Abstract
Treatments for Cocaine Use Disorder (CUD) are variably effective, and there are no FDA-approved medications. One approach to developing new treatments for CUD may be to investigate and target poor prognostic signs. One such sign is anhedonia (i.e. a loss of pleasure or interest in non-drug rewards), which predicts worse outcomes in existing CUD treatments. Inflammation is thought to underlie anhedonia in many other disorders, but the relationship between anhedonia and inflammation has not been investigated in CUD. Therefore, we assessed peripheral genome-wide gene expression in n = 48 individuals with CUD with high (n = 24) vs. low (n = 24) levels of anhedonia, defined by a median split of self-reported anhedonia. Our hypothesis was that individuals with high anhedonia would show differential gene expression in inflammatory pathways. No individual genes were significantly different between the low and high anhedonia groups when using t-tests with a stringent false discovery rate correction (FDR-corrected p < 0.05). However, an exploratory analysis identified 166 loci where t-tests suggested group differences at a nominal p < 0.05. We used DAVID, a bioinformatics tool that provides functional interpretations of complex lists of genes, to examine representation of this gene list in known pathways. It confirmed that mechanisms related to immunity were the top significant associations with anhedonia in the sample. Further, the two top differentially expressed genes in our sample, IRF1 and GBP5, both have primary inflammation and immune functions, and were significantly negatively correlated with total scores on our self-report of anhedonia across all 48 subjects. These results suggest that prioritizing development of anti-inflammatory medications for CUD may pay dividends, particularly in combination with treatment-matching strategies using either phenotypic measures of anhedonia or biomarkers of inflammatory gene expression to individualize treatment.
Highlights
Cocaine use disorder (CUD) affects approximately 913,000 people aged 12 or older in the United States, and constitutes a substantial burden on the health care system [1,2]
A better understanding of the biological and psychological underpinnings of these poor prognostic signs may critically assist the development of novel effective treatments for CUD
We examined genome-wide gene expression in peripheral blood mononuclear cells, with the hypothesis that participants with CUD and high levels of anhedonia would display a unique expression of inflammatory pathways, compared to individuals with CUD and low anhedonic symptoms
Summary
Cocaine use disorder (CUD) affects approximately 913,000 people aged 12 or older in the United States, and constitutes a substantial burden on the health care system [1,2]. Many treatments have been attempted for CUD, including psychosocial therapies and various pharmaceutical interventions. Psychosocial interventions show variable efficacy, and to date, no pharmaceutical interventions are FDA approved. Further investigation of the psychopathological manifestations and causes of CUD is needed to develop more effective therapies. One approach may be to identify symptoms associated with poor treatment outcomes, and investigate the mechanisms underlying these symptoms. A better understanding of the biological and psychological underpinnings of these poor prognostic signs may critically assist the development of novel effective treatments for CUD
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