Summary: A large genetic study expands the biological map of substance use disorder by identifying a primary genetic driver of cocaine addiction that operates in the liver rather than solely in the brain.
Using a genetically diverse cohort of nearly 900 heterogeneous stock rats to better mirror human population genetics, researchers mapped millions of genetic markers alongside detailed measures of compulsive drug-taking behavior. Their analysis highlighted a cluster of liver metabolic genes in the Carboxylesterase 1 family (Ces1) as a key regulator: variations in these genes determine how quickly cocaine is metabolized and strongly predict whether an individual is protected from or vulnerable to escalating, compulsive intake.
Key findings
- Addiction beyond the brain: While addiction research has largely focused on neural reward circuits, this study demonstrates that peripheral metabolism — especially liver enzymes — can powerfully shape compulsive drug use.
- The
Ces1gene cluster: The investigators linked a locus containing multiple carboxylesterase genes to variability in the time between cocaine infusions. These enzymes metabolize cocaine and the gene variants they identified alter drug clearance rates, which in turn influence patterns of intake. - Heterogeneous stock rats for translational relevance: The team intentionally used outbred HS rats to capture the messy genetic diversity found in humans. This model enabled them to detect naturally occurring genetic differences tied to addiction-related behaviors.
- Six genome regions tied to addiction-like traits: By analyzing millions of markers per animal across the cohort (n ≈ 836), researchers discovered six chromosomal regions associated with phenotypes such as escalation of intake and timing between self-administered doses.
- Replication of a human marker: The study reproduced a previously reported human association in the
Trak2gene region, strengthening cross-species translational relevance for therapeutic development. - New therapeutic direction: Targeting liver-based carboxylesterase activity could offer a way to change peripheral drug metabolism and reduce compulsive use without directly altering brain chemistry.
- Preclinical addiction biobank: The team established an extensive biobank containing blood, urine, brain, and peripheral tissues to support biomarker discovery and future translational research.
Source: UCSD
Researchers at the University of California San Diego completed a large genome-wide association study that points to a novel, liver-based target for cocaine addiction treatment.
Published in Nature Communications, the study used nearly 900 genetically diverse rats to map the genetics of compulsive cocaine self-administration. The strongest signal localized to a region containing carboxylesterase genes that are orthologous to the human CES1 gene family.
“Finding a liver-based enzyme that shapes cocaine-taking behavior was an ‘aha’ moment,” said co-corresponding author Olivier George, PhD, professor of psychiatry at UC San Diego School of Medicine. “It reminds us that addiction involves the whole body — not only the brain.”
Cocaine use disorder has a strong heritable component, but identifying the precise genes that confer risk has been challenging. Co-corresponding author Abraham A. Palmer, PhD, professor of psychiatry at UC San Diego School of Medicine, led the genetic modeling and noted, “Finding specific genes is crucial: once identified, they become potential targets for drugs that could shift susceptible individuals toward a resistant profile.”
The study measured multiple addiction-related phenotypes — acquisition of self-administration, escalation of intake, compulsive-like responding, and intervals between infusions — and estimated modest single-nucleotide polymorphism heritability for these traits (h2 ≈ 0.07–0.16). One chromosome 19 locus associated with post-infusion interval contained several Ces1 genes, and three non-synonymous coding variants in Ces1c and Ces1d were in perfect linkage with that locus. Other identified loci included coding and expression variants in genes such as Trak2, Slc10a7, Plcl1, and Satb2, some of which have prior links to substance use traits.
By demonstrating that peripheral metabolism shapes consumption patterns, the authors suggest a novel pharmacological approach: rather than altering brain reward systems — interventions that can carry substantial psychiatric side effects — therapeutics could modulate liver enzyme activity to change how cocaine is processed in the body and reduce the urgency to re-dose.
The research team is now investigating how the identified genetic variants change enzyme function and using the Preclinical Addiction Biobank to search for blood-based biomarkers that could predict individual risk before an addiction develops. These resources aim to translate genetic findings into diagnostics and treatments that stabilize people who are vulnerable to substance use disorders.
Additional coauthors 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, Giordano de Guglielmo, and others at UC San Diego, The Scripps Research Institute, and Wake Forest University School of Medicine.
Funding: This work was supported by the National Institute on Drug Abuse (NIH) through grants P50DA037844, P30DA060810, U01DA051234, U01DA043799, and U01DA060810.
Key questions answered
A: The liver controls how long and how much of a drug remains in the bloodstream. The Ces1 genes produce enzymes that metabolize cocaine; genetic variants that alter these enzymes change drug clearance. Rapid or abnormal drops in circulating drug levels can provoke urgent re-dosing, promoting compulsive intake and accelerating addiction.
A: Standard inbred strains lack the genetic diversity needed to model why some individuals develop addiction while others do not. Heterogeneous stock rats capture broad, naturally occurring variation, allowing researchers to link specific genetic differences to behavioral outcomes and improve translational relevance to humans.
A: Targeting peripheral metabolism could reduce compulsive drug use without directly manipulating brain reward circuits, potentially avoiding psychiatric side effects such as emotional blunting or disrupted mood that can accompany treatments aimed at central neurotransmission.
Editorial notes
- This article was edited by a Neuroscience News editor.
- The journal paper was reviewed in full.
- Additional context was added by staff.
About this research
Author: Miles Martin
Source: UCSD
Contact: Miles Martin – UCSD
Image credit: Neuroscience News
Original research: Open access. Title: “Genome-wide association study of cocaine self-administration behavior in Heterogeneous Stock rats.” Authors include Montana Kay Lara et al. Published in Nature Communications. DOI: 10.1038/s41467-026-73694-w
Abstract (condensed)
Cocaine use disorder is a major public health challenge and the genes that mediate liability are incompletely known. The authors conducted a GWAS in outbred N/NIH Heterogeneous Stock rats (n = 836) examining traits such as acquisition, escalation, and compulsive-like responding. Six genome-wide significant loci were identified. One locus on chromosome 19, associated with post-infusion interval, contains several carboxylesterase genes orthologous to human CES1, and non-synonymous variants in Ces1c and Ces1d were tightly linked to this signal. Other loci included genes previously associated with substance use traits. These results provide cross-species replication of human findings and support pharmacological strategies targeting carboxylesterases as a potential therapeutic avenue.