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Pharmacological activation of kappa opioid receptors: aversive effects in adolescent and adult male rats

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Abstract

Rationale

The dynorphin (DYN)/kappa opioid receptor (KOR) system is involved in the dysphoric properties of drugs of abuse. Given that adolescents show reduced sensitivity to aversive effects of many drugs, alterations in the DYN/KOR system may contribute to the prevalence of drug use during adolescence.

Objectives

The present study was designed to assess dysphoric properties of a selective kappa agonist, U62,066, in adolescent and adult rats using both conditioned taste aversion (CTA) and conditioned place aversion (CPA) paradigms.

Methods

For CTA, water-restricted rats were administered U62,066 following 30 min access to a saccharin solution, with subsequent saccharin consumption used to index aversion. For CPA, animals were allowed access to both compartments of a two-compartment chamber for a 15-min pre- and post-conditioning test. For conditioning, subjects were administered U62,066 prior to confinement to one side of the chamber and saline prior to confinement to the other side for a total of four pairings.

Results

Overall, adolescents displayed reduced sensitivity to the kappa agonist relative to adults. Adults demonstrated taste aversions to the 0.2 and 0.3 mg/kg doses of U62,066, whereas adolescents did not display aversions to any tested doses. Adults demonstrated a place aversion to the 0.1 and 0.2 mg/kg dose of U62,066 when paired with the preferred side of the conditioning chamber. Adolescents did not display aversions to any of the doses tested.

Conclusions

Reduced sensitivity to DYN/KOR system activation during adolescence may be a contributing factor to the age-typical insensitivity to aversive properties of drugs commonly abused by adolescents.

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References

  • Adriani W, Laviola G (2003) Elevated levels of impulsivity and reduced place conditioning with d-amphetamine: two behavioral features of adolescence in mice. Behav Neurosci 117:695–703

    Article  PubMed  CAS  Google Scholar 

  • Adriani W, Chiarotti F, Laviola G (1998) Elevated novelty seeking and peculiar d-amphetamine sensitization in periadolescent mice compared with adult mice. Behav Neurosci 112:1152–1166

    Article  PubMed  CAS  Google Scholar 

  • Anderson RI, Varlinskaya EI, Spear LP (2010) Ethanol-induced conditioned taste aversion in male Sprague–Dawley rats: impact of age and stress. Alcohol Clin Exp Res 34:2106–2115

    Article  PubMed Central  PubMed  Google Scholar 

  • Anderson RI, Agoglia AE, Morales M, Varlinskaya EI, Spear LP (2013) Stress, kappa manipulations, and aversive effects of ethanol in adolescent and adult male rats. Neuroscience. doi:10.1016/j.neuroscience.2012.12.028

    Google Scholar 

  • Badanich KA, Adler KJ, Kirstein CL (2006) Adolescents differ from adults in cocaine conditioned place preference and cocaine-induced dopamine in the nucleus accumbens septi. Eur J Pharmacol 550:95–106

    Article  PubMed  CAS  Google Scholar 

  • Bals-Kubik R, Ableitner A, Herz A, Shippenberg T (1993) Neuroanatomical sites mediating the motivational effects of opioids as mapped by the conditioned place preference paradigm in rats. J Pharmacol Exp Ther 264:489–495

    Google Scholar 

  • Bals-Kubik R, Herz A, Shippenberg TS (1989) Evidence that the aversive effects of opioid antagonists and kappa-agonists are centrally mediated. Psychopharmacology (Berlin) 98:203–206

    Article  CAS  Google Scholar 

  • Bardo MT, Rowlett JK, Harris MJ (1995) Conditioned place preference using opiate and stimulant drugs: a meta-analysis. Neurosci Biobehav Rev 19:39–51

    Article  PubMed  CAS  Google Scholar 

  • Barr GA, Wang S, Carden S (1994) Aversive properties of the kappa opioid agonist U50,488 in the week-old rat pup. Psychopharmacology (Berlin) 113:422–428

    Article  CAS  Google Scholar 

  • Collins RL, Zavala AR, Nazarian A, McDougall SA (2000) kappa-Opioid receptors in the substantia nigra pars reticulata mediate the U-50,488-induced locomotor activity of preweanling rats. Brain Res Dev Brain Res 119:97–103

    Article  PubMed  CAS  Google Scholar 

  • Cortez AM, Charntikov S, Der-Ghazarian T, Horn LR, Crawford CA, McDougall SA (2010) Age-dependent effects of kappa-opioid receptor stimulation on cocaine-induced stereotyped behaviors and dopamine overflow in the caudate-putamen: an in vivo microdialysis study. Neuroscience 169:203–213

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Cunningham CL, Ferree NK, Howard MA (2003) Apparatus bias and place conditioning with ethanol in mice. Psychopharmacology (Berlin) 170:409–422

    Article  CAS  Google Scholar 

  • Doremus-Fitzwater TL, Varlinskaya EI, Spear LP (2010) Motivational systems in adolescence: possible implications for age differences in substance abuse and other risk-taking behaviors. Brain Cogn 72:114–123

