A study in Biological Psychiatry has identified unique genetic changes in the brain’s reward circuitry that are associated with cocaine use, including first-time use, withdrawal, and re-exposure to the drug after prolonged withdrawal. The findings reveal important information on how cocaine addiction reprograms gene expression and provide insight 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.

“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.

Previous studies have been limited, focusing either on specific genes, a particular brain region, or one aspect of cocaine addiction. But 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.

“This study is the first of its kind to characterize the global transcriptome in brain during the life-cycle of cocaine self-administration,” said senior author Eric Nestler, MD, Ph.D., of Icahn School of Medicine at Mount Sinai, New York. The researchers examined six regions composing the brain’s reward circuitry, providing an enormous resource of information for studying the biological basis of cocaine addiction.

To characterize the entire life-cycle, Dr. Nestler and colleagues looked for 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. “The experimental design thus allowed us to study how gene expression across brain reward regions changes over time as a result of volitional cocaine intake,” said Dr. Nestler.

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