, Volume 235, Issue 1, pp 59–69 | Cite as

Effects of morphine on place conditioning and ERK1/2 phosphorylation in the nucleus accumbens of psychogenetically selected Roman low- and high-avoidance rats

  • Michela Rosas
  • Simona Porru
  • Marta Sabariego
  • Maria Antonietta Piludu
  • Osvaldo Giorgi
  • Maria G. Corda
  • Elio Acquas
Original Investigation



Extracellular signal-regulated kinase (ERK1/2) phosphorylation is critical for neuronal and behavioural functions; in particular, phosphorylated ERK1/2 (pERK1/2) expression in the nucleus accumbens (Acb) of the rat is stimulated by addictive drugs with the exception of morphine, which decreases accumbal ERK1/2 phosphorylation in the Sprague-Dawley and Wistar rats. The psychogenetically selected Roman low- (RLA) and high-avoidance (RHA) rats differ behaviourally and neurochemically in many responses to addictive drugs. In particular, morphine elicits a greater increment in locomotor activity and in dopamine transmission in the Acb of RHA vs RLA rats. However, the effects of morphine on place conditioning (conditioned place preference (CPP)) and ERK1/2 phosphorylation in the Roman lines remain unknown.

Objectives and methods

To characterize in the Roman lines the reinforcing properties of morphine (i.e. morphine-elicited CPP acquisition) and the relationship between these properties and its effects on ERK1/2 phosphorylation in the Acb, the behavioural effects of morphine were evaluated in a place-conditioning apparatus and ERK1/2 phosphorylation was assessed by immunohistochemistry in the shell and core subregions of the Acb of rats both acutely administered with morphine or undergoing conditioning.


Morphine elicited CPP in both Roman lines and decreased pERK1/2 expression in the Acb of RLA but not RHA rats. Such decrease was prevented by conditioning.


These findings indicate that the selective breeding of the Roman lines has generated a divergence, in terms of morphine-elicited pERK1/2 expression but not of morphine-elicited CPP, between RLA and RHA rats and sustain the observation that changes in pERK1/2 expression in the Acb are not a requisite for the reinforcing effects of morphine.


Conditioned place preference (CPP) Extracellular signal-regulated kinase (ERK) Morphine Nucleus accumbens Phosphorylated ERK (pERK) Psychogenetic selection RHA rats RLA rats 


Funding information

This study was supported by funds from MIUR (Ministero dell’Istruzione, Università e Ricerca, PRIN), Regione Autonoma della Sardegna (RAS) (L.R. 7/2007, CRP2_537), Fondazione Banco di Sardegna (Sassari, Italy) and from the University of Cagliari to EA and by grants from MIUR to OG and MGC and from RAS (L.R. 7/2007, CRP-59842) to OG.


