheral metabolic processes within the liver play a major role in shaping compulsive behavioral drives. The Ces1 Genetic Target : The team pinpointed a specific group of genes named Ces1 (Carboxylesterase 1), which encode the primary enzymes responsible for metabolizing cocaine. Structural mutations and variations inside this liver-based architecture directly dictate the frequency, volume, and urgency of drug intake.

: The team pinpointed a specific group of genes named (Carboxylesterase 1), which encode the primary enzymes responsible for metabolizing cocaine. Structural mutations and variations inside this liver-based architecture directly dictate the frequency, volume, and urgency of drug intake. The Power of Heterogeneous Stock : To ensure the findings translate to human medicine, researchers utilized heterogeneous stock rats. This specialized model system mimics the immense, messy genetic diversity found across human global populations, allowing scientists to draw robust conclusions about natural genetic resistance and vulnerability.

: To ensure the findings translate to human medicine, researchers utilized heterogeneous stock rats. This specialized model system mimics the immense, messy genetic diversity found across human global populations, allowing scientists to draw robust conclusions about natural genetic resistance and vulnerability. Six Addiction-Linked Genomic Regions : By processing millions of genetic markers per animal across nearly 900 subjects, quantitative geneticists isolated six major chromosomal zones linked to specific addiction-like phenotypes, such as rapid dose escalation and the exact time intervals elapsed between self-administered hits.

: By processing millions of genetic markers per animal across nearly 900 subjects, quantitative geneticists isolated six major chromosomal zones linked to specific addiction-like phenotypes, such as rapid dose escalation and the exact time intervals elapsed between self-administered hits. Replicating the Human Trak2 Bridge : Providing an invaluable translational anchor, the study successfully replicated a known human genetic vulnerability marker—the Trak2 gene region. This cross-species confirmation heavily strengthens the clinical argument that the biological pathways mapped in this rodent trial will match human treatment outcomes.

: Providing an invaluable translational anchor, the study successfully replicated a known human genetic vulnerability marker—the gene region. This cross-species confirmation heavily strengthens the clinical argument that the biological pathways mapped in this rodent trial will match human treatment outcomes. A Blunting Treatment Strategy : Dr. Lara and Dr. Palmer emphasize that identifying the Ces1 liver pathway unlocks an entirely new strategy for drug development. Instead of tinkering with fragile brain chemistry, future medications could target these liver enzymes to deliberately speed up or alter metabolism, essentially shifting a genetically susceptible individual into a naturally resistant phenotype and blunting the compulsive drive to use.

: Dr. Lara and Dr. Palmer emphasize that identifying the liver pathway unlocks an entirely new strategy for drug development. Instead of tinkering with fragile brain chemistry, future medications could target these liver enzymes to deliberately speed up or alter metabolism, essentially shifting a genetically susceptible individual into a naturally resistant phenotype and blunting the compulsive drive to use. The Preclinical Addiction Biobank: Moving immediately into the next stage of discovery, the international research team has established extensive tissue biobanks (containing blood, urine, brain, and peripheral tissues). These repositories will be leveraged to discover objective blood biomarkers capable of predicting an individual’s unique genetic risk for substance abuse before an addiction ever takes root.

Source: UCSD

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.

The liver-based Ces1 gene cluster regulates compulsive cocaine consumption by driving peripheral drug metabolism, presenting a revolutionary, non-neurotoxic therapeutic target to blunt addictive drives. Credit: Neuroscience News

“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.

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.

Funding: The study was funded by the National Institute on Drug Abuse within the National Institutes of Health (P50DA037844, P30DA060810, U01DA051234, U01DA043799, and U01DA060810)

Key Questions Answered:

Q: How can a gene located in the liver have such a massive impact on whether someone becomes addicted to a drug? A: Because the liver dictates the lifetime and speed of the drug inside your body. The Ces1 genes are responsible for producing the exact enzymes that break down and clean cocaine out of the system. If an individual has a genetic variation that causes their liver to process the drug too quickly or in an unusual way, it can create an intense, rapid drop in drug levels that triggers an urgent, compulsive behavioral drive to take another dose immediately, accelerating the path to addiction. Q: Why did the UC San Diego researchers use “heterogeneous stock” rats instead of normal lab mice? A: To perfectly mirror human genetic diversity. Standard laboratory rodents are typically inbred, meaning they are genetic clones of each other, which makes it impossible to study why one individual becomes addicted while another remains resistant. Heterogeneous stock rats possess a wide, diverse genetic background that mimics the natural genetic variation seen in human cities, allowing quantitative geneticists to accurately isolate the specific genes driving addiction. Q: What makes a liver-based treatment better than standard addiction medications that target the brain? A: It avoids the dangerous side effects of altering brain chemistry. Traditional addiction treatments try to change the brain’s reward center, which can often cause severe depression, emotional flatness, or a loss of pleasure in everyday life. By targeting the Ces1 liver enzymes instead, scientists can safely alter how the body processes the drug externally, blunting the compulsive drive to use without ever touching the patient’s delicate neurological wiring.

Editorial Notes:

This article was edited by a Neuroscience News editor.

Journal paper reviewed in full.

Additional context added by our staff.

About this genetics and addiction research news

Author: Miles Martin

Source: UCSD

Contact: Miles Martin – UCSD

Image: The image is credited to Neuroscience News

Original Research: Open access.

“Genome-wide association study of cocaine self-administration behavior in Heterogeneous Stock rats” byMontana Kay Lara, Lieselot L. G. Carrette, Thiago Missfeldt Sanches, Oksana Polesskaya, Alicia Avelar, Angela Beeson, Hassiba Beldjoud, Brent Boomhower, Molly Brennan, Denghui Chen, Riyan Cheng, Lindsey China, Apurva S. Chitre, Dana Elizabeth Conlisk, McKenzie 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, Kokila Shankar, Benjamin Sichel, Sierra Simpson, Lauren Cassandra Smith, Elizabeth A. Sneddon, Lani Tieu, Nathan Velarde, Selene Zahedi, Leah C. Solberg Woods, Marsida Kallupi, Giordano de Guglielmo, Abraham A. Palmer & Olivier George. Nature Communications

DOI:10.1038/s41467-026-73694-w

Abstract

Genome-wide association study of cocaine self-administration behavior in Heterogeneous Stock rats

Cocaine use disorder (CUD) is a major public health crisis. The specific genes mediating CUD remain largely unknown. We conducted a genome-wide association study (GWAS) using outbred N/NIH Heterogeneous Stock (HS; n = 836, female = 415, male = 421) rats.

We examined CUD-related phenotypes including acquisition of self-administration, escalation of intake, and compulsive-like responding. These traits were phenotypically correlated and exhibited modest SNP heritability (h2 = 0.07 – 0.16). We identified six genome-wide significant associations (>-log 10 (p)=5.58; α = 0.05 by permutation).

One locus on chromosome 19 was associated with variable time between cocaine infusions (post infusion interval) and contains several carboxylesterase genes that are orthologous to the human CES1 gene. Notably, carboxylesterases metabolize cocaine.

Three non-synonymous coding variants in Ces1c and Ces1d were in perfect linkage disequilibrium with this locus. The other five loci contained promising coding and expression variants, including Trak2, a gene previously associated with CUD in human GWAS and Slc10a7, Plcl1, and Satb2 which have been associated with alcohol and tobacco use disorder.

This is the largest genetic study of cocaine self-administration ever conducted in rats. Our results replicate previous loci associated with CUD in humans and provide several novel biological insights including the potential of pharmacological strategies targeting carboxylesterases.