Grant: Project Grant

The overarching goal of this research is to understand how interactions between inherited genes and early drug use can affect vulnerability to addictions. Genes determine how fast or slow or accurately particular proteins are produced, thereby affecting all aspects of our biology. Drug use can alter the expression level of genes leading to long-lasting changes in brain and behavior. Until recently, it has not been possible to study these "epigenetic" effects in much detail. Now, thanks to two major advances, we will conduct the following studies. First, we will use a recently developed brain imaging technique (PET with the tracer, [11C]Martinostat) to measure, in people and research animals, the effects of cocaine use on "HDACs," a class of enzymes that affects gene expression. Second, we will use new gene editing techniques to experimentally induce HDAC changes and measure the effects on gene expression and cocaine use in laboratory animals. Third, the gene expression changes seen in the research animals will serve as targets to investigate in postmortem brain tissue donated from people who had struggled with cocaine addiction. We are starting with the study of addictions because understanding better the causes of addiction could help us develop effective treatment and prevention strategies. And the need for new treatments is urgent. Substance use is associated with economic costs greater than all other psychiatric disorders combined, and the present research is expected to identify critical genes, enzymes, and brain pathways that could serve as important therapeutic targets. If the strategy is successful, the same approach can and will be applied to other problems.