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Comparative Study
, 31 (4), 787-94

Prior Activation of Kappa Opioid Receptors by U50,488 Mimics Repeated Forced Swim Stress to Potentiate Cocaine Place Preference Conditioning

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Comparative Study

Prior Activation of Kappa Opioid Receptors by U50,488 Mimics Repeated Forced Swim Stress to Potentiate Cocaine Place Preference Conditioning

Jay P McLaughlin et al. Neuropsychopharmacology.

Abstract

Repeated forced-swim stress (FSS) produced analgesia, immobility and potentiation of cocaine-conditioned place preference (CPP) in wild-type C57Bl/6 mice, but not in littermates lacking the kappa opioid receptor (KOR) gene. These results were surprising because kappa agonists are known to produce conditioned place aversion and to suppress cocaine-CPP when coadministered with cocaine. The possibility that disruption of the kappa system blocked the stress response by adversely affecting the hypothalamic-pituitary axis was examined by measuring plasma corticosterone levels. However, disruption of the dynorphin/kappa system by gene deletion or receptor antagonism did not reduce the FSS-induced elevation of plasma corticosterone levels. A second explanation for the difference is that kappa receptor activation caused by FSS occurred prior to cocaine conditioning rather than contemporaneously. To test this hypothesis, we measured the effects of the kappa agonist (trans)-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl]benzeneacetamide (U50,488) administered to mice at various intervals preceding cocaine conditioning. The results showed that the interaction between the kappa system and cocaine reinforcement depended on the timing of the drug pairing. Mice given U50,488 60 min prior to cocaine showed a robust, nor-BNI-sensitive potentiation of cocaine-CPP, whereas administration 15 min before cocaine significantly suppressed cocaine-CPP. In the absence of cocaine, U50,488 given 60 min prior to saline conditioning produced no place preference, whereas administration 15 min before saline conditioning produced significant place aversion. The results of this study suggest that kappa receptor activation induced by FSS prior to the cocaine-conditioning session may be both necessary and sufficient for potentiation of the reinforcing actions of cocaine.

