Assessment of individual differences in the rat nucleus accumbens transcriptome following taste-heroin extended access

Abstract

Heroin addiction is a disease of chronic relapse that harms the individual through devaluation of personal responsibilities in favor of finding and using drugs. Only some recreational heroin users devolve into addiction but the basis of these individual differences is not known. We have shown in rats that avoidance of a heroin-paired taste cue reliably identifies individual animals with greater addiction-like behavior for heroin. Here rats received 5 min access to a 0.15% saccharin solution followed by the opportunity to self-administer either saline or heroin for 6 hours. Large Suppressors of the heroin-paired taste cue displayed increased drug escalation, motivation for drug, and drug loading behavior compared with Small Suppressors. Little is known about the molecular mechanisms of these individual differences in addiction-like behavior. We examined the individual differences in mRNA expression in the nucleus accumbens (NAc) of rats that were behaviorally stratified by addiction-like behavior using next-generation sequencing. We hypothesized that based on the avoidance of the drug-paired cue there will be a unique mRNA profile in the NAc. Analysis of strand-specific whole genome RNA-Seq data revealed a number of genes differentially regulated in NAc based on the suppression of the natural saccharine reward. Large Suppressors exhibited a unique mRNA prolife compared to Saline controls and Small Suppressors. Genes related to immunity, neuronal activity, and behavior were differentially expressed among the 3 groups. In total, individual differences in avoidance of a heroin-paired taste cue are associated with addiction-like behavior along with differential NAc gene expression.

Oxycodone Self-Administration Induces Alterations in Expression of Integrin, Semaphorin and Ephrin Genes in the Mouse Striatum

“…We have found only one gene from the ephrin receptor family, Epha3, which was down-regulated in the NAc of oxycodone-treated mice. In other studies, similar down regulation in the expression of ephrin genes in the rat NAc was observed at 24 h after secession of heroin self-administration (6 h/day for 5 days) ( 12 ). In contrast, cocaine treatment increased expression of many ephrin and ephrin receptor in the rat and mouse striatum and hippocampus ( 14 , 7 ) and in striatum of nonhuman primates ( 46 ).…”

“…Previously, microarray studies of morphine-treated mice showed alterations in expression of genes related to the semaphorin pathway in the NAc such as Sema3f, Sema4b, sema6c, Sema6d, Sema7a, and Plxna3 ( 10 ) and Sema6a ( 44 ). Heroin self-administration induced downregulation of Sema5a, Sema6c and receptor Plxnb1 in the rat NAc ( 12 ). Consistent with these earlier reports, in this study we have found oxycodone-induced downregulation of Sema3c, Sema4g, Sema6a, Sema6d, and upregulation Sema7a in the mouse NAc.…”

“…However, axon guidance molecules are also expressed in adult brain, and may contribute to alterations in neural circuit regulation, throughout axon pruning, synaptogenesis, dendrite, and spine morphogenesis. Several studies showed an implication of axon guidance proteins in neuroadaptation following drugs of abuse administration, and response to brain injury ( 7 – 12 ).…”

Weight Loss Results in Increased Expression of Anti‐Inflammatory Protein CRISPLD2 in Mouse Adipose Tissue

“…The average read after filtering was 50,021,043 ± 12,710,549, and the sequencing depth was 1,495. The RNA‐sequencing (RNA‐Seq) data analysis and principal component analysis were conducted as previously described . Sequence data were submitted to the Sequence Read Archive.…”

Addiction: A preclinical and clinical analysis

“…In so doing, they reported that greater avoidance of the heroin-paired saccharin cue was accompanied by not only greater drug-seeking and taking, but also by greater escalation of drug-taking over time. Here, Imperio et al [in this issue] link these individual differences in behavior to individual differences in the expression profile of a range of genes in the nucleus accumbens via next generation gene sequencing. McFalls et al [in this issue] examine how such individual differences in avoidance of the heroin-paired saccharin cue are associated with individual differences in the expression of genes in the corticotrophin releasing hormone (CRH) signaling pathway in the prefrontal cortex, hippocampus, ventral tegmental area, and nucleus accumbens.…”