Stress-Induced Enhancement of Ethanol Intake in C57BL/6J Mice with a History of Chronic Ethanol Exposure: Involvement of Kappa Opioid Receptors

Abstract

Our laboratory has previously demonstrated that daily forced swim stress (FSS) prior to ethanol drinking sessions facilitates enhanced ethanol consumption in mice with a history of chronic intermittent ethanol (CIE) vapor exposure without altering ethanol intake in air-exposed controls. Because both stress and chronic ethanol exposure have been shown to activate the dynorphin/kappa opioid receptor (KOR) system, the present study was designed to explore a potential role for KORs in modulating stress effects on ethanol consumption in the CIE model of dependence and relapse drinking. After stable baseline ethanol intake was established in adult male C57BL/6J mice, subjects received chronic intermittent exposure (16 h/day × 4 days/week) to ethanol vapor (CIE group) or air (CTL group). Weekly cycles of inhalation exposure were alternated with 5-day limited access drinking tests (1 h access to 15% ethanol). Experiment 1 compared effects of daily FSS and KOR activation on ethanol consumption. CIE and CTL mice were either exposed to FSS (10 min), the KOR agonist U50,488 (5 mg/kg), or a vehicle injection (non-stressed condition) prior to each daily drinking session during test weeks. FSS selectively increased drinking in CIE mice. U50,488 mimicked this effect in CIE mice, but also increased drinking in CTL mice. Experiment 2 assessed effects of KOR blockade on stress-induced drinking in CIE and CTL mice. Stressed and non-stressed mice were administered the short-acting KOR antagonist LY2444296 (0 or 5 mg/kg) 30 min prior to each drinking session during test weeks. FSS selectively increased ethanol consumption in CIE mice, an effect that was abolished by LY2444296 pretreatment. In Experiment 3, CIE and CTL mice were administered one of four doses of U50,488 (0, 1.25, 2.5, 5.0 mg/kg) 1 h prior to each daily drinking test (in lieu of FSS). All doses of U50,488 increased ethanol consumption in both CIE and CTL mice. The U50,488-induced increase in drinking was blocked by LY2444296. Our results demonstrate that the KOR system contributes to the stress enhancement of ethanol intake in mice with a history of chronic ethanol exposure.

Synergistic blockade of alcohol escalation drinking in mice by a combination of novel kappa opioid receptor agonist Mesyl Salvinorin B and naltrexone

“…Acute alcohol exposure leads to increased dopamine levels in the NAc, leading to rewarding effects, and KOP-r agonists oppose these effects by modulating the dopamine system [Lindholm et al 2007], suggesting a potential interaction between dopamine in the NAc and KOP-r activation by MSB in alcohol-related behavior. However, there are a number of studies that have found that classic KOP-r agonists increase alcohol drinking and reward [Anderson et al 2016; Rose et al 2016; Sperling et al 2010], and induce alcohol-seeking behavior in a reinstatement model [Funk et al 2014]. Therefore, our new data that the KOP-r agonist MSB reduces alcohol intake presents a scenario that is opposite to the results of previous studies using classic KOP-r agonists, thus warranting further study.…”

“…Specifically, activation of the kappa opioid receptor (KOP-r) system has been implicated in the negative reinforcing aspects of alcohol, opiate, and psychostimulant addictions [Herz 1997; Koob and Kreek 2007]. In rats and mice, acute administration of KOP-r agonists attenuates alcohol drinking [Sandi et al 1988; Lindholm et al 2001; Henderson-Redmond and Czachowski 2014], increases alcohol drinking [Anderson et al 2016; Rose et al 2016], and alters alcohol-induced conditioned place preference [Logrip et al 2009; Sperling et al 2010], while the selective KOP-r antagonist nor-binaltorphimine (nor-BNI) increases alcohol drinking in Lewis rats with relatively high intake [Mitchell et al 2005]. Recently KOP-r antagonists have been reported to attenuate stress-induced alcohol-seeking behavior in mice and rats [Sperling et al 2010; Deehan et al 2012; Funk et al 2014] and to reduce alcohol consumption in alcohol “dependent” rats [Walker and Koob 2008].…”

Genetic divergence in the transcriptional engram of chronic alcohol abuse: A laser-capture RNA-seq study of the mouse mesocorticolimbic system

“…Most recent experiments have been performed in a single strain – B6 – due to the robust enhancement in alcohol consumption and behavior observed in this strain following CIE (Lopez, Becker, & Chandler, 2014; Lopez, Griffin, Melendez, & Becker, 2012) and following CIE and exposure to additional environmental stressors (Anderson, Lopez, & Becker, 2016a). These studies demonstrate concomitant changes in neurotransmitters (Griffin, Ramachandra, Knackstedt, & Becker, 2015) and neuropeptides (Maldonado-Devincci et al, 2014) following CIE, and suggest alterations in specific circuits and regions (Anderson, Lopez, & Becker, 2016b; Lopez, Moorman, Aston-Jones, & Becker, 2016; Samantaray et al, 2015). Whether or not these changes are unique to B6 or represent common mechanisms in the addiction process remains an open question.…”

Involvement of Activated Brain Stress Responsive Systems in Excessive and “Relapse” Alcohol Drinking in Rodent Models: Implications for Therapeutics

“…KOP-r/dynorphin activation is associated with the negative reinforcement aspects of alcohol addictions. It has been found that selective blockade of KOP-r attenuates excessive drinking, stress or cue -induced alcohol-seeking in mice and rats [Walker and Koob, 2008;Sperling et al, 2010;Deehan et al, 2012;Schank et al, 2012;Funk et al, 2014;Rorick-Kehn et al, 2014;Anderson et al, 2016;Zhou et al, 2017a] (but also see Mitchell et al, 2005;Sirohi et al, 2016). In line with these pharmacological results, alcohol drinking is decreased in KOP-r knockout mice [Kovacs et al, 2005].…”