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Endogenous kappa-opioid mediation of stress-induced potentiation of ethanol-conditioned place preference and self-administration

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Abstract

Rationale

Exposure to inescapable stressors increases both the rewarding properties and self-administration of cocaine through the signaling of the kappa-opioid receptor (KOR), but the effect of this signaling on other reinforcing agents remains unclear.

Objective

The objective of this study is to test the hypothesis that signaling of the KOR mediates the forced swim stress (FSS)-induced potentiation of ethanol reward and self-administration.

Methods

Male C57Bl/6J mice were tested in a biased ethanol-conditioned place preference (CPP) procedure, and both C57Bl/6J and prodynorphin gene-disrupted (Dyn −/−) mice were used in two-bottle free choice (TBC) assays, with or without exposure to FSS. To determine the role of the KOR in the resulting behaviors, the KOR agonist U50,488 (10 mg/kg) and antagonist nor-binaltorphimine (nor-BNI, 10 mg/kg) were administered prior to parallel testing.

Results

C57Bl/6J mice exposed to repeated FSS 5 min prior to daily place conditioning with ethanol (0.8 g/kg) demonstrated a 4.4-fold potentiation of ethanol-CPP compared to unstressed mice that was prevented by nor-BNI pretreatment. Likewise, pretreatment with U50,488 90 min prior to daily ethanol place conditioning resulted in a 2.8-fold potentiation of ethanol-CPP. In the TBC assay, exposure to FSS significantly increased the consumption of 10% (v/v) ethanol by 19.3% in a nor-BNI-sensitive manner. Notably, Dyn −/− mice consumed a similar volume of ethanol as wild-type littermates and C57Bl/6J mice, but did not demonstrate significant stress-induced increases in consumption.

Conclusions

These data demonstrated a stress-induced potentiation of the rewarding effects and self-administration of ethanol mediated by KOR signaling.

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References

  • Aldrich JV, Patkar KA, McLaughlin JP (2009) Zyklophin, a systemically active selective kappa opioid receptor peptide antagonist with short duration of action. Proc Natl Acad Sci USA 106:18396–18401

    Article  CAS  PubMed  Google Scholar 

  • Belknap JK, Crabbe JC, Young ER (1993) Voluntary consumption of ethanol in 15 inbred mouse strains. Psychopharmacology 112:503–510

    Article  CAS  PubMed  Google Scholar 

  • Blednov YA, Walker D, Martinez M, Harris RA (2006) Reduced alcohol consumption in mice lacking preprodynorphin. Alcohol 40:73–86

    Article  CAS  PubMed  Google Scholar 

  • Carey AN, Borozny K, Aldrich JV, McLaughlin JP (2007) Reinstatement of cocaine place-conditioning prevented by the peptide kappa-opioid receptor antagonist arodyn. Eur J Pharmacol 569:84–89

    Article  CAS  PubMed  Google Scholar 

  • Carey AN, Lyons AM, Shay CF, Dunton O, McLaughlin JP (2009) Endogenous κ opioid activation mediates stress-induced deficits in learning and memory. J Neurosci 29:4293–4300

    Article  CAS  PubMed  Google Scholar 

  • Cunningham CL, Neihus DR, Malott DH, Prather LK (1992) Genetic differences in the rewarding and activating effects of morphine and ethanol. Psychopharmacology (Berlin) 107:385–393

    Article  CAS  Google Scholar 

  • Faulkner TP, Cantleberry SB, Watts VJ, Hussain AS (1990) Comparative pharmacokinetics of ethanol in inbred strains of mice using doses based on total body water. Alcohol Clin Exp Res 14:82–86

    Article  CAS  PubMed  Google Scholar 

  • Funk D, Harding S, Juzytsch W, Lê AD (2005) Effects of unconditioned and conditioned social defeat on alcohol self-administration and reinstatement of alcohol seeking in rats. Psychopharmacologia 183:341–349

    Article  CAS  Google Scholar 

  • Gabriel KI, Cunningham CL (2008) Effects of maternal strain on ethanol responses in reciprocal F1 C57BL/6J and DBA/2J hybrid mice. Genes Brain Behav 7:276–287

