It’s no secret that long-term cocaine use alters the way some of your genes are expressed, resulting in changes to the structure and connectivity of your brain. These changes can lead to intense cravings for the drug, which is partly why so many recovering addicts tend to relapse even after they have become clean. Until now, the mechanisms behind these genetic alterations had not been well understood, although scientists have now identified a protein that appears to mediate the process.
Previous research had already shown that a transcription factor called SMAD3 is increased in cocaine-addicted rats around a week after going through withdrawal. Transcription factors control which genes are expressed and which are not, by interacting with proteins that remodel chromatin, the genetic material that makes up chromosomes. In particular, SMAD3 increases the expression of certain genes that control the formation of brain connections – or synapses – in a part of the brain called the nucleus accumbens (NAc).
Since the NAc is part of the brain’s reward center, any structural changes that occur here are likely to have a major impact on reward-seeking behavior, which would seem to explain why rats continue to self-administer cocaine even once they are no longer in withdrawal. To learn more about how SMAD3 increases the expression of certain genes related to cocaine use, the team used chromatin immunoprecipitation techniques to observe which proteins this transcription factor interacts with in these rats.
Reporting their findings in the journal Biological Psychiatry, the researchers reveal that a chromatin remodeler called BRG1 is not only increased by the onset of cocaine addiction, but the interactions between this protein and SMAD3 are also amplified. In particular, BRG1 binds to the promoter regions of certain genes in order to enable their expression by SMAD3. Since many of these genes are responsible for the creation of synapses in the NAc, it seems likely that this interaction is partly responsible for the cocaine cravings experienced by the rats involved in the study.
To confirm this, the team injected the rats with chemicals that block BRG1, and found that this eliminated their cocaine-seeking behaviors. They then infected the rats with a virus that caused them to create more BRG1 than normal, discovering that this intensified their cocaine cravings.
As well as improving our understanding of how drug addiction changes the brain in order to create cravings, this research also highlights a possible avenue for the creation of new treatments, by revealing how the inhibition of BRG1 puts a stop to certain addictive tendencies.