Strain and cocaine-induced differential opioid gene expression may predispose Lewis but not Fischer rats to escalate cocaine self-administration

Abstract

The aim of the present study was to investigate alterations in gene expression of opioid system components induced by extended access (18 h) cocaine self-administration and to determine the impact of genetic background in the vulnerability to escalate cocaine intake. Comparing two inbred rat strains, we previously reported that Lewis rats progressively escalated cocaine consumption compared to Fischer rats, in a new translational model of intravenous cocaine self-administration, which included 14 sessions of 18-h operant sessions in which rats were allowed to select the cocaine unit dose to self-administer. We compare here Fischer and Lewis rats in the gene expression of endogenous opioid peptides (Pomc, Penk, Pdyn) and cognate receptors (Oprm, Oprk and Oprd) in reward-related brain regions, after exposure to either cocaine self-administration or yoked-saline, in the aforementioned translational paradigm. We performed a correlation analysis between the mRNA level, found in the Dorsal Striatum (DS), Nucleus accumbens (NAcc) shell and core respectively, and individual cocaine intake. Our findings show that the gene expression of all the aforementioned opioid genes exhibit strain-dependent differences in the DS, in absence of cocaine exposure. Also, different strain-specific cocaine-induced mRNA expression of Oprm and Oprk was found in DS. Only few differences were found in the ventral parts of the striatum. Moreover, gene expression level of Pdyn, Penk, Oprk, and Oprm in the DS was significantly correlated with cocaine intake only in Fischer rats. Overall, these data shed light on potential genetic differences which may predispose of subjects to initiate and escalate cocaine consumption.

“Effects of the novel relatively short-acting kappa opioid receptor antagonist LY2444296 in behaviors observed after chronic extended-access cocaine self-administration in rats”

“…The operant procedure was carried out as previously published with some modifications (Valenza et al 2016). Rats were initially trained in the intravenous ( i.v. )…”

“…Procedures were carried out as previously published (Valenza et al 2016; Valenza et al 2015). About 30 h after the end of the last self-administration session, cocaine and yoked-saline rats were briefly anesthetized with carbon dioxide and decapitated.…”

“…Gene sequences were amplified using a two-temperature protocol, which included an initial step at 10 min at 95 °C to activate the polymerase, followed by 40 denaturation cycles at 95 °C for 15 sec, annealing and extension at 60 °C for 1 min. Experimental samples were amplified simultaneously with a standard curve constructed using serial 10-fold dilutions of purified fragments (QIAquick PCR purification kit, Qiagen) of the target gene (Valenza et al 2016). Standards and samples of both the target gene and the housekeeping gene of a given brain region were run in duplicate concurrently in the same plate, in the ABI Prism 7900HT Sequence Detection System (Applied Biosystem, Carlsbad, CA).…”

“…KOPr signaling tone is upregulated in depressive states, following both stress (Donahue et al 2015; Land et al 2008; Lucas et al 2011; Reed et al 2012) and chronic cocaine exposure, largely through increased mRNA transcription and activity of its endogenous peptides, the dynorphins (Fagergren et al 2003; Sivam 1996; Spangler et al 1996; Unterwald et al 1994; Valenza et al 2016). Activation of KOPr induces dysphoria in humans, as well as place aversion and depressive-like behaviors in preclinical models (Bruchas et al 2009; Carlezon et al 2006; Chefer et al 2013; Land et al 2008; Mucha and Herz 1985; Pfeiffer et al 1986a; Todtenkopf et al 2004).…”

“…Extended access self-administration protocols are translational models for the advanced stages of addiction seen in humans, where dysregulated drug intake and compulsivity drive behaviors (Ahmed and Koob 1998; Everitt and Robbins 2005; Kreek and Koob 1998). Rats that escalate cocaine intake over the 14 days of 18 h/day self-administration show higher striatal gene expression of Oprk1 , encoding for KOPr, compared to their respective yoked-saline rats, and compared to rats that do not escalate intake (Valenza et al 2016). Here, we also confirmed the activation of dyn/KOPr system in the dorsal striatum under these experimental conditions by gene expression analysis of prodynorphin.…”