    Article  CAS  PubMed  Google Scholar 

  • Gremel CM, Gabriel KI, Cunningham CL (2006) Topiramate does not affect the acquisition or expression of ethanol conditioned place preference in DBA/2J or C57BL/6J mice. Alcohol Clin Exp Res 30:783–790

    Article  CAS  PubMed  Google Scholar 

  • Herz A (1997) Endogenous opioid systems and alcohol addiction. Psychopharmacology 129:99–111

    Article  CAS  PubMed  Google Scholar 

  • Hiramatsu M, Hoshino T (2005) Improvement of memory impairment by (+)- and (−)-pentazocine via sigma, but not kappa opioid receptors. Brain Res 1057:72–80

    Article  CAS  PubMed  Google Scholar 

  • Hölter SM, Henniger MSH, Lipkowski AW, Spanagel R (2000) Kappa-opioid receptors and relapse-like drinking in long-term ethanol-experienced rats. Psychopharmacology 153:93–102

    Article  PubMed  Google Scholar 

  • Houchi H, Babovic D, Pierrefiche O, Ledent C, Daoust M, Naassila M (2005) CB1 receptor knockout mice display reduced ethanol-induced conditioned place preference and increased striatal dopamine D2 receptors. Neuropsychopharmacology 30:339–349

    Article  CAS  PubMed  Google Scholar 

  • Kelley BM, Bandy A-LE, Middaugh LD (1997) A study examining intravenous ethanol-conditioned place preference in C57BL/6J mice. Alcohol Clin Exp Res 21:1661–1666

    CAS  PubMed  Google Scholar 

  • Knoll AT, Meloni EG, Thomas JB, Carroll FI, Carlezon WA Jr (2007) Anxiolytic-like effects of kappa-opioid receptor antagonists in models of unlearned and learned fear in rats. J Pharmacol Exp Ther 323:838–845

    Article  CAS  PubMed  Google Scholar 

  • Koob GF, Ahmed SH, Boutrel B, Chen SA, Kenny PJ, Markou A, O'Dell LE, Parsons LH, Sanna PP (2004) Neurobiological mechanisms in the transition from drug use to drug dependence. Neurosci Biobehav Rev 27:739–749

    Article  CAS  PubMed  Google Scholar 

  • Kovacs KM, Szakall I, O'Brien D, Wang R, Vinod KY, Saito M, Simonin F, Kieffer BL, Vadasz C (2005) Decreased oral self-administration of alcohol in κ-opioid receptor knock-out mice. Alcohol Clin Exp Res 29:730–738

    Article  CAS  PubMed  Google Scholar 

  • Kuzman A, Sandin J, Terenius L, Ögren SO (2003) Acquisition, expression, and reinstatement of ethanol-induced conditioned place preference in mice: effects of opioid receptor-like 1 receptor agonists and naloxone. J Pharmacol Exp Ther 304:310–318

    Article  Google Scholar 

  • Kuzmin A, Madjid N, Terenius L, Ogren SO, Bakalkin G (2006) Big dynorphin, a prodynorphin-derived peptide produces NMDA receptor-mediated effects on memory, anxiolytic-like and locomotor behavior in mice. Neuropsychopharmacology 31:1928–1937

    Article  CAS  PubMed  Google Scholar 

  • Lê AD, Harding S, Juzytsch W, Watchus J, Shalev U, Shaham Y (2000) The role of the corticotrophin-releasing factor in stress-induced relapse to alcohol-seeking behavior in rats. Psychopharmacology 150:317–324

    Article  PubMed  Google Scholar 

  • Li XC, Karadsheh MS, Jenkins PM, Stitzel JA (2005) Genetic correlation between free-choice oral consumption of nicotine and alcohol in C57BL/6J x C3H/HeJ F2 intercross mice. Behav Brain Res 157:79–90

    Article  CAS  PubMed  Google Scholar 

  • Lindholm S, Werme M, Berne S, Franck J (2001) The selective κ-opioid receptor U50, 488H attenuates voluntary ethanol intake in the rat. Behav Brain Res 120:137–146

