Oxycodone self-administration activates the mitogen-activated protein kinase/mitogen- and stress-activated protein kinase (MAPK-MSK) signaling pathway in the rat dorsal striatum

Abstract

To identify signaling pathways activated by oxycodone self-administration (SA), Sprague-Dawley rats self-administered oxycodone for 20 days using short-access (ShA, 3 h) and long-access (LgA, 9 h) paradigms. Animals were euthanized two hours after SA cessation and dorsal striata were used in post-mortem molecular analyses. LgA rats escalated their oxycodone intake and separated into lower (LgA-L) or higher (LgA-H) oxycodone takers. LgA-H rats showed increased striatal protein phosphorylation of ERK1/2 and MSK1/2. Histone H3, phosphorylated at serine 10 and acetylated at lysine 14 (H3S10pK14Ac), a MSK1/2 target, showed increased abundance only in LgA-H rats. RT-qPCR analyses revealed increased AMPA receptor subunits, GluA2 and GluA3 mRNAs in the LgA-H rats. GluA3, but not GluA2, expression correlated positively with changes in pMSK1/2 and H3S10pK14Ac. Our findings indicate that escalated oxycodone SA results in MSK1/2-dependent histone phosphorylation, which promoted increases in striatal gene expression. Our observations offer novel avenues for pharmacological interventions against oxycodone addiction.

GluA2‐lacking AMPA receptors in the nucleus accumbens core and shell contribute to the incubation of oxycodone craving in male rats

“…This elevation in responding persisted on WD30 [Figure 2C; WD1 vs. WD30: F (1,28) = 40.40, Tukey's post hoc p = 0.012]. These findings are consistent with prior studies of the incubation of craving for oxycodone (e.g., previous works 12,14,30 ).…”

“…Recent studies have reported incubation of oxycodone craving. 12,14,30,31 The goals of the first experiment were to verify that incubation of craving occurs under our experimental conditions and to assess the duration of changes in drug-seeking. NAc tissue from these rats was then used to examine whether this incubation was accompanied by changes in AMPAR subunit surface expression (see next section).…”

“…Inactivation of the orbitofrontal cortex reduces expression of oxycodone incubation 12 and altered functional connectivity of orbitofrontal cortex and dorsal striatum has been implicated 13 . In addition, molecular adaptations accompanying this incubation have been identified (e.g., Blackwood et al 14 ). Surprisingly, the role of the nucleus accumbens (NAc) in the incubation of oxycodone craving has not been examined, even though the NAc has been implicated in heroin relapse in extinction‐reinstatement models 11 and, very recently, in oxycodone seeking during abstinence (incubation was not assessed) 15 .…”

Convergence of case-specific epigenetic alterations identify a confluence of genetic vulnerabilities tied to opioid dependence

“…Consistent with this known biological function, the MAP kinase pathway was the most enriched GO molecular function term associated with the set of differentially expressed genes in opioid cases versus controls (P adj < 0.01) (Figure 1I) (Chen et al, 2013;Kuleshov et al, 2016) . Both the input transcription factors to the 388 loci (FOS AP1 factors) and output MAPK genes are consistent with known addiction pathways (Al-Hasani and Bruchas, 2011) (Blackwood et al, 2021) (Browne et al, 2020) (Qiao et al, 2021) (Brynildsen et al, 2020).…”

“…< 1×10 -7 ) (Figure 1B,C, Table S2). An exemplar locus linked to target gene DUAL-SPECIFICITY PHOSPHATASE 4 (DUSP4) in DLPFC promoter capture Hi-C data, involved in the addiction-relevant GPCR and MAPK signaling pathways (Blackwood et al, 2021;Qiao et al, 2021), is shown in Figure 1D. Strikingly, no significant hyperacetylated peaks in cases were found.…”