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. 2016 Aug;41(9):2263-74.
doi: 10.1038/npp.2016.21. Epub 2016 Feb 10.

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

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

Anushree N Karkhanis et al. Neuropsychopharmacology. 2016 Aug.

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.

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Figures

Figure 1
Figure 1
(a) A schematic of the experimental paradigm. Male, Long–Evans rats arrived at the facility on postnatal day (PD 21) and were maintained in group housing to acclimate for 1 week. On PD 28, half the rats were housed individually while the other half remained in group housing. ELISA, voltammetry, and microdialysis experiments were conducted between PD 84 and PD 110. (b) After the housing paradigm was completed, all rats were single housed on PD 84. Ethanol drinking experiments began on PD 87 and continued for 7 weeks. (c) Coronal sections showing microdialysis probe locations. Microdialysis probes were inserted in the NAc using the rat atlas by Paxinos and Watson (2007).
Figure 2
Figure 2
Social isolation facilitated DA release and uptake in the NAc core (a–d) and shell (e–h) as measured using voltammetry. Background subtracted color plots (a: GH, top; SI, bottom; x axis: time, y axis: voltage, z axis: current) along with corresponding DA traces illustrating electrically stimulated DA release (peak) in GH (red) and SI (blue) rats (b) in the NAc core. (c) DA release per pulse was significantly increased in SI compared with GH animals. (d) Social isolation resulted in facilitated DA uptake rates. Background subtracted color plots (e: GH, top; SI, bottom; x axis: time, y axis: voltage, z axis: current) along with corresponding DA traces illustrating electrically stimulated DA release (peak) in GH (red) and SI (blue) rats (f) in the NAc shell. (g) DA release per pulse was significantly augmented in SI compared with GH animals. (h) Social isolation resulted in increased DA uptake rates. NAc core: GH, n=7; SI, n=6. NAc shell: GH, n=7; SI, n=7. **p<0.01; ***p<0.001. A full color version of this figure is available at the Neuropsychopharmacology journal online.
Figure 3
Figure 3
Voltammetric measurements of KOR agonist, U50,488, mediated decrease in DA release in the NAc core and shell slices. (a) Social isolation-induced chronic stress resulted in increased functional responsivity of KORs. Bath application KOR agonist, U50,488, augmented the decrease in electrically stimulated DA release in the NAc core in a dose-dependent manner (percentage of baseline). (b) A significant difference in the percentage of decrease in DA release was observed between GH and SI animals (left). The EC50 of U50,488 was also significantly different between SI and GH rats (right). (c) Decrease in raw DA release in the NAc core was significantly greater in SI compared with GH animals. (d) Change in DA release between baseline and 1 μM concentration of U50,488 (left) and the EC50 of U50,488 (right) was significantly greater in SI compared with GH animals. (e) A facilitated reduction in electrically stimulated DA release was observed in the NAc shell of SI compared with GH animals. These data imply that social isolation increased functional responsivity of the KORs in the NAc shell. (f) The maximal percentage of decrease in DA release was not significantly different between SI and GH animals when DA release at 1 μM was subtracted from baseline because DA release at these two points was similar in the two groups (left). However, the EC50 of U50,488 was significantly different between the two groups (right). (g) The reduction in DA release (raw) by KOR activation was facilitated in SI compared with GH rats. (h) The maximal change in DA release was greater in SI animals (left) and the EC50 of U50,488 was significantly lower in SI compared with GH animals (right). BL: baseline measures of DA release; this denotes the raw values for the vehicle condition. NAc core: GH, n=7; SI, n=6. NAc shell: GH, n=7; SI, n=7. *p<0.05, **p<0.01 (interaction between concentration and housing variables); Δp<0.05 (main effect of housing); #p<0.05, ##p<0.01 (Bonferroni post hoc); δp<0.05, δδp<0.01, δδδp<0.001 (comparison between the maximal change in DA release in GH and SI animals or the comparison between the EC50 of U50,488 in GH and SI animals).
Figure 4
Figure 4
KOR blockade enhances ethanol-mediated extracellular DA response in the NAc in SI but not in GH rats (microdialysis). (a) DA levels (baseline levels prior to ethanol administration) in the NAc are stable across the 2 days of the microdialysis experiments in both GH (open red bar, control day 1; solid red bar, control day 2) and SI (open blue bar, control day 1; solid blue bar, control day 2) animals. (b) Administration of nor-BNI, KOR antagonist, increased baseline DA levels (prior to ethanol administration) in SI (blue bars), but not in GH (red bars) animals. These data suggest that social isolation during adolescence resulted in supersensitive KORs. (c) Ethanol (1 g/kg) induced DA response in GH animals before (open red symbols) and 24 h after (solid red symbols) nor-BNI administration as a percentage of baseline. No difference between the two groups was observed. (d) Ethanol (1 g/kg) induced DA response in SI rats before (open blue symbols) and 24 h after (solid blue symbols) nor-BNI administration as a percentage of baseline. Nor-BNI pretreatment augmented the ethanol-mediated DA response in SI animals. (e) The raw value curve of ethanol (1 g/kg) mediated DA response in GH rats (control; open blue symbols) and 24 h after nor-BNI administration (solid blue symbols). Ethanol-induced DA elevation was not different in the absence and presence of nor-BNI. (f) The raw value curve of ethanol (1 g/kg) mediated DA response in SI rats (control; open blue symbols) and 24 h after nor-BNI administration (solid blue symbols). Ethanol-induced DA elevation was enhanced in the presence of nor-BNI. These data suggest that KORs become sensitized following social isolation during adolescence. A 1-g/kg dose of ethanol administered on 2 consecutive days resulted in a similar DA response in both GH (g) and SI (h) rats. n-BNI experiments: GH, n=8; SI, n=8. Control experiments: GH, n=6; SI, n=6. *p<0.05; **p<0.01; ***p<0.001 (comparison between before and after nor-BNI treatment). #p<0.05; ##p<0.01; ###p<0.001 (effect of acute ethanol within the respective group). A full color version of this figure is available at the Neuropsychopharmacology journal online.
Figure 5
Figure 5
Ethanol intake and preference during the first 30 min following bottle exchange in GH and SI animals. (a) Average weekly ethanol intake and intake on the test day (24 h after nor-BNI administration). Social isolation potentiated ethanol consumption, which was reduced following nor-BNI administration. *p<0.05 (housing); ##p<0.01 (week). (b) Comparison of ethanol consumption before and after nor-BNI administration in GH and SI animals. KOR antagonism did not affect ethanol intake in GH animals; however, KOR blockade significantly decreased ethanol intake in SI animals. *p<0.05. (c) Average weekly ethanol preference over water and preference on the test day (24 h after nor-BNI administration). Social isolation facilitated ethanol preference, which was decreased following nor-BNI administration. *p<0.05 (housing); ###p<0.001 (week). (d) Comparison of ethanol preference ratio before and after nor-BNI administration in GH and SI animals. KOR antagonism did not affect preference ratio in GH animals. KOR blockade significantly decreased preference for ethanol in SI animals. **p<0.01. GH, group housed, n=7; SI, socially isolated, n=8.