    Google Scholar 

  • Douglas LA, Varlinskaya EI, Spear LP (2003) Novel-object place conditioning in adolescent and adult male and female rats: effects of social isolation. Physiol Behav 80:317–325

    Article  PubMed  CAS  Google Scholar 

  • Hartup WW, Stevens N (1997) Friendships and adaptation in the life course. Psychol Bull 121:355–370

    Article  Google Scholar 

  • Holson RR, Pearce B (1992) Principles and pitfalls in the analysis of prenatal treatment effects in multiparous species. Neurotoxicol Teratol 14:221–228

    Article  PubMed  CAS  Google Scholar 

  • Hurwitz ZE, Merluzzi AP, Riley AL (2012) Age-dependent differences in morphine-induced taste aversions. Dev Psychobiol. doi:10.1002/dev.21046

    PubMed  Google Scholar 

  • Infurna RN, Spear LP (1979) Developmental changes in amphetamine-induced taste aversions. Pharmacol Biochem Behav 11:31–35

    Article  PubMed  CAS  Google Scholar 

  • Iwamoto EI (1986) Place-conditioning properties of mu, kappa, and sigma opioid agonists. Alcohol Drugs Res 6:327–339

    CAS  Google Scholar 

  • Johnston LD, O’Malley PM, Bachman JG, Schulenberg JE (2012) Monitoring the Future national results on adolescent drug use: overview of key findings, 2011. Institute for Social Research, The University of Michigan, Ann Arbor

    Google Scholar 

  • Kelley AE, Schochet T, Landry CF (2004) Risk taking and novelty seeking in adolescence: introduction to part I. Ann N Y Acad Sci 1021:27–32

    Article  PubMed  Google Scholar 

  • Laviola G, Macri S, Morley-Fletcher S, Adriani W (2003) Risk-taking behavior in adolescent mice: psychobiological determinants and early epigenetic influence. Neurosci Biobehav Rev 27:19–31

    Article  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  PubMed Central  PubMed  CAS  Google Scholar 

  • McDougall SA, Garmsen GM, Meier TL, Crawford CA (1997) Kappa opioid mediated locomotor activity in the preweanling rat: role of pre- and postsynaptic dopamine receptors. Psychopharmacology (Berlin) 133:62–68

    Article  CAS  Google Scholar 

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

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Michaels CC, Holtzman SG (2008) Early postnatal stress alters place conditioning to both mu- and kappa-opioid agonists. J Pharmacol Exp Ther 325:313–318

    Article  PubMed  CAS  Google Scholar 

  • Morales L, Perez-Garcia C, Herradon G, Alguacil LF (2007) Place conditioning in a two- or three-conditioning compartment apparatus: a comparative study with morphine and U-50,488. Addict Biol 12:482–484

    Article  PubMed  CAS  Google Scholar 

  • Mucha RF, Herz A (1985) Motivational properties of kappa and mu opioid receptor agonists studied with place and taste preference conditioning. Psychopharmacology (Berlin) 86:274–280

    Article  CAS  Google Scholar 

  • Nizhnikov ME, Pautassi RM, Varlinskaya EI, Rahmani P, Spear NE (2012) Ontogenetic differences in ethanol's motivational properties during infancy. Alcohol 46:225–234

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Petrov ES, Nizhnikov ME, Varlinskaya EI, Spear NE (2006) Dynorphin A (1-13) and responsiveness of the newborn rat to a surrogate nipple: immediate behavioral consequences and reinforcement effects in conditioning. Behav Brain Res 170:1–14

    Google Scholar 

  • Primus RJ, Kellogg CK (1989) Pubertal-related changes influence the development of environment-related social interaction in the male rat. Dev Psychobiol 22:633–643

    Article  PubMed  CAS  Google Scholar 

  • Roma PG, Riley AL (2005) Apparatus bias and the use of light and texture in place conditioning. Pharmacol Biochem Behav 82:163–169

    Article  PubMed  CAS  Google Scholar 

  • Sante AB, Nobre MJ, Brandao ML (2000) Place aversion induced by blockade of mu or activation of kappa opioid receptors in the dorsal periaqueductal gray matter. Behav Pharmacol 11:583–589

    Article  PubMed  CAS  Google Scholar 

  • Schramm-Sapyta NL, Morris RW, Kuhn CM (2006) Adolescent rats are protected from the conditioned aversive properties of cocaine and lithium chloride. Pharmacol Biochem Behav 84:344–352

    Article  PubMed  CAS  Google Scholar 

  • Schramm-Sapyta NL, Cha YM, Chaudhry S, Wilson WA, Swartzwelder HS, Kuhn CM (2007) Differential anxiogenic, aversive, and locomotor effects of THC in adolescent and adult rats. Psychopharmacology (Berlin) 191:867–877

    Article  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

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

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Shram MJ, Funk D, Li Z, Le AD (2006) Periadolescent and adult rats respond differently in tests measuring the rewarding and aversive effects of nicotine. Psychopharmacology 186:201–208

    Google Scholar 

  • Spear LP (2000) The adolescent brain and age-related behavioral manifestations. Neurosci Biobehav Rev 24:417–463

