Anhedonia in cocaine use disorder is associated with inflammatory gene expression

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.

Peripheral blood microRNA levels in females with cocaine use disorder

“…Furthermore, the PDK4 gene, which is another regulator of glucose metabolism, was also a predicted target of miR-181. Evidence suggests that individuals with CUD present altered mRNA levels of PDK4 in their peripheral blood cells, particularly in those patients with high levels of depression (Fries, Khan, Stamatovich et al, 2018). Therefore, it is possible that alterations in miR-181 and miR-124 expression in the blood are relevant to metabolic changes that occur in individuals with CUD, particularly during periods of drug withdrawal.…”

“…The hallmarks of the systemic pathophysiology of cocaine use disorder (CUD) include metabolic syndrome, as well as altered levels of neurotrophins, oxidative stress parameters, neuroendocrine hormones, and inflammatory cytokines (Grassi-Oliveira, Pezzi, Daruy-Filho et al, 2012;Levandowski, Viola, Prado et al, 2016;Viola, Tractenberg, Kluwe-Schiavon et al, 2015;Viola, Tractenberg, Levandowski et al, 2014;Virmani, Binienda, Ali et al, 2007;Zaparte, Viola, Grassi-Oliveira et al, 2015). Recent findings suggest that cocaine-induced regulation of these signaling pathways in peripheral blood cells are mediated through persistent changes in gene expression (Fries, Khan, Stamatovich et al, 2018). Therefore, epigenetic mechanisms, including DNA modifications, chromatin remodeling factors, histone modifications, and various classes of non-coding RNAs, may be fundamental processes implicated in the molecular signature of CUD in both the brain and systemically (Doura & Unterwald, 2016;Leighton, Zhao, Li et al, 2018;Nestler, 2014;Viola, Wearick-Silva, De Azeredo et al, 2016).…”

Interaction between maternal immune activation and peripubertal stress in rats: impact on cocaine addiction-like behaviour, morphofunctional brain parameters and striatal transcriptome

“…For example, the gene for Neurogranin (Nrgn), present in this ontology (Table S3), responds to cocaine in several ways. For example, it is induced by cocaine in neural progenitor cells [33] and it is related to anhedonia in cocaine users [34]. Moreover, neurogranin in the NAcc also regulates the sensitivity to other drugs, such as alcohol [35].…”

Additive, synergic and antagonistic interactions between maternal immune activation and peripubertal stress in cocaine addiction-like behaviour, morphofunctional brain parameters and striatal transcriptome

“…We have observed that MIA affected a gene ontology with potential implication for this pattern of results in the NAcc: 'regulation of long-term synaptic potentiation', which may affect the capacity for plasticity of the NAcc upon exposure to cocaine. For example, the gene for Neurogranin (Nrgn), present in this ontology (Figure 5 A, C; Table S3), responds to cocaine in several ways: it is induced by cocaine in neural progenitor cells (35) and it is related to anhedonia in cocaine users (36). Moreover, neurogranin in the NAcc also regulates the sensitivity to other drugs such as alcohol (37).…”