Everything we do is the result of our brains firing off a series of signals. These neurobiological events have long fascinated scientists interested in questions surrounding why we do what we do and how to help people when thing go awry in the brain.
Greg Sartor, an assistant professor of pharmacology and toxicology at the University of Connecticut’s School of Pharmacy, has dedicated his career to understanding how molecular-scale events in the brain drive substance use disorder.
As an undergraduate at the University of Mississippi, Sartor joined a behavioral pharmacology lab studying new treatments for anxiety. As a graduate student at the Medical University of South Carolina, Sartor honed his focus onto substance use disorder and the neural circuits that drive drug craving and relapse.
While working on his Ph.D., Sartor realized he lacked training in the molecular aspects of his research, which he acquired through postdoctoral training at the University of Miami Miller School of Medicine.
Sartor, now the head of his own lab, currently focuses on epigenetic mechanisms involved in substance use disorder. Epigenetics is the study of how environmental factors affect gene expression.
“The environmental factor for substance use disorder is the drug of abuse,” Sartor says. “Chronic drug use leads to maladaptive changes in gene expression in the brain that promote drug intake and relapse. These changes in gene expression are mediated, in part, by epigenetic mechanisms.”
Sartor is currently working on new epigenetic therapeutics that target BET (Bromodomain and extra terminal domain) proteins to block and reverse transcription alterations caused by drug abuse. Undoing these changes could reduce cravings for the drug of abuse and incidences of relapse. In animal models of cocaine use disorder, this treatment has proven to reduce drug-seeking behaviors.
The main problem with developing new treatments for psychiatric diseases, including substance abuse disorder, is that many molecules cannot cross the blood-brain barrier. This barrier is a highly selective filtering mechanism in the brain which prevents pathogens circulating in the blood from reaching the brain.
“This barrier also prevents many therapeutics from entering the brain, which is a major impediment for the advancement of new treatments for substance use disorder,” Sartor says.
Through a grant from the National Institute on Drug Abuse, Sartor is collaborating with Raman Bahal, also an assistant professor in the School of Pharmacy, who specializes in making nanoparticles for drug delivery.
The nanoparticles Bahal creates allow the drug to pass through this barrier and reach the brain.
By combining Sartor’s knowledge of brain epigenetics and substance use disorder and Bahal’s knowledge of nanoparticle delivery systems, the two have successfully partnered on this initiative.
“By combining our two areas of expertise, we’re able to accomplish a goal we otherwise would not be able to do individually,” Sartor says.
Sartor says they hope to build on this research by eventually developing a nanoparticle that can selectively bind to the specific brain cells affected by the drug of abuse.
Many current therapies cannot distinguish between brain cell types and thus bind to all cells. This results in less effective treatment with more side effects.
Sartor hopes to determine which kinds of brain cells are impacted by substance use disorder and develop treatments that can target them selectively.
“In our ongoing research, we’re using more precise measures to target and manipulate molecular functions in a cell-type-specific manner,” Sartor says.
Researching for the Moment
For most of his career, Sartor’s work has focused on cocaine and other psychostimulants. This is an important topic, as there are no FDA-approved treatments for cocaine addiction. It is also a result of timing.
Many of Sartor’s mentors began working during the crack cocaine epidemic of the 1980s, and continued to train their students to work on cocaine addiction.
However, Sartor is looking to transition his work to opioids to help address the contemporary epidemic raging in the United States.
“Because of the ongoing opioid epidemic, we are now testing epigenetic-based therapeutics for the treatment of opioid use disorder,” Sartor says.
While the news cycle has shifted much of its attention to the COVID-19 pandemic, the opioid crisis is still a serious threat to public health. Studies suggest drug overdoses and incidences of relapse have increased during the pandemic.
“The opioid crisis is still ongoing, and it will continue once the COVID pandemic subsides,” Sartor says. “We must continue to develop more effective treatments for opioid use disorder.”
While scientists have identified multiple new therapeutic targets, there has been a lack of action on the part of pharmaceutical companies to turn this science into treatments. Most treatments used today were developed in the 1960s or 1970s.
“Many novel molecular targets have been identified in animal models of addiction, but why isn’t this knowledge being translated into clinical therapeutics for patients?” Sartor says. “Pharmaceutical companies are resistant to develop and test new treatments for substance use disorder.”
Sartor attributes much of this inertia to the stigma surrounding substance use disorder. He says many people do not view psychiatric disorders like substance abuse in the same light as something like cancer or heart disease. People often lack an understanding of the underlying causes of these conditions, he explains.
“That’s a challenge,” Sartor says. “We as researchers have to do a better job communicating to the public that this a chronic brain disease and not a moral failing. Drug abuse causes physical changes in the brain that limit a person’s ability to stop using drugs.”
Training Young Researchers
Sartor says seeing his students develop into independent researchers and thinkers is one of the highlights of his role as a principal investigator.
“At the beginning, many of the students don’t have any experience working in a lab,” Sartor says. “But over months and years, they develop into independent researchers who are able to conduct their own experiments, problem-solve, and ask novel research questions I haven’t thought of.”
Sartor says his career in research has taught him the value of having the patience to learn new skills and work through problems.
“To be a researcher, you have to be patient and persistent, because many of the questions we’re asking are complex. Working in the lab is an ongoing learning experience that takes a lot of time and dedication, but making new discoveries makes it a worthwhile endeavor.”