Effects of acute and chronic social defeat stress are differentially mediated by the dynorphin/kappa-opioid receptor system

Donahue, Rachel; Landino, Samantha M.; Golden, Sam A.; Carroll, F. Ivy; Russo, Scott J.; Carlezon, William A.

doi:10.1097/fbp.0000000000000155

Cited by 52 publications

(59 citation statements)

References 50 publications

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“…In California mice, real-time PCR analysis of prodynorphin mRNA in the NAc showed no effects of social defeat, although mean levels were lower in stressed males and females [46]. In male C57Bl6 mice, a single episode of defeat increased prodynorphin mRNA in the NAc but 10 days of defeat reduced prodynorphin mRNA [17]. Interestingly, social defeat also decreased in prodynorphin mRNA in the medial preoptic area of sexually experienced male California mice (Kowalcyzk and Trainor, in prep.).…”

Section: Discussionmentioning

confidence: 99%

“…In these studies, aggressive contests occurred over a 10-day period, a much longer time frame than studies examining effects of KOR antagonists in the context of stress. Similarly, administration of the long lasting KOR antagonist JDTic before 10 days of social defeat stress did not prevent the development of decreased social interaction or anhedonia in male mice [17]. These data suggest that, over time, neuroadaptations induced by stress may alter the function of KORs.…”

Section: Introductionmentioning

confidence: 99%

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The long-term effects of stress and kappa opioid receptor activation on conditioned place aversion in male and female California mice

Laman-Maharg

Copeland

Sanchez

et al. 2017

Behavioural Brain Research

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Psychosocial stress leads to the activation of kappa opioid receptors (KORs), which induce dysphoria and facilitate depression-like behaviors. However, less is known about the long-term effects of stress and KORs in females. We examined the long-term effects of social defeat stress on the aversive properties of KOR activation in male and female California mice (Peromyscus californicus) using a conditioned place aversion paradigm. Female California mice naïve to social defeat, formed a place aversion following treatment with 2.5 mg/kg of the KOR agonist U50,488, but females exposed to defeat did not form a place aversion to this dose. This supports the finding by others that social defeat weakens the aversive properties of KOR agonists. In contrast, both control and stressed males formed an aversion to 10 mg/kg of U50,488. We also examined EGR1 immunoreactivity, an indirect marker of neuronal activity, in the nucleus accumbens (NAc) and found that stress and treatment with 10 mg/kg of U50,488 increased EGR1 immunoreactivity in the NAc core in females but reduced activation in males. The effects of stress and U50,488 on EGR1 were specific to the NAc, as we found no differences in the bed nucleus of the stria terminalis. In summary, our data indicate important sex differences in the long-term effects of stress and indicate the need for further study of the molecular mechanisms mediating the behavioral effects of KOR in both males and females.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The long-term effects of stress and kappa opioid receptor activation on conditioned place aversion in male and female California mice

Laman-Maharg

Copeland

Sanchez

et al. 2017

Behavioural Brain Research

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“…Previous findings on stress-induced dynorphin changes are inconsistent. A recent study showed a reduction in the dynorphin mRNA levels following chronic exposure to social defeat stress in adult mice (Donahue et al, 2015). Conversely, there is evidence for increased tissue concentrations of dynorphin and dynorphin mRNA levels following repeated exposure to ethanol, which is considered a stressor, in adult rats (Lindholm et al, 2000;Kissler et al, 2014).…”

Section: Si-induced Potentiation Of Kor System Responsivenessmentioning

confidence: 99%

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

Karkhanis¹,

Rose

Weiner³

et al. 2016

Neuropsychopharmacol

106

107

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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.

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“…KOPr signaling tone is upregulated in depressive states, following both stress (Donahue et al 2015; Land et al 2008; Lucas et al 2011; Reed et al 2012) and chronic cocaine exposure, largely through increased mRNA transcription and activity of its endogenous peptides, the dynorphins (Fagergren et al 2003; Sivam 1996; Spangler et al 1996; Unterwald et al 1994; Valenza et al 2016). Activation of KOPr induces dysphoria in humans, as well as place aversion and depressive-like behaviors in preclinical models (Bruchas et al 2009; Carlezon et al 2006; Chefer et al 2013; Land et al 2008; Mucha and Herz 1985; Pfeiffer et al 1986a; Todtenkopf et al 2004).…”

Section: Introductionmentioning

confidence: 99%

“Effects of the novel relatively short-acting kappa opioid receptor antagonist LY2444296 in behaviors observed after chronic extended-access cocaine self-administration in rats”

2017

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Rationale The recruitment of the stress circuitry contributes to a shift from positive to negative reinforcement mechanisms sustaining long-term cocaine addiction. The kappa opioid receptor (KOPr) signaling is upregulated by stress and chronic cocaine exposure. While KOPr agonists induce anhedonia and dysphoria, KOPr antagonists display antidepressant and anxiolytic properties. Most of the knowledge on KOPr antagonism is based on drugs with unusual pharmacokinetic and pharmacodynamic properties, complicating interpretation of results. Here we characterized in vivo behavioral and neuroendocrine effects of the novel relatively short-acting KOPr antagonist LY2444296. To date, no study has investigated whether systemic KOPr blockade reduced anxiety-like and depressive-like behaviors in animals previously exposed to chronic extended access cocaine self-administration. Objectives We tested the effect of LY2444296 in blocking KOPr-mediated aversive and neuroendocrine effects. Then, we tested acute systemic LY2444296 in reducing anxiety- and depression-like behaviors, as well as releasing the stress hormone corticosterone (CORT), observed after chronic extended access (18 h/day for 14 days) cocaine self-administration. Results LY2444296 blocked both U69,593-induced place aversion and reduced motor activity, as well as U69,593-induced release of serum CORT, which confirmed its major site of action, without exerting an effect per se. Acute systemic administration of LY2444296 reduced anxiety-like and depressive-like behaviors, as well as CORT release, in rats tested after chronic extended access cocaine self-administration, but not in cocaine naïve rats. Conclusions Results suggest that acute blockade of KOPr by a relatively short-acting antagonist produces therapeutic-like effects selectively in rats with a history of chronic extended access cocaine self-administration.

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Effects of acute and chronic social defeat stress are differentially mediated by the dynorphin/kappa-opioid receptor system

Cited by 52 publications

References 50 publications

The long-term effects of stress and kappa opioid receptor activation on conditioned place aversion in male and female California mice

The long-term effects of stress and kappa opioid receptor activation on conditioned place aversion in male and female California mice

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

“Effects of the novel relatively short-acting kappa opioid receptor antagonist LY2444296 in behaviors observed after chronic extended-access cocaine self-administration in rats”

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