Supersensitive Kappa Opioid Receptors Promotes Ethanol Withdrawal-Related Behaviors and Reduce Dopamine Signaling in the Nucleus Accumbens

Abstract

Background:Chronic ethanol exposure reduces dopamine transmission in the nucleus accumbens, which may contribute to the negative affective symptoms associated with ethanol withdrawal. Kappa opioid receptors have been implicated in withdrawal-induced excessive drinking and anxiety-like behaviors and are known to inhibit dopamine release in the nucleus accumbens. The effects of chronic ethanol exposure on kappa opioid receptor-mediated changes in dopamine transmission at the level of the dopamine terminal and withdrawal-related behaviors were examined.Methods:Five weeks of chronic intermittent ethanol exposure in male C57BL/6 mice were used to examine the role of kappa opioid receptors in chronic ethanol-induced increases in ethanol intake and marble burying, a measure of anxiety/compulsive-like behavior. Drinking and marble burying were evaluated before and after chronic intermittent ethanol exposure, with and without kappa opioid receptor blockade by nor-binaltorphimine (10mg/kg i.p.). Functional alterations in kappa opioid receptors were assessed using fast scan cyclic voltammetry in brain slices containing the nucleus accumbens.Results:Chronic intermittent ethanol-exposed mice showed increased ethanol drinking and marble burying compared with controls, which was attenuated with kappa opioid receptor blockade. Chronic intermittent ethanol-induced increases in behavior were replicated with kappa opioid receptor activation in naïve mice. Fast scan cyclic voltammetry revealed that chronic intermittent ethanol reduced accumbal dopamine release and increased uptake rates, promoting a hypodopaminergic state of this region. Kappa opioid receptor activation with U50,488H concentration-dependently decreased dopamine release in both groups; however, this effect was greater in chronic intermittent ethanol-treated mice, indicating kappa opioid receptor supersensitivity in this group.Conclusions:These data suggest that the chronic intermittent ethanol-induced increase in ethanol intake and anxiety/compulsive-like behaviors may be driven by greater kappa opioid receptor sensitivity and a hypodopaminergic state of the nucleus accumbens.

Chronic ethanol exposure increases inhibition of optically targeted phasic dopamine release in the nucleus accumbens core and medial shell ex vivo

“…An important caveat in the current study is that basal DA release magnitudes resulting from light stimulations are dependent on the amount of expression of ChR2 in the fields being stimulated. However, the variability of release across slices was comparable to studies using electrical stimulation (Rose et al 2016), suggesting that there was consistency in the viral injection and expression of ChR2 between animals. Another consideration is that super-physiological Ca 2+ entry during light stimulation (Zhang and Oertner 2007) occludes potential ethanol-induced decreases in terminal Ca 2+ signaling and transmitter release.…”

“…We have previously reported decreased electrically stimulated DA release in NAc core slices from mice following chronic intermittent ethanol exposure (Rose et al 2016; Karkhanis et al 2015); however, this finding did not extend to rats (Budygin et al 2003) under a similar ethanol exposure paradigm, and there were regionally divergent effects in primates with a history of chronic daily ethanol self-administration (Siciliano et al 2015a). These inconsistencies suggest that species, region and pattern of ethanol administration may be important in determining ethanol-induced changes in release parameters.…”

“…The goal of these studies was to extend our investigations of chronic ethanol-induced alterations of DA signaling in the ventral striatum (Karkhanis et al 2015; Rose et al 2016; Siciliano et al 2015a) across three novel parameters. 1) We measured DA signals in the NAc shell to provide a direct comparison to NAc core DA terminal fields in order to determine whether chronic ethanol exposure results in differential adaptations between regions.…”

Early-Life Social Isolation Stress Increases Kappa Opioid Receptor Responsiveness and Downregulates the Dopamine System

“…These behavioral data are also consistent with the selective enhancing effect of nor-BNI on baseline DA in SI rats observed in the current study. Adult rodents exposed to chronic ethanol (Becker, 2012;Berger et al, 2013;Rose et al, 2015) and rats exposed to adolescent SI (Karkhanis et al, 2014) exhibit increased anxiety-like behaviors. Thus it is possible that escalated ethanol intake in dependent and SI rats is driven, at least in part, by a persistent elevation of stress and anxiety.…”

“…Both repeated forced swim stress and pharmacological activation of KORs with U50,488 increases ethanol consumption in mice (Sperling et al, 2010;Rose et al, 2015). CIE exposure and withdrawal lead to increases in anxiety-like and anhedonic behaviors in addition to promoting an escalation in ethanol intake (Berger et al, 2013).…”