With their sights on developing more effective treatments for addiction, scientists in recent years have been making rapid progress in understanding the biology of addiction. They have started to decode “epigenetic” processes―the adding and subtracting of chemical “marks” on an individual’s DNA―linked to drug addiction (as well as other psychiatric illnesses). These epigenetic marks enable cells to activate or de-activate genes without altering the underlying DNA sequence, and they can be heritable.
Foundation Scientific Council member and 1996 NARSAD Distinguished Investigator Grantee Eric Nestler, M.D., Ph.D., has been a leader in this area. In new work to study how epigenetic marks influence addiction to cocaine, he led a team of researchers across institutions (including the Icahn School of Medicine at Mount Sinai, Massachusetts Institute of Technology, McGill University, The Rockefeller University, University of Buffalo, University of California-Los Angeles and the University of Maryland), including 2010 NARSAD Young Investigator Grantee, Anne Schaefer, M.D., Ph.D. The research team made an unexpected new discovery. The results of their work were published online on March 2nd in the journal Nature Neuroscience.
The research team performed experiments in mice to better understand how a protein called G9a is associated with addiction. It had already been established that in neurons located in a part of the brain centrally involved in addiction, the nucleus accumbens (NAc), G9a protein is less active than in healthy, non-addicted brains. In this work, the researchers sought to understand what specifically G9a does that affects both the body’s physiological response and a person’s behavior toward cocaine.
Using different mouse models with the gene encoding G9a either missing or present and overactive, they discovered that in the early stages of a mouse’s development, the presence or absence of G9a was determinant in the long-term development of neural cells. When G9a was absent, they found evidence that a subtype of NAc neurons changed their developmental path in a way that made the mice unusually sensitive to the “reward” generated by cocaine as adults.
With these new findings, Dr. Nestler and team hope to have identified a new biological target for medications to treat this hypersensitivity when it results in addiction. To date, very few medications have proven effective in resolving the compulsion to use (or seek reward) in addiction.
Other team members who have received NARSAD Grant support include: Mary Kay Lobo, Ph.D. (2010); Gustavo Turecki, M.D., Ph.D. (2000 and 2008); Rachael Neve, Ph.D. (1997) and Ming-Hu Han, Ph.D. (2007).