Studies in postmortem brain tissue by researchers at the Icahn School of Medicine at Mount Sinai have found that individuals with cocaine use disorder (CUD) exhibit gene expression changes in two brain regions, the nucleus accumbens (NAc), which is associated with reward, and the caudate nucleus (CN), which is implicated in mediating habit formation.

The team’s findings were supported by their analysis of transcriptomic data from cocaine self-administering mouse models, which suggested evolutionarily conserved gene networks in CUD. The studies also found that genes linked to schizophrenia and major depressive disorder (MDD) were dysregulated in CUD, suggesting that these two complex disorders may recruit some of the same gene regulatory and neural circuit systems. Conversely, the study highlighted differences in transcriptional abnormalities within the NAc linked to CUD, compared with those found in datasets published on opioid use disorder (OUD).

The collective findings, the researchers suggested, could help the development of targeted treatments that are specific to CUD. “Together, these findings represent a considerable advance in our understanding of the molecular abnormalities in cocaine use disorder and provide a highly valuable resource for future investigations,” said Eric J. Nestler, MD, PhD, the Nash Family professor of neuroscience, director of the Friedman Brain Institute, dean for academic affairs at Icahn Mount Sinai, and CSO of the Mount Sinai Health System. “ … we found many previously known changes associated with CUD in both brain regions but because of the size of the cohort (number of brains), their quality, and the comprehensive nature of RNA-sequencing, we were also able to discover large numbers of changes not previously known,” Nestler told GEN. “These discoveries in turn now provide a template for future efforts to better understand CUD and develop more effective treatments.”

Nestler is senior author of the investigators’ published paper in Science Advances, which is titled “Convergent abnormalities in striatal gene networks in human cocaine use disorder and mouse cocaine administration disorders.” In their paper the team concluded, “Overall, this study provides a comprehensive molecular description of the transcriptional signatures associated with cocaine use in humans and highlights the validity of animal models in gaining mechanistic insight into the neuronal subtype–specific function of conserved striatal gene networks that drive molecular alterations in CUD.”

CUD is a chronic, relapsing brain disorder for which there are currently no FDA-approved medication treatments. As the authors commented, CUD represents a major public health problem that is associated with substantial morbidity and mortality. “CUD is an intractable syndrome, and rising overdose death rates represent a substantial public health crisis that exacts tremendous personal and financial costs on patients and society … Within the United States, the rate of cocaine overdose deaths has markedly risen—almost threefold—over the past decade,” they stated.

While it is hypothesized that regulation of gene expression in the brain’s reward and motivational centers plays a critical role in the persistent behavioral changes that define addiction, knowledge remains limited of the maladaptive gene activity in these circuits that is caused by chronic cocaine use, and which underlies CUD. “While the biological effects of repeated cocaine use have been a major focus of preclinical research in animal models, CUD remains incompletely understood and insight into the cocaine-related molecular alterations in the human brain that characterize CUD is narrow,” the investigators stated.

To address the existing knowledge gap, the researchers performed RNA sequencing (RNA-seq) on both ventral (NAc) and dorsal (CN) striatum postmortem tissue from 25 individuals with CUD, and from 20 matched control subjects. They aimed to characterize transcriptome-wide changes in gene expression within the two brain regions, and identify differentially expressed transcripts (DETs). The NAc and CN are striatal brain regions that are “heavily implicated in CUD,” the investigators noted. Nestler further explained to GEN, “It is a challenge to obtain the brains of people with CUD for research. We benefited tremendously from the outstanding work of our co-author, Deborah Mash, who collected the brains we used. Postmortem human brain tissue is most useful when it can be secured and frozen in less than 12–24 hr of death and when the cause of death is sudden (so as to avoid brain changes during a prolonged illness). And to have the brains of healthy controls of similar demographics and cause of death. The availability of this collection made the current study possible.”

With data generated from what they suggest is the largest and most diverse cohort examined to date, the team found that the observed changes in the NAc and CN, which are key contributors to the persistent behavioral abnormalities seen in addiction to drugs, occur because cocaine use sets off a series of chemical reactions that lead to increases in the amount of mRNA being produced from some of the affected genes in these two brain regions, whereas the activity of other genes decreases.

