Individual differences in gene expression of vasopressin, D2 receptor, POMC and orexin: Vulnerability to relapse to heroin-seeking in rats

Abstract

Individual vulnerability to stress-induced relapse during abstinence from chronic heroin exposure is a key feature of opiate addiction, with limited studies on this topic. Arginine vasopressin (AVP) and its V1b receptor, components of the brain stress responsive systems, play a role in heroin-seeking behavior triggered by foot shock (FS) stress in rats. In this study, we tested whether individual differences in the FS-induced heroin-seeking were associated with alterations of AVP and V1b, as well as other stress responsive systems, including pro-opiomelanocortin (POMC), orexin, plasma ACTH and corticosterone, as well as dopamine D2 receptor (D2) and plasma prolactin. Sprague-Dawley rats were subjected to 3-hour intravenous heroin self-administration (SA) and then tested in extinction, FS-induced and heroin priming-induced reinstatements. The rats that self-administered heroin were divided to high and low reinstatement responders induced by FS (H-RI; L-RI). Over SA sessions, both the H-RI and L-RI displayed similar active lever responding, heroin infusion and total heroin intake. Compared to the L-RI, however, the H-RI showed greater active lever responses during stress-induced reinstatement, with higher AVP mRNA levels in medial/basolateral amygdala and lower D2 mRNA levels in caudate putamen. However, heroin priming resulted in similar reinstatement in both groups and produced similarly low POMC and high orexin mRNA levels in hypothalamus. Our results indicate that: 1) enhanced amygdalar AVP and reduced striatal D2 expression may be related to individual vulnerability to stress-induced reinstatement of heroin- seeking; and 2) heroin abstinence-associated alterations of hypothalamic orexin and POMC expression may be involved in drug priming-induced heroin-seeking.

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

“…For example, individual differences in responding to heroin-primed reinstatement were linked with differences in gene expression of vasopressin, D2 receptor, and orexin [49]. Based on the RNA-Seq analysis here, a large number of mRNA expression changes occurred among the three conditions in the NAc with the majority of the changes in gene expression observed when comparing the heroin groups to the Saline controls.…”

“…Moreover, additional experiments should be devoted to seeing if mRNA changes are evident in other brain regions associated with drug addiction such as the medial prefrontal cortex and ventral tegmental area. Given that drug addiction affects multiple regions of the brain as shown in Kuntz et al [15] and Zhou et al [49], it is worth investigating if region specific differences in mRNA expression exist following heroin self-administration and avoidance of the drug-paired taste cue. Future experiments also should examine if these changes in mRNA are persistent, or even enhanced during abstinence.…”

Combination of Levo-Tetrahydropalmatine and Low Dose Naltrexone: A Promising Treatment for Prevention of Cocaine Relapse

“…In addition to being a contributing factor in cocaine, nicotine, and heroin craving, a b-endorphin deficit is hypothesized as a contributing factor in relapse of alcohol use (Roth-Deri et al, 2004;Dikshtein et al, 2013). Hypothalamic POMC expression is significantly reduced in animals that return to heroin-seeking behavior during relapse (Zhou, Y et al, 2015).…”

“…Pro-opiomelanocortin (POMC), also a part of the endogenous opioid system, is the precursor to b-endorphin, adrenocorticotropic hormone, or melanocyte-stimulating hormone. POMC is thought to play an important role in reinstatement to drug-seeking behavior, and in a recent study it was observed that animals with higher instances of reinstatement displayed a significant reduction in POMC expression (Zhou et al, 2015). Taken together these data suggest that the endogenous opioid system may be an important target in medication development for treatment of cocaine dependence.…”

The genetic epidemiology of substance use disorder: A review

“…Moreover, decreased D2-like dopamine receptor expression is associated with increased disposition to develop alcohol use disorder (Samochowiec et al, 2000). Further, rat alcohol self-administration was decreased by overexpressing D2 dopamine receptors in the nucleus accumbens (Thanos, et al, 2001), rats that are more prone to resume heroin-seeking behavior in response to stress express less striatal D2 dopamine receptors (Zhou, Leri, Cummins, & Kreek, 2015), and D3 dopamine receptor knockout mice exhibit increased cocaine self-administration (Song et al, 2012). …”