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Comparative Study
, 31 (6), 1241-8

Social Defeat Stress-Induced Behavioral Responses Are Mediated by the Endogenous Kappa Opioid System

Affiliations
Comparative Study

Social Defeat Stress-Induced Behavioral Responses Are Mediated by the Endogenous Kappa Opioid System

Jay P McLaughlin et al. Neuropsychopharmacology.

Abstract

Previous studies have demonstrated that repeated forced-swim stress-induced behaviors (including analgesia, immobility, and increased drug reward) were mediated by the release of endogenous prodynorphin-derived opioid peptides and subsequent activation of the kappa opioid receptor (KOR). We tested the generality of these effects using a different type of stressful situation: repeated social defeat. C57Bl/6 mice subjected to social defeat stress (SDS) over 3 days showed a characteristic stress-induced immobility and defeated-postural response, as well as stress-induced analgesia (SIA). Daily pretreatment with the KOR antagonist nor-binaltorphimine (nor-BNI, 10 mg/kg, i.p.) blocked the SIA and significantly reduced the stress-induced immobility on the second and third days of SDS exposure. In contrast, prodynorphin gene-disrupted mice showed no significant increase in immobility, socially defeated postures, or SIA following repeated exposure to SDS. Since both stress and the kappa opioid system can modulate the response to drugs of abuse, we tested the effects of SDS on cocaine-conditioned place preference (CPP). SDS-exposed mice conditioned with cocaine (15 mg/kg, s.c.) showed significant potentiation of place-preference for the drug-paired chamber over the responses of unstressed mice. Nor-BNI pretreatment blocked stress-induced potentiation of cocaine-CPP. Consistent with this result, mice lacking the prodynorphin gene did not show stress-induced potentiation of cocaine-CPP, whereas wild-type littermates did. The findings suggest that chronic SDS may activate the kappa opioid system to produce analgesia, immobility, social defeat postures, and resulting in a potentiation of the acute rewarding properties of cocaine.

Figures

Figure 1
Figure 1
Social defeat stress (SDS)-induced analgesia is blocked by pretreatment with nor-BNI or prodynorphin gene derived disruption. Tailwithdrawal latencies presented were obtained 5–9 min after exposure to SDS, on the first, second, or third day. Mice were tested in the 55°C warmwater tail-withdrawal assay before (open bars) and after exposure to the SDS (thatched bars), as described in ‘Materials and methods’. (a) On each day, C57Bl/6 mice pretreated with vehicle i.p. demonstrated a tailwithdrawal response that was approximately doubled after social stress. (b) Pretreatment 60 min prior to SDS with the KOR-selective antagonist, nor- BNI (10 mg/kg, i.p.) did not significantly change baseline tail-withdrawal latencies (open bars, b), but blocked the increase in SIA produced by SDS (thatched bars, b). (c) Similar to nor-BNI, disruption of the prodynorphin gene prevented SDS-induced analgesia in vehicle-treated mice in each trial over 3 days. * significantly different from matching pre-stress latencies on day 1, day 2, p<0.05, as determined by one-way ANOVA followed by Fisher’s LSD multiple-comparison post hoc test. * significantly different than matching pre-stress latencies on day3, p<0.05, as determined by Student’s t-test. Bars represent n = 23–32 WT or 12 DYN(−/−) mice.
Figure 2
Figure 2
Time spent in socially defeated postures is reduced on the second and third day of testing by pretreatment with nor-BNI or prodynorphin gene disruption. The time mice spent immobile and in socially defeated postures during each trial exposure to social-defeat stress was measured over five trials across 3 days. WT mice received either vehicle or nor-BNI 1 h prior to daily SDS. Prodynorphin gene disrupted mice received vehicle. All mice exposed to two trials of SDS on day 1 demonstrated no difference in immobility response on the first day, regardless of pretreatment. However, mice pretreated with either nor-BNI or lacking prodynorphin spent significantly less time immobile and in socially defeated postures from the second SDS trial on the second and third days than vehicle-treated WT mice. * significant difference between immobility and socially defeated postural responses of stress-exposed vehicletreated and nor-BNI treated WT mice or DYN(−/−) mice, p<0.05, as determined by two-way ANOVA followed by Fisher’s LSD multiplecomparison post hoc test.
Figure 3
Figure 3
Exposure to SDS produces a nor-BNI sensitive potentiation of cocaine-CPP. (a) Schematic of training paradigm. The CPP protocol was as described in ‘Materials and methods.’ Preference testing allowed mice to move freely for 30 min in the morning to measure preconditioning and subsequent responses for either of two conditioning chambers as described in Materials and methods (represented here with triangles). Following assessment of preconditioning preference, mice were exposed to repeated SDS over the next 72 h as detailed in Materials and methods (diamonds) or allowed to remain in home cages without stress. Within 10 min after SDS exposure on day 2, mice were administered cocaine (15 mg/kg, s.c.) and confined to the drug-paired box for a 30-min conditioning session (squares). After 4 h, mice were administered vehicle and confined to the vehicle-paired box for a 30-min conditioning session (circles). After a final SDS exposure on the third day (diamond), cocaine and saline conditioning was repeated, separated again by 4 h (represented by the joined square and circle icons, day 3). On day 4, the final preference test was performed blind to determine the effect of treatment and conditioning on place preference. (b) Preference test data demonstrates a nor-BNI-sensitive, SDS-induced potentiation of cocaine-CPP. Preferences are given as difference between time spent in drug-paired chamber and time in saline-paired chamber during the 30-min trial. A positive value represents greater time spent in the drug-paired chamber. Mice were divided into four groups. The first group was unstressed, remaining in home cages and not exposed to SDS prior to 2 days of cocaine and saline conditioning as described in ‘Materials and methods.’ The second group was administered vehicle and exposed to a novel, unoccupied environment with a littermate (‘Mock social stress’) prior to cocaine conditioning. The third group was administered vehicle and exposed to SDS prior to 2 days of cocaine and saline conditioning. The fourth group was administered nor-BNI and exposed to the SDS as described above, then conditioned over two days with cocaine and saline. After conditioning, all four groups demonstrated an increase in time spent in the cocaine-paired chamber that was significantly greater than the time spent in that chamber prior to conditioning, an example of CPP. Control unstressed mice, mock social-defeat stressed, and SDS-exposed mice pretreated with nor-BNI demonstrated an equivalent degree of cocaine-CPP. In contrast, vehicle-treated mice exposed to SDS demonstrated a significant potentiation over the unstressed animals responses. * significant difference in cocaine-CPP compared with unstressed mice; p<0.05, as determined by Kruskal–Wallis one-way ANOVA Ranks followed by Fisher’s LSD multiple-comparison post hoc test (The behavioral data did not meet the assumptions of normal distribution necessary to permit parametric evaluation). Bars represent n = 18–23 mice, except mock social stress group, for which n = 4 mice.
Figure 4
Figure 4
Disruption of prodynorphin gene prevents the SDS-induced potentiation of cocaine-CPP. Prodynorphin gene knockout or WT littermate mice were exposed to 3-day SDS and then used in cocaine- CPP assays as detailed in Figure 3a and ‘Materials and methods.’ All animals demonstrated cocaine-CPP after conditioning that was significantly greater than preference during the preconditioning trial. However, SDS-exposed WT littermates demonstrated cocaine-CPP that was approximately double the preference responses of the social defeat-stressed prodynorphin KO mice. * significant difference in matching cocaine-CPP response of SDS-exposed prodynorphin WT vs gene disrupted mice, p<0.05 for all as determined by Student’s t-test. Bars each represent n = 11–12 animals.

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