Summary: New preclinical research identifies how a chromatin remodeler in the nucleus accumbens contributes to cocaine craving and relapse after withdrawal.
Source: University at Buffalo
Preclinical evidence reveals a molecular mechanism that helps explain persistent cocaine craving after abstinence and points to a potential therapeutic target.
Understanding how cocaine permanently rewires the brain is essential for developing treatments that prevent relapse. Researchers at the Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, report new preclinical findings showing that the chromatin remodeler BRG1 in the nucleus accumbens works with the transcription factor SMAD3 to regulate genes that drive cocaine-seeking behavior after withdrawal.
Led by David M. Dietz, PhD, associate professor of Pharmacology and Toxicology, the team used a rat model of cocaine self-administration followed by a week of abstinence. They observed that cocaine exposure and subsequent withdrawal increased BRG1 expression in the nucleus accumbens and strengthened the interaction between BRG1 and SMAD3. Zi-jun Wang, PhD, a postdoctoral fellow, is first author on the study.
BRG1 and SMAD3: partners in cocaine-induced plasticity
Transcription factors such as SMAD3 influence which genes are turned on or off. In 2015, the research group identified SMAD3 as a driver of relapse-like behaviors following cocaine withdrawal. The current study shows that BRG1, an adenosine triphosphatase–containing chromatin remodeler also known as SMARCA4, partners with SMAD3 after cocaine exposure. BRG1’s role is to alter chromatin structure and therefore control transcription factor access to DNA.
The investigators found that BRG1 not only increases in expression after withdrawal, but also forms larger complexes with SMAD3. This interaction enhances binding to promoter regions of target genes that are implicated in synaptic and cellular changes associated with addiction, including Ctnnb1, Mef2d, and Dbn1. These changes in gene regulation are consistent with the neuroplastic processes that underlie persistent drug-seeking and relapse vulnerability.
Functional evidence: manipulating BRG1 changes cocaine-seeking behavior
To test whether BRG1 contributes directly to relapse-related behavior, the researchers altered BRG1 function in the nucleus accumbens. Pharmacological inhibition of BRG1 using the small-molecule inhibitor PFI3 reduced cocaine-reinstatement behavior in animals, while viral-mediated overexpression of Brg1 enhanced cocaine seeking. These behavioral experiments support a causal role for BRG1 in mediating the SMAD3-dependent transcriptional program that promotes cocaine craving after withdrawal.
Implications for addiction treatment
These findings provide a more detailed mechanistic picture of how cocaine alters gene regulation and chromatin structure in the nucleus accumbens to sustain long-term changes in behavior. By identifying BRG1 as a key mediator of SMAD3-dependent chromatin remodeling and transcriptional control after cocaine exposure, the study highlights BRG1–SMAD3 interactions as a potential target for interventions designed to reduce relapse risk.
“To develop effective treatments for drug addiction, we need a precise understanding of the molecular events that maintain craving and relapse vulnerability after abstinence,” said Dietz. “Targeting the BRG1–SMAD3 axis could represent a promising approach to disrupt the pathological gene programs that support cocaine seeking.”
The study was supported in part by a National Institute on Drug Abuse grant awarded to Dietz in 2014 to investigate short- and long-term neurobiological changes (neuroplasticity) produced by cocaine addiction. Co-authors include Zi-Jun Wang, Jennifer A. Martin, Lauren E. Mueller, Aaron Caccamise, Craig T. Werner, Rachael L. Neve, Amy M. Gancarz, Jun-Xu Liu, and David M. Dietz from the Department of Pharmacology and Toxicology at the University at Buffalo, and collaborators from the Department of Brain and Cognitive Sciences at MIT.
Study overview (abstract summary)
This preclinical study examined how BRG1 interacts with SMAD3 and how this interaction affects chromatin accessibility and gene expression in the nucleus accumbens after cocaine self-administration and withdrawal. Using western blotting, co-immunoprecipitation, and chromatin immunoprecipitation, the team demonstrated increased BRG1 expression, enhanced BRG1–SMAD3 complex formation, and greater BRG1 binding to promoters of addiction-related genes following withdrawal. Behavioral tests showed that blocking BRG1 reduced cocaine-seeking, while overexpression increased reinstatement. The results indicate that BRG1 is a key regulator of SMAD3-dependent cellular and behavioral plasticity that mediates cocaine seeking after abstinence.
Reference: BRG1 in the Nucleus Accumbens Regulates Cocaine-Seeking Behavior. Biological Psychiatry. Published online May 2016. doi:10.1016/j.biopsych.2016.04.020