    Article  PubMed  CAS  Google Scholar 

  • Spear LP (2010) The behavioral neuroscience of adolescence. Norton, New York

  • Spear LP (2011) Rewards, aversions and affect in adolescence: emerging convergences across laboratory animal and human data. Dev Cogn Neurosci 1:390–403

    Article  PubMed Central  Google Scholar 

  • Steinberg L (2008) A social neuroscience perspective on adolescent risk-taking. Dev Rev 28:78–106

    Article  PubMed Central  PubMed  Google Scholar 

  • Tejeda HA, Natividad LA, Orfila JE, Torres OV, O'Dell LE (2012) Dysregulation of kappa-opioid receptor systems by chronic nicotine modulate the nicotine withdrawal syndrome in an age-dependent manner. Psychopharmacology (Berl) 224:289–301

    Google Scholar 

  • Torres OV, Tejeda HA, Natividad LA, O'Dell LE (2008) Enhanced vulnerability to the rewarding effects of nicotine during the adolescent period of development. Pharmacol Biochem Behav 90:658–663

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Tzschentke TM (1998) Measuring reward with the conditioned place preference paradigm: a comprehensive review of drug effects, recent progress and new issues. Prog Neurobiol 56:613–672

    Article  PubMed  CAS  Google Scholar 

  • Tzschentke TM (2007) Measuring reward with the conditioned place preference (CPP) paradigm: update of the last decade. Addict Biol 12:227–462

    Article  PubMed  CAS  Google Scholar 

  • Varlinskaya EI, Spear LP (2008) Social interactions in adolescent and adult Sprague–Dawley rats: impact of social deprivation and test context familiarity. Behav Brain Res 188:398–405

    Article  PubMed Central  PubMed  Google Scholar 

  • Vastola BJ, Douglas LA, Varlinskaya EI, Spear LP (2002) Nicotine-induced conditioned place preference in adolescent and adult rats. Physiol Behav 77:107–114

    Article  PubMed  CAS  Google Scholar 

  • Vetter-O'Hagen CS, Spear LP (2012) Hormonal and physical markers of puberty and their relationship to adolescent-typical novelty-directed behavior. Dev Psychobiol 54:523–535

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Vetter-O'Hagen C, Varlinskaya E, Spear L (2009) Sex differences in ethanol intake and sensitivity to aversive effects during adolescence and adulthood. Alcohol Alcohol 44:547–554

    Article  PubMed Central  PubMed  Google Scholar 

  • Wadenberg ML (2003) A review of the properties of spiradoline: a potent and selective kappa-opioid receptor agonist. CNS Drug Rev 9:187–198

    Article  PubMed  CAS  Google Scholar 

  • Wee S, Koob GF (2010) The role of the dynorphin-kappa opioid system in the reinforcing effects of drugs of abuse. Psychopharmacology (Berl) 210:121–135

    Article  CAS  Google Scholar 

  • Wilmouth CE, Spear LP (2004) Adolescent and adult rats’ aversion to flavors previously paired with nicotine. Ann N Y Acad Sci 1021:462–464

    Article  PubMed  Google Scholar 

  • Zakharova E, Leoni G, Kichko I, Izenwasser S (2009a) Differential effects of methamphetamine and cocaine on conditioned place preference and locomotor activity in adult and adolescent male rats. Behav Brain Res 198:45–50

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Zakharova E, Wade D, Izenwasser S (2009b) Sensitivity to cocaine conditioned reward depends on sex and age. Pharmacol Biochem Behav 92:131–134

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Zhang Y, Butelman ER, Schlussman SD, Ho A, Kreek MJ (2005) Effects of the plant-derived hallucinogen salvinorin A on basal dopamine levels in the caudate putamen and in a conditioned place aversion assay in mice: agonist actions at kappa opioid receptors. Psychopharmacology (Berlin) 179:551–558

    Article  CAS  Google Scholar 

  • Zorrilla EP (1997) Multiparous species present problems (and possibilities) to developmentalists. Dev Psychobiol 30:141–150

    Article  PubMed  CAS  Google Scholar 

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The authors have no conflicts of interest to disclose.

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Authors and Affiliations

  1. Center for Development and Behavioral Neuroscience, Department of Psychology, Binghamton University, 4400 Vestal Parkway East, Binghamton, NY, 13902-6000, USA

    Rachel I. Anderson, Melissa Morales, Linda P. Spear & Elena I. Varlinskaya

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  1. Rachel I. Anderson
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  2. Melissa Morales
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  3. Linda P. Spear
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  4. Elena I. Varlinskaya
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Corresponding author

Correspondence to Rachel I. Anderson.

Additional information

The work presented in this manuscript was funded by grants AA017823 to LPS and AA012453 to EIV.

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Anderson, R.I., Morales, M., Spear, L.P. et al. Pharmacological activation of kappa opioid receptors: aversive effects in adolescent and adult male rats. Psychopharmacology 231, 1687–1693 (2014). https://doi.org/10.1007/s00213-013-3095-8

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  • DOI: https://doi.org/10.1007/s00213-013-3095-8

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