Transcriptomic profiling of the ventral tegmental area and nucleus accumbens in rhesus macaques following long-term cocaine self-administration

Abstract

Background The behavioral consequences associated with addiction are thought to arise from drug-induced neuroadaptation. The mesolimbic system plays an important initial role in this process, and while the dopaminergic system specifically has been strongly interrogated, a complete understanding of the broad transcriptomic effects associated with cocaine use remains elusive. Methods Using next generation sequencing approaches, we performed a comprehensive evaluation of gene expression differences in the ventral tegmental area and nucleus accumbens of rhesus macaques that had self-administered cocaine for roughly 100 days and saline-yoked controls. During self-administration, the monkeys increased daily consumption of cocaine until almost the maximum number of injections were taken within the first 15 min of the one hour session for a total intake of 3 mg/kg/day. Results We confirm the centrality of dopaminergic differences in the ventral tegmental area, but in the nucleus accumbens we see the strongest evidence for an inflammatory response and large scale chromatin remodeling. Conclusions These findings suggest an expanded understanding of the pathology of cocaine addiction with the potential to lead to the development of alternative treatment strategies.

Environmental, genetic and epigenetic contributions to cocaine addiction

“…Even though the identity of the specific genes underlying the heritability of cocaine addiction remains elusive, there is abundant evidence that repeated exposure to cocaine results in pronounced changes in gene expression in various nuclei, particularly in the limbic system. Candidate gene, gene array, and genome-wide approaches have delineated changes in gene expression in the nucleus accumbens, the hub of the limbic system that modulates numerous cocaine-mediated behaviors [73][74][75][76]. Changes in gene expression are regulated by complex interactions between transcription factors, chromatin, and epigenetic processes.…”

Cocaine Self-administration Alters Transcriptome-wide Responses in the Brain’s Reward Circuitry

“…The few studies investigating transcriptome-wide changes after short-term WD from cocaine SA (13, 14), or long-term WD but without re-exposure (15), focused primarily on nucleus accumbens (NAc), ventral tegmental area (VTA) (14), or prefrontal cortex (PFC) (13, 15). No study has characterized transcriptome-wide changes across multiple interconnected brain reward regions.…”

Regional elevations in microglial activation and cerebral glucose utilization in frontal white matter tracts of rhesus monkeys following prolonged cocaine self-administration

“…With chronic activation microglia can become primed, such that subsequent challenges induce exaggerated immune responses (Perry 2007). It seems possible then, that with chronic exposure, recurrent binding of cocaine to the microglial TLR4 complex may initiate abnormal activation and heightened secretion of cytokines, chemokines and other components of the pro-inflammatory cascade; an idea that is consistent with reports of increased expression of components of the innate immune response following cocaine administration (Clark et al 2013;Vallender et al 2017).…”

“…Altered levels of pro-inflammatory immune signaling molecules, for example, have been identified in human cocaine abusers (Fox et al 2012;Levandowski et al 2016a) as well as in rodents (Cearley et al 2011;Clark et al 2013;Periyasamy et al 2018) and in vitro models of cocaine exposure (Guo et al 2015;Northcutt et al 2015;Periyasamy et al 2018). Gene expression analysis of the nucleus accumbens in rhesus monkeys with an extensive history of cocaine self-administration identified a cluster of upregulated immune response and inflammation related genes, associated predominately with microglial activation (Vallender et al 2017).…”