Low expression of D2R and Wntless correlates with high motivation for heroin.

Abstract

Drug overdose now exceeds car accidents as the leading cause of accidental death in the U.S. Of those drug overdoses, a large percentage of the deaths are due to heroin and/or pharmaceutical overdose, specifically misuse of prescription opioid analgesics. It is imperative, then, that we understand the mechanisms that lead to opioid abuse and addiction. The rewarding actions of opioids are mediated largely by the mu opioid receptor (MOR), and signaling by this receptor is modulated by various interacting proteins. The neurotransmitter dopamine also contributes to opioid reward, and opioid addiction has been linked to reduced expression of dopamine D2 receptors (D2R) in brain. That said, it is not known if alterations in the expression of these proteins relates to drug exposure and/or to the “addiction-like” behavior exhibited for drug. Here, we held total drug self-administration constant across acquisition and showed that reduced expression of the D2R and the MOR interacting protein, Wntless, in the medial prefrontal cortex was associated with greater “addiction-like” behavior for heroin, in general, and with a greater willingness to work for drug, in particular. In contrast, reduced expression of the D2R in the nucleus accumbens and hippocampus was correlated with greater seeking during signaled non-availability of drug. Taken together, these data link reduced expression of both the D2R and Wntless to the explicit motivation for drug, rather than to differences in total drug intake, per se.

Early avoidance of a heroin-paired taste-cue and subsequent addiction-like behavior in rats

“…Significant changes in WLS expression, however, were only reached in the PFC for a decrease in the smallest suppressors vs. saline animals ( p = 0.03) and, in the hippocampus, an increase in the largest suppressors vs. saline ( p = 0.007) and vs. the smallest suppressors ( p = 0.007). Finally, as in our previous study (Tacelosky et al, 2015), no differences in WLS expression were observed between saline animals and those receiving heroin, overall (graphs not shown), indicating that heroin exposure, alone, did not alter WLS expression. Because WLS is essential for Wnt secretion, we next chose to look at a downstream component of the Wnt pathway to determine whether Wnt signaling was altered in the brains of rats displaying ALB for heroin.…”

“…Surprisingly, out of 31 rats, only 1 rat (3.2%) scored a 3 and 8 rats (25.8%) scored a 2. This is less than Deroche-Gamonet et al, 2004 reported with cocaine, less than we reported with cocaine (Puhl et al, 2011), and less than we found using a similar regimen with heroin (Tacelosky et al, 2015). When examined as a function of the small and large suppressors, the large suppressor group accounted for the only subject to score a 3 and for 6/8 (75%) of the subjects that scored a 2.…”

“…Recently, using a similar intermittent access model as that used in this study (albeit without saccharin suppression training), Tacelosky et al 2015 found a significant correlation such that lower levels of WLS expression in the PFC were associated with increasing addiction-like behavior scores for heroin in rats. In the current study, when looking at all of the experimental subjects tested, we did not observe a similar decrease in WLS expression with increasing addiction score (Fig.…”

“…There was a tendency for the number of infusions per 2 h to increase slightly across trials 1–24, overall, but this trend was not significant. Thus, unlike the extended access model where escalation is the norm (Imperio and Grigson, 2015; Koob and Kreek, 2007), rats failed to evidence escalation of drug self-administration across trials here, as is typical for this paradigm (Deroche-Gamonet et al, 2004; Puhl et al, 2011; Tacelosky et al, 2015). …”

“…Previous studies by our laboratory and others have suggested that WLS expression decreases with opioid use in the brains of rats, mice, and zebrafish (Herrero-Turrion et al, 2014; Petko et al, 2013;Tacelosky et al, 2015). Recently, using a similar intermittent access model as that used in this study (albeit without saccharin suppression training), Tacelosky et al 2015 found a significant correlation such that lower levels of WLS expression in the PFC were associated with increasing addiction-like behavior scores for heroin in rats.…”