The research team analyzed how cocaine use disorder impacts gene activity in the striatum, a brain region involved in motivation, reward, and habit formation. They found that cocaine use alters gene networks that control neurotransmission in two striatal brain regions, the nucleus accumbens (NAc) and the caudate nucleus (CN). The team likewise analyzed gene activity in mice that self-administered cocaine and found that many of the cocaine-related changes seen in humans were also present in these mice. Their analyses revealed that human gene modules governing brain plasticity are similarly altered by cocaine in a particular subtype of neuron in mice that respond to dopamine, the D1 medium spiny neurons (D1 MSNs). Together, these conserved molecular signatures indicate that key gene networks may be critical to the development of cocaine use disorder, and that animal models are valuable in studying how cocaine alters the human brain. [Ashley M. Cunningham, MS]

Changes in gene expression levels, and so the amount of mRNA produced, lead to changes in the amount of proteins that are produced. The research team found a significant overlap between the RNAs expressed in the two brain regions, suggesting that these molecular changes may be key to the development and maintenance of cocaine use disorder. Their results indicated that neuroinflammatory processes are suppressed and that synaptic transmembrane transporters and ionotropic receptors—proteins that control how nerve cells communicate with one another in the brain—are enriched in the striatum of people with CUD.

Cocaine increases the amount of the neurotransmitter dopamine at synapses, or junctions between two brain cells where electrical signals are converted into chemical signals. By doing so, the research team found, cocaine sets off a cascade of events that activate a chemical messenger in the brain called cyclic AMP, which then triggers changes in gene expression. And as the authors noted, “Our findings further support the hypothesis that cocaine-responsive genes participate in the vulnerability to substance use disorders, as we found a convergence of up-regulated DETs in individuals with CUD and genes associated with risk-taking behavior.”

Philipp Mews, PhD, instructor of neuroscience at Icahn Mount Sinai and co-first first author of the paper, together with Ashley M. Cunningham, a neuroscience PhD student, further stated, “In addition to the new insights into the molecular changes that cocaine use confers, we found that people with cocaine use disorder have dysregulated genes associated with schizophrenia and major depressive disorder, which indicates that these disorders may share some underlying gene regulatory and neural circuit systems.” Nestler expanded to GEN, “All mental illnesses as currently diagnosed are syndromes, not specific diseases. Syndromes are a collection of many diseases of different etiologies that share symptoms. The partial overlap that we see between gene expression abnormalities in the brain in CUD with genome sequence variations that control risk for other psychiatric disorders suggests that there is considerable overlap between the genetic diatheses for many mental disorders. The same conclusion is being reached by genetic studies, which show this overlap in heritable diatheses more directly.”

Importantly, Mews added, “… the transcriptional abnormalities—in particular, the neuroinflammatory responses that are suppressed in the nucleus accumbens of people with cocaine use disorder—are directionally opposite of the proinflammatory cascade responses conferred by opioid use disorder. The observation that there are distinct molecular changes conferred by each of the two substance use disorders could be valuable for the development of targeted, effective treatments specific to cocaine use disorder.” Nestler commented to GEN, “… we see major differences in inflammatory pathways between the two disorders, which was unexpected. This finding highlights the differences between CUD and OUD and the different types of therapeutics that would help one of the disorders or the other.”

Because it is difficult to directly study how drugs like cocaine affect the human brain, researchers often use animal models to study their effects. However, a key question is whether what is learned from these animal models can be extrapolated to what happens in the brains of humans who use cocaine. “Our research team looked at studies performed in mice that were given the opportunity to self-administer cocaine and compared the resulting molecular changes to those seen in postmortem brain tissue of people with cocaine use disorder,” Nestler stated. “Our analysis revealed strikingly similar changes in the brain’s gene expression profiles in both the mice and humans, validating the use of mouse models to study the pathophysiological basis of cocaine use disorder.”

He further explained to GEN, “We show that large swaths of the molecular abnormalities seen in the NAc of humans with CUD are replicated in mice that self-administer cocaine. This provides the most robust validation of that mouse model to date and indicates that insights from the mouse model can be used to better understand and treat CUD … we are taking several of the lead findings and exploring ways to take advantage of them for new therapeutics.”

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