Figures

Figure 1
Figure 1
FSS-induced analgesia and immobility is reduced on the second day of testing by pretreatment with nor-BNI or by disruption of the kappa opioid receptor (KOR) gene. (a) Tail withdrawal latencies in the 55°C warm-water assay presented were obtained 5–9 min after forced swim on the second day. * = Significantly different than matching preswim latencies, P < 0.05, as determined by two-way ANOVA followed by Newman–Keuls Multiple-Comparison post-hoc test. (b). The time mice spent immobile during the last 4 min of the forced swim test was measured during multiple trials over 2 days. (P < 0.05, Figure 1b, trials 3–5). KOR WT mice received either vehicle (open bars) or nor-BNI (10 mg/kg, i.p., grey bars) in a bolus of 0.3 ml/30 g body wt 1 h prior to daily swimming. KOR (−/−) mice received vehicle (black bars) on the same protocol and schedule. * = significant difference between immobility responses of stress-exposed vehicle-treated and nor-BNI treated WT mice or between immobility responses of WT and KOR gene disrupted mice, P < 0.05, as determined by one-way ANOVA followed by Newman-Keuls Multiple-comparison post hoc test. Bars represent n = 16–22 animals in both (a and b).
Figure 2
Figure 2
Exposure to FSS results in a KOR-mediated potentiation of cocaine conditioned place preference. WT and KOR (−/−) mice were divided into three groups each. The first group was unstressed, remaining in home cages prior to 2 days of cocaine and saline conditioning (left pair). The remaining groups were administered either vehicle (center pair) or nor-BNI (10 mg/kg, i.p., right pair) in a bolus of 0.3 ml/30 g body wt 1 h before repeated FSS and then conditioned over 2 days with cocaine and saline as previously described (McLaughlin et al, 2003). Subsequent preference results collected blind are plotted in seconds to highlight time spent on the drug-paired side of the apparatus. Y-axis values represent the difference in time spent in the cocaine-paired compartment subtracted from the saline-paired side on test day. * = significant difference in cocaine-CPP compared with CPP for both unstressed and nor-BNI-treated mice. P < 0.05, as determined by one-way ANOVA followed by Newman–Keuls Multiple-comparison post hoc test. (Bars represent n = 12–22 mice).
Figure 3
Figure 3
Stress-induced increases in corticosterone do not account for potentiation of cocaine conditioned place preference. Serum corticosterone levels in WT mice subjected to FSS increased three-fold (from a baseline of 16.0 ± 4.70 ng/ml, n = 11 to 49.5 ± 1.470 ng/ml, n = 8). Notably, both WT mice pretreated with nor-BNI and prodynorphin (−/−) mice showed a normal three-fold increase in serum corticosterone levels not significantly different from the response of WT mice, although both of these treatments prevented stress-induced potentiation of cocaine-conditioned place preference. Statistical comparisons were carried out for DYN, WT, and −/− mice separately to define effects of nor-BNI and swim stress. *P < 0.05 compared with untreated control as determined by one-way ANOVA followed by Newman–Keuls Multiple-comparison post hoc test. (Bars represent n = 8–11 mice).
Figure 4
Figure 4
Dose–response of U50,488-induced antinociception in the mouse 55°C warm-water tail withdrawal assay. Response latencies were obtained both before and 30 min after C57Bl/6 mice (dark circles) were injected with a single dose of U50,488 (2, 5, 10, or 25 mg/kg i.p.). Similarly, tail withdrawal latencies were obtained both before and 30 min after KOR (−/−) mice (open circles) were injected with U50,488 (25 mg/kg i.p.). Circles represent n = 6–9 mice (WT) or n = 24 mice (KOR knockout). * = significantly different than vehicle-treated mice, P < 0.05, as determined by one-way ANOVA followed by Fisher’s LSD Multiple-comparison post hoc test.
Figure 5
Figure 5
Pretreatment with KOR agonist is sufficient to produce a time-dependent potentiation or suppression of cocaine conditioned place preference. (a). Schematic of training paradigm. Preference testing allowed mice to move freely for 30 min between the three chambers (triangles). Mice were pretreated on day 2 with vehicle or U50,488 (5 mg/kg, i.p.; diamonds) at a time ranging from 6 h before to 30 min after administration of cocaine (15 mg/kg, s.c.) then confined to the drug-paired box for a 30-min conditioning session (squares, referring to b). Mice used in conditioned place aversion studies (c) received saline instead of cocaine. After 4 h, mice were given vehicle and confined to the vehicle-paired box for a 30-min conditioning session (circles). Drug pretreatment and conditioning were repeated the next day, separated again by 4 h (represented by the diamond and 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 time-dependent activation of the KOR-induced potentiation of cocaine-CPP. * = Significantly greater difference in cocaine-CPP compared with CPP for saline-pretreated mice; ζ = significantly less difference in cocaine-CPP compared with CPP for saline-pretreated mice, P < 0.05, as determined by one-way ANOVA followed by Newman–Keuls Multiple-comparison post hoc test. (Bars represent n = 12–36 mice). (c) Preference test data identifies a matching time course for conditioned place aversion induced by U50,488. These experiments replaced cocaine with saline as detailed above in (a); preferences are given as the difference between time spent in the first-saline-paired chamber and time spent in the second-saline-paired chamber during the 30-min trial. A positive value represents the time spent in the first-saline-paired chamber. Treatment of mice with U50,488 30 min after initial injection (and conditioning) with saline did not produce a significant preference or aversion for either chamber. * = significant difference in saline-CPP response compared with CPP for saline-pretreated mice, P < 0.05, as determined by one-way ANOVA followed by Newman–Keuls Multiple-comparison post hoc test. (Bars represent n = 8–12 mice).

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