  1. Acquas E, Di Chiara G (1994) D1 receptor blockade stereospecifically impairs the acquisition of drug-conditioned place preference and place aversion. Behav Pharmacol 5(6):555–569Google Scholar
  2. Acquas E, Carboni E, Leone P, Di Chiara G (1989) SCH 23390 blocks drug-conditioned place-preference and place-aversion: anhedonia (lack of reward) or apathy (lack of motivation) after dopamine-receptor blockade? Psychopharmacology 99(2):151–155CrossRefPubMedGoogle Scholar
  3. Acquas E, Pisanu A, Spiga S, Plumitallo A, Zernig G, Di Chiara G (2007) Differential effects of intravenous R,S-(±)-3,4-methylenedioxymethamphetamine (MDMA, ecstasy) and its S(+)- and R(−)-enantiomers on dopamine transmission and extracellular signal regulated kinase phosphorylation (pERK) in the rat nucleus accumbens shell and core. J Neurochem 102:121–132CrossRefPubMedGoogle Scholar
  4. Baars MY, Müller MJ, Gallhofer B, Netter P (2013) Relapse (number of detoxifications) in abstinent male alcohol-dependent patients as related to personality traits and types of tolerance to frustration. Neuropsychobiology 67:241–248CrossRefPubMedGoogle Scholar
  5. Belin D, Mar AC, Dalley JW, Robbins TW, Everitt BJ (2008) High impulsivity predicts the switch to compulsive cocaine-taking. Science 320:1352–1355CrossRefPubMedPubMedCentralGoogle Scholar
  6. Beninger RJ, Gerdjikov T (2004) The role of signaling molecules in reward-related incentive learning. Neurotox Res 61:91–104CrossRefGoogle Scholar
  7. Berke JD, Hyman SE (2000) Addiction, dopamine, and the molecular mechanisms of memory. Neuron 25:515–532CrossRefPubMedGoogle Scholar
  8. Brami-Cherrier K, Valjent E, Hervé D, Darragh J, Corvol JC, Pages C, Arthur SJ, Girault JA, Caboche J (2005) Parsing molecular and behavioural effects of cocaine in mitogen- and stress-activated protein kinase-1-deficient mice. J Neurosci 25:11444–11454CrossRefPubMedGoogle Scholar
  9. Carr GD, Fibiger HC, Phillips AG (1989) Conditioned place preference as a measure of drug reward. In: Liebman J, Cooper S (eds) The neuropharmacological basis of reward. Oxford Science Publication, Clarendon Press, Oxford, pp 264–319Google Scholar
  10. Ciccarelli A, Giustetto M (2014) Role of ERK signaling in activity-dependent modifications of histone proteins. Neuropharmacology 80:34–44Google Scholar
  11. Colombo G, Lobina C, Carai MA, Gessa GL (2006) Phenotypic characterization of genetically selected Sardinian alcohol-preferring (sP) and -non-preferring (sNP) rats. Addict Biol 11:324–338CrossRefPubMedGoogle Scholar
  12. Coppens CM, de Boer SF, Steimer T, Koolhaas JM (2013) Correlated behavioural traits in rats of the Roman selection lines. Behav Genet 430:220–226CrossRefGoogle Scholar
  13. Corda MG, Piras G, Piludu MA, Giorgi O (2014) Differential effects of voluntary ethanol consumption on dopamine output in the nucleus accumbens shell of Roman high- and low-avoidance rats: a behavioural and brain microdialysis study. World J Neurosci 4:279–292CrossRefGoogle Scholar
  14. Crabbe JC, Belknap JK, Buck KJ (1994) Genetic animal models of alcohol and drug abuse. Science 264:1715–1723CrossRefPubMedGoogle Scholar
  15. Davis S, Laroche S (2006) Mitogen-activated protein kinase/extracellular regulated kinase signalling and memory stabilization: a review. Genes Brain Behav 5(Suppl 2):61–72CrossRefPubMedGoogle Scholar
  16. Di Chiara G, Bassareo V, Fenu S, De Luca MA, Spina L, Cadoni C, Acquas E, Carboni E, Valentini V, Lecca D (2004) Dopamine and drug addiction: the nucleus accumbens shell connection. Neuropharmacology 47:227–241Google Scholar
  17. Driscoll P, Battig K (1982) Behavioural, emotional, and neurochemical profiles of rats selected for extreme differences in active, two-way avoidance performance. In: Lieblich I (ed) Genetics of the brain. Elsevier, Amsterdam, pp 95–123Google Scholar
  18. Ersche KD, Simon Jones P, Williams GB, Smith DG, Bullmore ET, Robbins TW (2013) Distinctive personality traits and neural correlates associated with stimulant drug use versus familial risk of stimulant dependence. Biol Psychiatry 74:137–144CrossRefPubMedPubMedCentralGoogle Scholar
  19. Fattore L, Piras G, Corda MG, Giorgi O (2009) The Roman high- and low-avoidance rat lines differ in the acquisition, maintenance, extinction, and reinstatement of intravenous cocaine self-administration. Neuropsychopharmacology 34:1091–1101CrossRefPubMedGoogle Scholar
  20. Fenu S, Spina L, Rivas E, Longoni R, Di Chiara G (2006) Morphine-conditioned single-trial place preference: role of nucleus accumbens shell dopamine receptors in acquisition, but not expression. Psychopharmacology 187(2):143–153CrossRefPubMedGoogle Scholar
