University of California San Diego School of Medicine has received a five-year, $8 million grant from the National Institute on Drug Abuse (NIDA) to study the genetics of substance use disorders. The grant will support a NIDA P30 Core Center of Excellence, which ultimately aims to understand why some people are more susceptible to addiction than others. This knowledge will be instrumental in developing more personalized and effective treatments to address the public health crisis posed by substance use disorders, which affect tens of millions of Americans at an enormous cost to the U.S. economy.
Some people who drink alcohol or try illicit substances become addicted to these drugs, but most do not, according to principal investigator Abraham Palmer, Ph.D., professor and vice chair for basic research in the School of Medicine's Department of Psychiatry.
"And that vulnerability is partially genetic," said Palmer. "We're very interested to know: what are the genetic differences between people who develop substance use disorders and those who do not?"
The P30 center uses heterogeneous stock (HS) rats as a model organism to address this question because, like humans, they display individual differences in drug-seeking behaviors and their genomes lend themselves to genotype-phenotype association studies. They also share many of the same genes that control reward pathways in the brain thought to be important in substance use disorders. The center will build upon 10 years of NIDA-supported research mapping the relationship between HS rat genotypes and these complex behavioral traits.
We have an enormous database of both the behavior of the animals and of the genetic characteristics of those animals. And that allows us to look at the relationship between the genotype of an animal and its phenotype to understand which important genetic differences shape certain behaviors."
Abraham Palmer, Ph.D., professor and vice chair for basic research in University of California San Diego School of Medicine's Department of Psychiatry
Research by Palmer, Francesca Telese, Ph.D., associate professor of psychiatry, and colleagues used single nucleus RNA sequencing to compare gene expression of individual brain cells in the amygdalas of HS rats who sought large amounts of cocaine versus those who abstained. The amygdala is an area of the brain found in all mammals, including humans, and it plays a central role in addiction.
"By looking at these single nuclei, we were able to see lots of differences that persist weeks after the drug has gone away," said Palmer.
One of the strongest patterns was a difference in genes related to oxidative stress, which affects cellular energy metabolism. The brain cells of the cocaine-preferring rats also showed increased GABAergic signaling, which regulates cognition, emotion and motivation. In addition, these rats engaged in relapse-like behavior.
"Our results suggested to us that vulnerability to cocaine addiction affects the way cells produce and use energy," said Telese.
Glyoxalase 1 (also known as Glo1) is a gene that codes for an enzyme which mediates the relationship between oxidative stress and energy metabolism. The researchers found that inhibiting the enzyme's activity using a molecule called pBBG reversed the drug-seeking behavior of rats who had previously shown a preference for cocaine.
"Those animals dramatically reduced the amount of cocaine that they took, whereas the normal animals didn't show any response to the drug," said Palmer. "It's as if the drug is specifically doing something in these vulnerable individuals."
Based on these findings, the researchers believe Glo1 could be a promising target for the development of new therapeutic compounds to treat substance use disorders in humans. And Glo1 is just one of many genes the center is investigating as potential drug targets. With the costs of addiction to individuals and society so high, better treatment options are sorely needed.
The center supports a growing national and international community of researchers studying the genes behind substance use disorders. It conducts genome-wide association studies and maintains and distributes data from its vast repository of genotype-behavioral phenotype relationships to other investigators. Its comprehensive database allows the center to provide researchers with drug-naive HS rats at predictably high and low genetic risk for drug abuse, which make them a particularly good model for studying human addiction.
To foster innovation and support workforce development, the center also provides grants and services to early-stage investigators for pilot studies. In addition, it offers immersive research opportunities for high school and undergraduate students in the laboratories affiliated with the center. Research supported by the center could lead to new treatments for other psychiatric disorders as well.
Additional principal investigators (PIs) on the project include Oksana Polesskaya, Ph.D., in the Department of Psychiatry at UC San Diego, Leah Solberg Woods, Ph.D., professor of physiology and pharmacology at Wake Forest University, and Pejman Mohammadi, Ph.D., associate professor at the Seattle Children's Research Institute and the Department of Genome Sciences at University of Washington School of Medicine.
The title of the grant, awarded by the National Institute on Drug Abuse, is "Center for Genetics, Genomics, and Epigenetics of Substance Use Disorders in Outbred Rats" (P30DA060810).
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