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

Abstract

Chronic early-life stress increases vulnerability to alcoholism and anxiety disorders during adulthood. Similarly, rats reared in social isolation (SI) during adolescence exhibit augmented ethanol intake and anxiety-like behaviors compared with group housed (GH) rats. Prior studies suggest that disruption of dopamine (DA) signaling contributes to SI-associated behaviors, although the mechanisms underlying these alterations are not fully understood. Kappa opioid receptors (KORs) have an important role in regulating mesolimbic DA signaling, and other kinds of stressors have been shown to augment KOR function. Therefore, we tested the hypothesis that SI-induced increases in KOR function contribute to the dysregulation of NAc DA and the escalation in ethanol intake associated with SI. Our ex vivo voltammetry experiments showed that the inhibitory effects of the kappa agonist U50,488 on DA release were significantly enhanced in the NAc core and shell of SI rats. Dynorphin levels in NAc tissue were observed to be lower in SI rats. Microdialysis in freely moving rats revealed that SI was also associated with reduced baseline DA levels, and pretreatment with the KOR antagonist nor-binaltorphimine (nor-BNI) increased DA levels selectively in SI subjects. Acute ethanol elevated DA in SI and GH rats and nor-BNI pretreatment augmented this effect in SI subjects, while having no effect on ethanol-stimulated DA release in GH rats. Together, these data suggest that KORs may have increased responsiveness following SI, which could lead to hypodopaminergia and contribute to an increased drive to consume ethanol. Indeed, SI rats exhibited greater ethanol intake and preference and KOR blockade selectively attenuated ethanol intake in SI rats. Collectively, the findings that nor-BNI reversed SI-mediated hypodopaminergic state and escalated ethanol intake suggest that KOR antagonists may represent a promising therapeutic strategy for the treatment of alcohol use disorders, particularly in cases linked to chronic early-life stress.

Adolescent Social Isolation as a Model of Heightened Vulnerability to Comorbid Alcoholism and Anxiety Disorders

“…Activation of KORs reduces dopamine release in the NAc (Ebner et al, 2010; Werling et al, 1988). In another recent study, we showed that KOR-mediated inhibition of dopamine release was enhanced in aSI compared to aGH rats (Karkhanis et al, 2016). These data suggest that aSI results in increased functional responsiveness of KORs in the NAc which may contribute to the observed increase in EtOH intake.…”

“…Importantly, aSI also leads to robust, long-lasting increases in multiple measures of voluntary EtOH drinking (Chappell et al, 2013; McCool and Chappell, 2009; Skelly et al, 2015) and enhances EtOH CPP (Whitaker et al, 2013). In addition, 2 studies have examined the pharmacology of EtOH drinking in aSI rats and reported that anxiolytic medications targeting the noradrenergic system and KORs significantly attenuated binge-like EtOH drinking in aSI rats at doses that had no significant effect in aGH subjects (Karkhanis et al, 2016; Skelly et al, 2015). Collectively, these findings provide promising initial evidence that this model has both face and predictive validity.…”

“…These studies employed the intermittent model discussed above and found that systemic administration of 3 anxiolytic medications that modulate noradrenergic signaling (prazosin, propranolol, and duloxetine) and NOR-BNI, a kappa opioid receptor (KOR) antagonist that also has anxiolytic properties, all significantly decreased the binge-like EtOH drinking promoted by the intermittent model in aSI rats (Karkhanis et al, 2016; Skelly et al, 2015). In contrast, none of these medications significantly influenced EtOH drinking in aGH subjects.…”

Switch from excitatory to inhibitory actions of ethanol on dopamine levels after chronic exposure: Role of kappa opioid receptors

“…Moreover, it has been postulated that a shift in hedonic set point is driven, in part, by hyperactivity of the dynorphin/KOR system in dependent animals (Bruchas et al, 2010). Thus it is possible that KOR blockade, which decreases ethanol intake selectively in dependent animals (Walker and Koob, 2008; Walker et al, 2011; Rose et al, 2015) and in animals exposed to chronic early-life stress (Karkhanis et al, 2016), relieves the negative affective state that the animals is in, potentially by normalizing dopamine system function.…”

The effect of forced swim stress on morphine sensitization: Involvement of D1/D2-like dopamine receptors within the nucleus accumbens

“…Although some incongruous studies have revealed that repeated exposure to opioids and stressors reduces dopamine release in the NAc and inhibits sensitization (Karkhanis et al, 2016;Kaufling and Aston-Jones, 2015). This raises the question: which paradigms lead to sensitization?…”