Study of genetically varied mouse populations can reveal what factors lead to compulsive cocaine intake.
What brain states makes one person more susceptible to cocaine addiction than others? Unfortunately, in people, the way to learn how to predict who’s vulnerable is to look at who’s already become addicted.
The dangers of cocaine addiction
For some people, a single hit of cocaine is enough to produce addiction, especially if it is smoked as crack. According to the National Institute on Drug Abuse (NIDA), an estimated 1.5 million people have used cocaine in the past month, and about 913,000 Americans met the Diagnostic and Statistical Manual of Mental Disorders criteria for dependence or abuse of cocaine (in any form) during the past 12 months.
Cocaine in any form is potentially deadly; toxic amounts can cause heart attacks, strokes or seizures. The drug is linked to more than a third of drug-related hospital emergency department visits, and is often contaminate with other drugs, leading to opioid overdose.
New ways to prevent and treat cocaine addiction will require advances in identifying the genetic, behavioral and neurobiological factors that make some individuals more or less susceptible to the drug’s addictive properties. Elissa Chesler, Ph.D.Develops software tools and resources for multi-species data integration in the study of health and disease and researches the genetic and biological basis for relationships among behavioral traits including addiction and other behaviors.Elissa Chesler , Ph.D., a professor and Ann Watson Symington Chair in Addiction Research at The Jackson Laboratory (JAX), leads a research team that uses a combination of genetics, behavioral science and bioinformatics to understand the biological basis for addiction and other behavioral traits.
Searching for the genetic root of addiction
NIDA has announced a five-year grant renewal totaling $3,974,177 for Chesler to continue her work to discover addiction-related genes. “Our overarching goal is to discover the genetic and genomic mechanisms underlying behavioral predisposition and development of addiction,” Chesler says. “Addiction remains a substantial worldwide social and economic burden despite extensive efforts to curb drug availability and use.”
And, she notes, “Addiction to cocaine is more heritable than other substances,” and the high heritability of cocaine addiction indicates that the propensity to develop a substance use disorder after drug exposure is genetically influenced. “Both human and animal studies indicate that behavioral traits such as novelty seeking and risk taking are strongly correlated with the propensity to develop a substance use disorder, but the biological basis of this relationship is unknown,” she says.
To identify and characterize biological mechanisms of addiction and predisposing behavior, the Chesler lab is harnessing advances in RNA sequence analysis to measure gene expression, computational and statistical methods in systems genetics, and mouse genetic resources including engineered mouse models and the Diversity Outbred (DO) mouse population. Unlike standard, inbred laboratory mice, DO mice possess genetic and behavioral variability that can be related to the variability in the human population.
United in the fight against drug addiction
For the new grant Chesler is continuing her collaboration on multi-species bioinformatics with Rohan Palmer, Ph.D., director of the Behavioral Genetics of Addiction Laboratory at Emory University in Atlanta to do just that. They recently published several papers showing that what we learn from mouse genetics and genomics can be used to explain human genetic variability and addiction risk.
JAX Assistant Professor Erik Bloss, Ph.D.The Bloss Lab uses various genetic, structural and functional approaches to understand how synaptic connectivity among cortical cell types underlies behaviorally-relevant neural computations.Erik Bloss , an expert in advanced brain imaging and computational techniques, has also joined the research team. Chesler notes, “Previous studies indicate a strong relationship between cocaine use and variations in the fronto-striatal connections,” neural pathways that are involved in motor, cognitive and behavioral functions in the brain. Bloss will help the team identify precisely how this process differs in vulnerable and resistant individuals.
Because many neurobiological processes that drive progression to addiction are similar across drugs, Chesler says, “it is likely that we will discover mechanisms underlying cocaine addiction that generalize more broadly to other addictive drugs.”
Discovery of Addiction-Related Genes with Advanced Mouse Resources, National Institute on Drug Abuse, grant number 2R01DA037927-06A1