    Article  CAS  PubMed  Google Scholar 

  • Logrip ML, Janak PH, Ron D (2009) Blockade of ethanol reward by the kappa opioid receptor agonist U50, 488H. Alcohol 43:359–365

    Article  CAS  PubMed  Google Scholar 

  • Lowery EG, Sparrow AM, Breese GR, Knapp DJ, Thiele TE (2008) The CRF-1 receptor antagonist, CP-154, 526, attenuates stress-induced increases in ethanol consumption by BALB/cJ mice. Alcohol Clin Exp Res 32:240–248

    Article  CAS  PubMed  Google Scholar 

  • Lucki I, Dalvi A, Mayorga AJ (2001) Sensitivity to the effects of pharmacologically selective antidepressants in different strains of mice. Psychopharmacology (Berl) 155:651–657

    Article  Google Scholar 

  • Matsuzawa S, Suzuki T, Misawa M (1998) Conditioned fear stress induces ethanol-associated place preference in rats. Eur J Pharmacol 341:127–130

    Article  CAS  PubMed  Google Scholar 

  • Matsuzawa S, Suzuki T, Misawa M, Nagase H (1999) Different roles of μ-, δ- and κ-opioid receptors in ethanol-associated place preference in rats exposed to conditioned fear stress. Eur J Pharmacol 368:9–16

    Article  CAS  PubMed  Google Scholar 

  • McKenzie-Quirk SD, Miczek KA (2008) Social rank and social separation as determinants of alcohol drinking in squirrel monkeys. Psychopharmacology 201:137–145

    Article  CAS  PubMed  Google Scholar 

  • McLaughlin JP, Marton-Popovici M, Chavkin C (2003) κ Opioid receptor antagonism and prodynorphin gene disruption block stress-induced behavioral responses. J Neurosci 23:5674–5683

    CAS  PubMed  Google Scholar 

  • McLaughlin JP, Land BB, Li S, Pintar JE, Chavkin C (2006) Prior activation of kappa opioid receptors by U50, 488 mimics forced swim stress to potentiate cocaine place preference conditioning. Neuropsychopharmacology 31:787–794

    Article  CAS  PubMed  Google Scholar 

  • Middaugh LD, Bandy A-LE (2000) Naltrexone effects on ethanol consumption and response to ethanol conditioned cues in C57Bl/6 mice. Psychopharmacology 151:321–327

    Article  CAS  PubMed  Google Scholar 

  • Mills KC, Bean JW, Hutcheson JS (1977) Shock induced ethanol consumption in rats. Pharmacol Biochem Behav 6:107–115

    Article  CAS  PubMed  Google Scholar 

  • Mitchell JM, Liang MT, Fields HL (2005) A single injection of the kappa opioid antagonist norbinaltorphimine increases ethanol consumption in rats. Psychopharmacology 182:384–392

    Article  CAS  PubMed  Google Scholar 

  • Negus SS (2004) Effects of the kappa opioid agonist U50, 488 and the kappa opioid antagonist nor-binaltorphimine on choice between cocaine and food in rhesus monkeys. Psychopharmacology (Berlin) 176:204–213

    Article  Google Scholar 

  • Nocjar C, Middaugh LD, Tavernetti M (1999) Ethanol consumption and place-preference conditioning in the alcohol-preferring C57BL/6 mouse: relationship with motor activity patterns. Alcohol Clin Exp Res 23:683–692

    CAS  PubMed  Google Scholar 

  • Orsini C, Bonito-Oliva A, Conversi D, Cabib S (2005) Susceptibility to conditioned place preference induced by addictive drugs in mice of the C57BL/6 and DBA/2 inbred strains. Psychopharmacology 181:327–336

    Article  CAS  PubMed  Google Scholar 

  • Peele S, Brodsky A (2000) Exploring psychological benefits associated with moderate alcohol use: a necessary corrective to assessments of drinking outcomes? Drug Alcohol Depend 60:221–247

