Cocaine induces paradigm-specific changes to the transcriptome within the ventral tegmental area

Abstract

During the initial stages of drug use, cocaine-induced neuroadaptations within the ventral tegmental area (VTA) are critical for drug-associated cue learning and drug reinforcement processes. These neuroadaptations occur, in part, from alterations to the transcriptome. Although cocaine-induced transcriptional mechanisms within the VTA have been examined, various regimens and paradigms have been employed to examine candidate target genes. In order to identify key genes and biological processes regulating cocaine-induced processes, we employed genome-wide RNA-sequencing to analyze transcriptional profiles within the VTA from male mice that underwent one of four commonly used paradigms: acute home cage injections of cocaine, chronic home cage injections of cocaine, cocaine-conditioning, or intravenous-self administration of cocaine. We found that cocaine alters distinct sets of VTA genes within each exposure paradigm. Using behavioral measures from cocaine self-administering mice, we also found several genes whose expression patterns corelate with cocaine intake. In addition to overall gene expression levels, we identified several predicted upstream regulators of cocaine-induced transcription shared across all paradigms. Although distinct gene sets were altered across cocaine exposure paradigms, we found, from Gene Ontology (GO) term analysis, that biological processes important for energy regulation and synaptic plasticity were affected across all cocaine paradigms. Coexpression analysis also identified gene networks that are altered by cocaine. These data indicate that cocaine alters networks enriched with glial cell markers of the VTA that are involved in gene regulation and synaptic processes. Our analyses demonstrate that transcriptional changes within the VTA depend on the route, dose and context of cocaine exposure, and highlight several biological processes affected by cocaine. Overall, these findings provide a unique resource of gene expression data for future studies examining novel cocaine gene targets that regulate drug-associated behaviors.

Transcriptional signatures of heroin intake and seeking throughout the brain reward circuit

“…Further, genes positively associated with the AI were enriched for processes related to metabolic functions and energy utilization. These results are consistent with previous work using cocaine which identified distinct cocaine-induced transcriptional responses depending on exposure paradigm, but a convergent role for disruptions to energetic functions in mediating cocaine effects ( 38 ). These results suggest that molecular changes within the VTA may represent a pan-addiction target for disruption of drug intake and potentially drug-seeking.…”

Multi-omics profiling of DNA methylation and gene expression alterations in human cocaine use disorder

“…Evaluating the convergence of results at the pathway level revealed widespread molecular alterations in synaptic signaling represented by functional module FM1 in the GO enrichment analysis. Our findings are well in line with previous literature that reported on cocaine-associated DNAm and expression changes in genes involved in neurotransmission 14–16,18,48 . The observed overrepresentation of neuronal marker genes in the upregulated DEGs together with the non-neuronal marker gene enrichment in the downregulated DEGs further suggests a particular importance of CUD-associated expression changes in altering neurotransmission.…”

“…Gene expression levels are tightly regulated by epigenetic mechanisms and DNA methylation (DNAm) changes especially in gene promoter regions were shown to alter transcript abundance 13 . In line with this, differential gene expression in rodent models of cocaine addiction was reported in different brain regions where transcription factors of the immediate early gene (IEG) family such as Egr1, Nr4a1, and Fos were found to be differentially expressed [14][15][16][17] . At the transcriptome-wide scale, differentially expressed genes were consistently enriched in biological processes related to neurotransmission and ion channel activity, but also metabolic alterations related to lipid metabolism and ATP homeostasis were found 14 .…”

Transcriptional signatures of heroin intake and relapse throughout the brain reward circuitry in male mice

“…Furthermore, genes positively associated with the AI were enriched for processes related to metabolic functions and energy utilization. These results are consistent with previous work on the VTA using cocaine, which identified distinct cocaine-induced transcriptional responses depending on exposure paradigm, but a convergent role for disruptions to energetic functions in mediating cocaine effects ( 32 ). These results suggest that molecular changes within the VTA may represent a pan-addiction target for disruption of drug intake and potentially drug-seeking.…”