Disturbances in behavior and cortical enkephalin gene expression during the anticipation of ethanol in rats characterized as high drinkers

Abstract

The process of ethanol anticipation is a particularly important phenomenon that can determine subsequent drug-taking behavior. Recent studies suggest that systems within the medial prefrontal cortex (mPFC), during anticipation, may contribute to the goal-directed seeking of ethanol. The current investigation examined the possibility that the opioid peptide enkephalin (ENK), known to mediate some of the reinforcing properties of ethanol, may function in the mPFC during the anticipation of ethanol access. Using a limited access (3 h/d) paradigm for 10 days with 20% ethanol, Sprague-Dawley rats were first identified either as low drinkers (LD, <1.0 g/kg/3 h) or as high drinkers (HD, >2.0 g/kg/3 h) that exhibited a long-term phenotype of high ethanol consumption and a significant ethanol deprivation effect. During the anticipation period immediately preceding daily ethanol access, the HD rats compared to LD or Control animals with ad libitum ethanol access exhibited increased anticipatory behaviors, including greater exploratory behavior in a novel open field as revealed by significantly more time spent in the rearing position (+53–65%, p < 0.05) and increased number of rears made (+33–44%, p < 0.05) and greater novelty-seeking behavior in a hole-board apparatus revealed by an increase in total (+50–52%, p < 0.05) and novel nose pokes (+45–48%, p < 0.05). In the HD rats, analysis of the mPFC using real-time quantitative PCR showed significantly greater mRNA levels of ENK (p < 0.05) and the mu-opioid receptor (MOR) (p < 0.05), but not delta-opioid receptor (DOR), and this increase in ENK expression was found, using in situ hybridization, to occur specifically in the prelimbic (PrL) subregion of the mPFC. When injected into the PrL during the anticipation period, a MOR agonist but not DOR agonist significantly increased consumption of 20% ethanol (p < 0.05). These findings support the role of ENK, acting through MOR within the PrL to promote the anticipation and excessive consumption of ethanol.

Feeding-modulatory effects of mu-opioids in the medial prefrontal cortex: a review of recent findings and comparison to opioid actions in the nucleus accumbens

“…Several studies have suggested that these deficits arise from supernormal opioid transmission (Blasio et al 2014; Gorelick et al 2008; Love et al 2009; Mitchell et al 2012; Morganstern et al 2012; Selleck et al 2015; Zubieta et al 1996), and these studies are supported by clinical findings that opioid antagonists have at least some degree of efficacy across several disorders characterized by loss of control over goal-seeking behavior (Cambridge et al 2013; Kim et al 2001; Mitchell et al 2007; Volpicelli et al 1992). However, there is variability in the reports of opiate antagonist clinical efficacy (McElroy et al 2013; Ziauddeen et al 2013), suggesting that further studies are needed to more thoroughly delineate opioid actions within the brain and how normal brain function is influenced by opioid antagonists.…”

Endogenous Opioid Signaling in the Medial Prefrontal Cortex is Required for the Expression of Hunger-Induced Impulsive Action

“…μORs are upregulated in the PFC (along with the Acb and amygdala) in individuals with trait impulsivity, and these individuals display exaggerated stressor-induced PFC opioid release (Love et al, 2009). In animal studies, PFClocalized μ-opioid peptides are elevated after exposure to 'binge-like' palatable feeding or cocaine self-administration schedules, and in rats predisposed to excessive ethanol intake (Blasio et al, 2013;Morganstern et al, 2012). Finally, intra-PFC naloxone infusion reduced food-reinforced PR responding in rats that had experienced a 'binge'-inducing schedule of sugar access (Blasio et al, 2013).…”

A Genetic Animal Model of Alcoholism for Screening Medications to Treat Addiction

“…For example, high alcohol drinking rats exhibit a greater level of mu-opioid receptor (MOR)-associated and enkephalin mRNA, compared to low alcohol drinking rats (Morganstern et al, 2012). For a review of neurobiological differences in the opioid system between selectively bred high and low alcohol-consuming rats see Bell et al (2012).…”