    Article  CAS  PubMed  Google Scholar 

  • Piazza PV, Deminiere JM, Le Moal M, Simon H (1990) Stress- and pharmacologically induced behavioral sensitization increases vulnerability to acquisition of amphetamine self-administration. Brain Res 514:22–26

    Article  CAS  PubMed  Google Scholar 

  • Pohorecky LA (1981) The interaction of alcohol and stress: a review. Neurosci Biobehav Rev 5:209–229

    Article  CAS  PubMed  Google Scholar 

  • Risinger FO, Brown MM, Doan AM, Oakes RA (1998) Mouse strain difference in oral operant ethanol reinforcement under continuous access conditions. Alcohol Clin Exp Res 22:677–684

    Article  CAS  PubMed  Google Scholar 

  • Roberts AJ, McDonald JS, Heyser CJ, Kieffer BL, Matthes HWD, Koob GF, Gold LH (2000) μ-opioid receptor knockout mice do not self-administer alcohol. J Pharmacol Exp Ther 293:1002–1008

    CAS  PubMed  Google Scholar 

  • Rockman GE, Hall A, Hong J, Glavin GB (1987) Unpredictable cold-immobilization stress effects voluntary ethanol consumption in rats. J Life Sci 40:1245–1251

    Article  CAS  Google Scholar 

  • Shaham Y, Stewart J (1994) Exposure to mild stress enhances the reinforcing efficacy of intravenous heroin self-administration in rats. Psychopharmacology (Berl) 114:523–527

    Article  CAS  Google Scholar 

  • Sharifi N, Diehl N, Yaswen L, Brennan MB, Hochgeschwender U (2001) Generation of dynorphin knockout mice. Brain Res Mol Brain Res 86:70–75

    Article  CAS  PubMed  Google Scholar 

  • Shippenberg TS, Herz A (1986) Differential effects of mu and kappa opioid systems on motivational processes. NIDA Res Monogr 75:563–566

    CAS  PubMed  Google Scholar 

  • Shippenberg TS, Zapata A, Chefer VI (2007) Dynorphin and the pathophysiology of drug addiction. Pharmacol Ther 116:306–321

    Article  CAS  PubMed  Google Scholar 

  • Shirayama Y, Ishida H, Iwata M, Hazama GI, Kawahara R, Duman RS (2004) Stress increases dynorphin immunoreactivity in limbic brain regions and dynorphin antagonism produces antidepressant-like effects. J Neurochem 90:1258–1268

    Article  CAS  PubMed  Google Scholar 

  • Sommer W, Hyytiä P, Kiianmaa K (2006) The alcohol-preferring AA and alcohol-avoiding ANA rats: neurobiology of the regulation of alcohol drinking. Addict Biol 11:289–309

    Article  PubMed  Google Scholar 

  • Spanagel R, Montkowski A, Allingham K, Stohr T, Shoaib M, Holsboer F, Landgraf R (1995) Anxiety: a potential predictor of vulnerability to the initiation of ethanol self-administration in rats. Psychopharmacology (Berl) 122:369–373

    Article  CAS  Google Scholar 

  • Stromberg MF, Casale M, Volpicelli L, Volpicelli JR, O'Brien CP (1998) A comparison of the effects of the opioid antagonists naltrexone, naltrindole, and beta-funaltrexamine on ethanol consumption in the rat. Alcohol 15:281–289

    Article  CAS  PubMed  Google Scholar 

  • Suzuki T, Shiozaki Y, Masukawa Y, Misawa M, Nagase H (1992) The role of mu- and kappa-opioid receptors in cocaine-induced conditioned place preference. Jpn J Pharmacol 58:435–442

    Article  CAS  PubMed  Google Scholar 

  • Thanos PK, Dimitrakakis ES, Rice O, Gifford A, Volkow ND (2005) Ethanol self-administration and ethanol conditioned place preference are reduced in mice lacking cannabinoid CB1 receptors. Behav Brain Res 164:206–213

    Article  CAS  PubMed  Google Scholar 

  • Thiele TE, Marsh DJ, Ste ML, Bernstein IL, Palmiter RD (1998) Ethanol consumption and resistance are inversely related to neuropeptide Y levels. Nature 396:366–369