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References

    1. Anda RF, Whitfield CL, Felitti VJ, Chapman D, Edwards VJ, Dube SR et al (2002). Adverse childhood experiences, alcoholic parents, and later risk of alcoholism and depression. Psychiatr Serv 53: 1001–1009. - PubMed
    1. Baarendse PJ, Limpens JH, Vanderschuren LJ (2014). Disrupted social development enhances the motivation for cocaine in rats. Psychopharmacology 231: 1695–1704. - PMC - PubMed
    1. Beardsley PM, Howard JL, Shelton KL, Carroll FI (2005). Differential effects of the novel kappa opioid receptor antagonist, JDTic, on reinstatement of cocaine-seeking induced by footshock stressors vs cocaine primes and its antidepressant-like effects in rats. Psychopharmacology 183: 118–126. - PubMed
    1. Becker HC (2012). Effects of alcohol dependence and withdrawal on stress responsiveness and alcohol consumption. Alcohol Res 34: 448–458. - PMC - PubMed
    1. Berger AL, Williams AM, McGinnis MM, Walker BM (2013). Affective cue-induced escalation of alcohol self-administration and increased 22-kHz ultrasonic vocalizations during alcohol withdrawal: role of kappa-opioid receptors. Neuropsychopharmacology 38: 647–654. - PMC - PubMed

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