NEW YORK – The University of California San Diego School of Medicine recently received an $8 million grant from the National Institute on Drug Abuse (NIDA) to study the genetics of substance abuse disorders.
The NIDA P30 Core Center of Excellence grant will support a specialized colony of outbred rats, the maintenance and distribution of data from those rats, smaller grants and services to support early-stage investigators, and education for high school and undergraduate students.
Abraham Palmer, professor and vice chair for basic research in the School of Medicine's Department of Psychiatry and principal investigator on the grant, said that this grant effectively extends a prior NIDA P50 grant that has supported drug abuse research at UCSD for the past 10 years.
That earlier grant, Palmer said, enabled multiple investigators to gather the data needed to apply for separate grants for their own projects. "We now have lots of projects that are independently funded," Palmer said, "and we're now providing some core services to support an ecosystem of interacting grants."
One of those core services is to provide researchers with heterogeneous stock (HS) rats, which are highly prized in addiction genetics research for their wide range of individual drug-seeking behaviors.
The HS rat colony is maintained by both Wake Forest University and UCSD. Leah Solberg Woods, professor of medicine at Wake Forest, maintains the primary colony, of which UCSD maintains a satellite. Palmer previously led the NIDA Center for Genome-Wide Association Studies in Outbred Rats, based at the University of Chicago.
Palmer explained that in contrast to inbred animals, which are homozygous at all genetic loci, outbred animals are considerably less uniform, which contributes to their greater variation in individual behaviors.
"They don't have the same genetic variance as people, but they allow us to detect how genes influence behavior and are associated with behavior through the lifespan," said Elissa Chesler, professor of addiction research and animal model expert at the Jackson Laboratory. Chesler is also a member of UCSD's advisory board, although her work is not supported by that institution's NIDA grant.
Chesler praised Palmer and Woods' efforts to use HS rats to improve knowledge of rat genetics over the past 10 years, particularly with respect to segregating variation in that model organism. In the case of laboratory mice, Chesler said, many of the alleles that would have contributed to drug-seeking and drug-taking behaviors have been bred out of the population, lost as collateral damage in a broader effort to breed more docile easy-to-handle mice.
"They developed tools and capabilities to do [in rats] what we've been able to do in mice for a long time," she said, "which is to readily map genes and variants associated with behavioral variation."
One of these tools is RATTACA, a database and suite of bioinformatic tools to predict phenotypes of newborn HS rats based on their genotype, which is intended to enable even non-geneticists to study individual differences in rat behavior using statistically valid methodology.
The database's name is an allusion to the 1997 dystopian science fiction film GATTACA, in which people's place in society is determined by predictions made from analyzing their genomes. "We gave it a cute and memorable name," Palmer said, "but it's actually a serious project, and we think that there is an untapped market for this."
Data contained in RATTACA comes from genotyping HS rats at low depth –– approximately 0.25X coverage –– and imputing their genotypes along with millions of single-nucleotide polymorphisms with an accuracy better than 99 percent.
"One of our advantages is that, since there are only eight founders, and since we've deeply sequenced those eight founders, our algorithm is really good at figuring out from this very light coverage which founder haplotype is present at [a] particular part of the chromosome," Palmer said.
A key goal in building RATTACA was to enable more precise methods for disambiguating underlying genetic predispositions to drug-related behaviors in drug-naïve rats from gene expression changes caused by drug use.
In prior studies that Palmer has conducted using rats and cocaine, he said very clear changes in gene expression can be seen between rats that self-administer lots of cocaine and their more moderate companions, but it's often unclear whether those changes might simply occur because of the amount of cocaine administered.
"It's easy to imagine that cocaine would change gene expression," Palmer said, "but alternatively, it might be that the gene expression differences are due to the preexisting gene expression differences that actually cause some of them to take a lot of cocaine and cause others to take very little cocaine."
Supported by the NIDA P30 grant, Palmer and his colleagues will be able to supply researchers with fully genotyped "RATTACA rats" in a highly efficient manner.
"In a day," he said, "we can run an analysis that would take a lot of labs six months to set up and run."
Under the P30 grant, UCSD is currently supporting roughly a dozen pilot projects, all using HS rats to investigate various aspects of drug dependency.
Francesca Telese, associate professor of psychiatry at UCSD, is one beneficiary of this support. Her lab is currently using single-cell genomic techniques to study genetic and epigenetic changes linked to the susceptibility and resilience to substance abuse disorders in complex animal models of addiction.
"We hope to identify key genetic risk factors and potential therapeutic targets for substance abuse disorders," she said via email. "Our current work with highly genetically diverse HS rats provides enormous advantages to studying extremely complex traits in controlled experimental settings, which are not feasible in the human population," Telese added. "Our goal is to translate findings from HS rats to human populations."
In both ongoing and future studies, Telese aims to leverage high-resolution, multiomic data from humans affected by substance abuse disorders to identify conserved molecular pathways and genetic factors associated with addiction susceptibility across species.
Telese and Palmer have collaborated in past research, wherein single-cell RNA-seq studies led to the discovery that vulnerability to cocaine addiction affects the way cells produce and use energy. Specifically, they discovered in HS rats that a gene called Glo1 altered animal responses to cocaine and that these responses could be pharmacologically modulated with the Glo1 inhibitor S-bromobenzylglutathione cyclopentyl diester (pBBG).
"We were guided by the single-cell RNA-seq results that pointed us in an unexpected direction," Palmer said, "and that led us to look at this compound, which does look like it would have promise for treating cocaine addiction."
In particular, it shows evidence in rats for treating the most troublesome part of addiction, which Palmer said is not the acute withdrawal but rather the long-term tendency to relapse into drug-seeking behavior. Although Palmer said that pBBG itself might not have the properties needed to become an effective therapy itself, such as oral availability and a long half-life, he hopes that it can serves as something of a launchpad for further drug development.
"Nothing would make me happier than seeing this research lead to practical applications that would help people," Palmer said.