    Article  CAS  PubMed  Google Scholar 

  • van Erp AM, Miczek KA (2001) Persistent suppression of ethanol self-administration by brief social stress in rats and increased startle response as index of withdrawal. Physiol Behav 73:301–311

    Article  PubMed  Google Scholar 

  • van Erp AM, Tachi N, Miczek KA (2001) Short or continuous social stress: suppression of continuously available ethanol intake in subordinate rats. Behav Pharmacol 12:335–342

    PubMed  Google Scholar 

  • Vengeliene V, Bilbao A, Molander A, Spanagel R (2008) Neuropharmacology of alcohol addiction. Br J Pharmacol 154:299–315

    Article  CAS  PubMed  Google Scholar 

  • Walker BM, Koob GF (2008) Pharmacological evidence for a motivational role of κ-opioid systems in ethanol dependence. Neuropsychopharmacology 33:643–652

    Article  CAS  PubMed  Google Scholar 

  • Will MJ, Watkins LR, Maier SF (1998) Uncontrollable stress potentiates morphine's rewarding proprieties. Pharmacol Biochem Beh 60:655–664

    Article  CAS  Google Scholar 

  • Willinger U, Lenzinger E, Hornik K, Fischer G, Schonbeck G, Aschauer HN, Meszaros K, European fluvoxamine in alcoholism study group (2002) Anxiety as a predictor of relapse in detoxified alcohol-dependent patients. Alcohol 37:609–612

    Google Scholar 

  • Wilson MA, Burghardt PR, Ford KA, Wilkinson MB, Primeaux SD (2004) Anxiolytic effects of diazepam and ethanol in two behavioral models: comparison of males and females. Pharmacol Biochem Behav 78:445–458

    Article  CAS  PubMed  Google Scholar 

  • Wolffgramm J (1990) Free choice ethanol intake of laboratory rats under different social conditions. Psychopharmacology 101:233–239

    Article  CAS  PubMed  Google Scholar 

  • Zapata A, Shippenberg TS (2006) Endogenous κ opioid receptor systems modulate the responsiveness of mesoaccumbal dopamine neurons to ethanol. Alcohol Clin Exp Res 30:592–597

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We thank Dr. Ute Hochgeschwender for generously providing the prodynorphin gene-disrupted mice. This research is supported by R03 DA16415 from the National Institute on Drug Abuse to JPM and funds from the State of Florida, Executive Office of the Governor's Office of Tourism, Trade, and Economic Development. Mice were housed and cared for in the Northeastern University or TPIMS animal facilities in accordance with the 1996 National Institutes of Health Guide for the Care and Use of Laboratory Animals. All studies were performed after prior approval by the local Institutional Animal Care and Use Committee and are in full compliance with the current laws of the USA.

Conflicts of interest

The authors declare that they have full control of all primary data. Except for income received from our primary employers, no financial support or compensation has been received from any individual or corporate entity over the past 3 years for research or professional services related to this project, and there are no personal financial holdings that could be perceived as constituting a potential conflict of interest.

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Authors and Affiliations

  1. Department of Psychology, Northeastern University, Boston, MA, 02115, USA

    Robin E. Sperling, Stacey M. Gomes, Elizabeth I. Sypek, Amanda N. Carey & Jay P. McLaughlin

  2. Torrey Pines Institute of Molecular Studies, 11350 SW Village Parkway, Port St. Lucie, FL, 34987, USA

    Stacey M. Gomes & Jay P. McLaughlin

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  1. Robin E. Sperling
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  2. Stacey M. Gomes
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Correspondence to Jay P. McLaughlin.

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Robin E. Sperling and Stacey M. Gomes contributed equally to this project.

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Sperling, R.E., Gomes, S.M., Sypek, E.I. et al. Endogenous kappa-opioid mediation of stress-induced potentiation of ethanol-conditioned place preference and self-administration. Psychopharmacology 210, 199–209 (2010). https://doi.org/10.1007/s00213-010-1844-5

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