Potential Cocaine Addiction Targets Identified Through Genetic Mapping in Rats

Scientists at the University of California San Diego have reported the results of a genome-wide association study in rats that identified key biological drivers of cocaine addiction. Using a genetically diverse group of nearly 900 rats to map genetic markers associated with compulsive drug use, the researchers uncovered a potential new therapeutic target that resides in the liver rather than in the brain.

Current research in this field often focuses on the brain, but the UC San Diego team’s findings suggest that how the body metabolizes cocaine may be just as critical in determining whether somebody develops an addiction.

“Finding a liver-based enzyme that shapes cocaine-taking behavior was a real ‘aha’ moment for us,” said Olivier George, PhD, a professor of psychiatry at UC San Diego School of Medicine. The George 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.”

George is co-corresponding author of the team’s published paper in Nature Communications, titled “Genome-wide association study of cocaine self-administration behavior in Heterogeneous Stock rats.”

Cocaine use disorder (CUD) has a strong genetic component, the authors noted. “Twin studies estimate the heritability of cocaine dependence to be as high as 70%, a finding supported by recent comprehensive reviews,” they wrote.  GWAS have also uncovered a significant heritable component, the team continued, with single nucleotide polymorphism (SN)-based heritability estimated at 27-30%. However, scientists have struggled to pinpoint the specific genes that make certain individuals more vulnerable to addiction.

“The paucity of significant and replicated associations for CUD limits our understanding of this disorder, hampering our ability to identify novel pharmacological targets,” the investigators added. 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, further commented, “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.”

To investigate further, the team carried out a GWAS in nearly 900 outbred Heterogeneous Stock (HS) rats—a model system capable of mimicking the vast genetic diversity found in human populations. By using HS rats the team was able to capture the critical differences between individuals who are genetically susceptible to addiction and those who are naturally more resistant. “Prior work has established the phenotypic diversity of HS rats across a broad range of addiction-relevant behaviors, including cocaine self-administration,” the researchers commented.

“The extended access model allowed us to characterize escalating intake, increased motivation to take the drug, and compulsive-like behavior despite negative consequences.” In addition to the GWAS results the researchers carried out a range of secondary analysis strategies to uncover what they describe as novel genetic drivers of cocaine self-administration behaviors.

Analyzing millions of genetic markers in each animal, the team discovered six major genetic regions linked to addiction-like behaviors, such as the escalation of drug intake and the time elapsed between doses. The researchers identified in the rats a specific group of carboxylesterase genes that are orthologous to the human CES1 gene, 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.

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. “Genes associated with CUD in humans remain limited, however our GWAS identified one gene (Trak2) that has also been identified by human GWAS of CUD, and the novel identification of Ces1 offers a fresh avenue for future studies,” they stated.

The collective 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. In their paper they concluded “Our results replicate previous loci associated with CUD in humans and provide several novel biological insights including the potential of pharmacological strategies targeting carboxylesterases.”

Palmer said, “This work showcases the power of long-term, team-science collaboration that pairs experts in rodent behavior with quantitative geneticists. A decade of coordinated effort across multiple cohorts and federal partners made possible a discovery that no single lab could achieve alone.”

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, said, “Seeing the Ces1 signal validate a hypothesis that has been circulating for decades is incredibly exciting. 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 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.

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