Cocaine Use Alters Gene Expression in Brain Reward Circuits
Mount Sinai researchers investigate transcriptome-wide alterations in response to cocaine self-administration in mice
Unique genetic changes in the brain’s reward circuitry are associated with cocaine use, including first-time use, withdrawal, and re-exposure to the drug after prolonged withdrawal, according to a study conducted at the Icahn School of Medicine at Mount Sinai and published Thursday, May 31, in the journal Biological Psychiatry. The findings reveal important information on how cocaine addiction reprograms gene expression and provides a look into the molecular basis of cocaine addiction in unprecedented detail.
In the study, mice were allowed to self-administer cocaine as a model of human addiction, and the gene expression changes were associated with their addiction-like behavior. Mount Sinai researchers examined six regions composing the brain’s reward circuitry, providing an enormous resource of information for studying the biological basis of cocaine addiction.
“This study is the first of its kind to characterize the complete genome-wide map of gene expression or RNA expression in the brain during the life-cycle of cocaine self-administration,” said senior author Eric Nestler, MD, PhD, Nash Family Professor of Neuroscience and Director of The Friedman Brain Institute at the Icahn School of Medicine at Mount Sinai.
To characterize the entire life-cycle, Dr. Nestler and colleagues identified differences in gene expression when mice were first exposed to cocaine, in cocaine-addicted mice after a short (24 hours) or long (30 days) period of withdrawal from the drug, and when addicted mice were re-exposed to cocaine after the 30-day withdrawal. Gene expression was determined by performing RNA-sequencing on six brain regions isolated from mice under these different conditions. This experimental design allowed the research team to study how gene expression across brain reward regions changes over time as a result of volitional cocaine intake.
Previous studies have been limited—focusing either on specific genes, a particular brain region, or one aspect of cocaine addiction—and molecular studies aimed at improving addiction treatment have been complicated by alterations in genes that differ throughout the brain, increasing in some regions and decreasing in others.
The new analysis revealed changes in many genes involved in key biological processes, providing clues into the brain functions that might lead to cocaine addiction. Many changes were in the same direction (increased or decreased) throughout the reward circuitry, suggesting they may be good targets for new treatments. Interestingly, the size of the changes depended on the condition—where the mice were in the life-cycle of cocaine self-administration—highlighting unique gene changes associated with the different stages of drug-taking. The study also identified several molecules responsible for regulating the expression of genes associated with addiction-like behavior.
“This study elegantly highlights the complexity of the brain’s molecular response to self-administered cocaine, pointing to mechanisms that might be targeted by treatments,” said John Krystal, Editor of Biological Psychiatry.
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