  21. Fernàndez-Teruel A, Escorihuela RM, Castellano B, González B, Tobeña A (1997) Neonatal handling and environmental enrichment effects on emotionality, novelty/reward seeking, and age-related cognitive and hippocampal impairments: focus on the Roman rat lines. Behav Genet 27:513–526CrossRefPubMedGoogle Scholar
  22. Fernàndez-Teruel A, Driscoll P, Gil L, Aguilar R, Tobeña A, Escorihuela RM (2002a) Enduring effects of environmental enrichment on novelty seeking, saccharin and ethanol intake in two rat lines (RHA/Verh and RLA/Verh) differing in incentive-seeking behaviour. Pharmacol Biochem Behav 73(1):225–231CrossRefPubMedGoogle Scholar
  23. Fernàndez-Teruel A, Giménez-Llort L, Escorihuela RM, Gil L, Aguilar R, Steimer T, Tobeña A (2002b) Early-life handling stimulation and environmental enrichment: are some of their effects mediated by similar neural mechanisms? Pharmacol Biochem Behav 73(1):233–245CrossRefPubMedGoogle Scholar
  24. Flagel SB, Robinson TE, Clark JJ, Clinton SM, Watson SJ, Seeman P, Phillips PE, Akil H (2010) An animal model of genetic vulnerability to behavioural disinhibition and responsiveness to reward-related cues: implications for addiction. Neuropsychopharmacology 35:388–400CrossRefPubMedGoogle Scholar
  25. Funada M, Suzuki T, Narita M, Misawa M, Nagase H (1993) Blockade of morphine reward through the activation of kappa-opioid receptors in mice. Neuropharmacology 32:1315–1323CrossRefPubMedGoogle Scholar
  26. Gerdjikov TV, Ross GM, Beninger RJ (2004) Place preference induced by nucleus accumbens amphetamine is impaired by antagonists of ERK or p38 MAP kinases in rats. Behav Neurosci 118:740–750CrossRefPubMedGoogle Scholar
  27. Giorgi O, Orlandi M, Escorihuela RM, Driscoll P, Lecca D, Corda MG (1994) GABAergic and dopaminergic transmission in the brain of Roman high-avoidance and Roman low-avoidance rats. Brain Res 638(1–2):133–138CrossRefPubMedGoogle Scholar
  28. Giorgi O, Lecca D, Piras G, Driscoll P, Corda MG (2003) Dissociation between mesocortical dopamine release and fear-related behaviours in two psychogenetically selected lines of rats that differ in coping strategies to aversive conditions. Eur J Neurosci 17:2716–2726CrossRefPubMedGoogle Scholar
  29. Giorgi O, Piras G, Lecca D, Corda MG (2005) Differential activation of dopamine release in the nucleus accumbens core and shell after acute or repeated amphetamine injections: a comparative study in the Roman high- and low-avoidance rat lines. Neuroscience 135:987–998CrossRefPubMedGoogle Scholar
  30. Giorgi O, Piras G, Corda MG (2007) The psychogenetically selected Roman high- and low-avoidance rat lines: a model to study the individual vulnerability to drug addiction. Neurosci Biobehav Rev 31(1):148–163CrossRefPubMedGoogle Scholar
  31. Giorgi O, Corda MG, Sabariego M, Giugliano V, Piludu MA, Rosas M, Acquas E (2015) Differential effects of cocaine on extracellular signal-regulated kinase phosphorylation in nuclei of the extended amygdala and prefrontal cortex of psychogenetically selected Roman high- and low-avoidance rats. J Neurosci Res 93:714–721CrossRefPubMedGoogle Scholar
  32. Girault JA, Valjent E, Caboche J, Herve D (2007) ERK2: a logical AND gate critical for druginduced plasticity? Curr Opin Pharmacol 7:77–85CrossRefPubMedGoogle Scholar
  33. Glover EM, Davis M (2008) Anxiolytic-like effects of morphine and buprenorphine in the rat model of fear-potentiated startle: tolerance, cross-tolerance, and blockade by naloxone. Psychopharmacology 198(2):167–180CrossRefPubMedGoogle Scholar
  34. Guitart-Masip M, Johanson B, Fernández-Teruel A, Tobeña A, Giménez-Llort (2008) Divergent effect of the selective D3 receptor agonist PD-128,907 on locomotor activity in Roman high- and low-avoidance rats: relationship to NGFI-A gene expression in the Calleja islands. Psychopharmacology 196:39–49CrossRefPubMedGoogle Scholar
  35. Ibba F, Vinci S, Spiga S, Peana AT, Assaretti AR, Spina L, Longoni R, Acquas E (2009) Ethanol-induced extracellular signal regulated kinase: role of dopamine D1 receptors. Alcohol Clin Exp Res 33:858–867CrossRefPubMedGoogle Scholar
  36. Kapur JN, Sahoo PK, Wong KC (1985) A new method for gray-level picture thresholding using the entropy of the histogram. Comput Vis Graph Image Process 29:273–285CrossRefGoogle Scholar
  37. Kennedy BC, Panksepp JB, Runckel PA, Lahvis GP (2012) Social influences on morphine-conditioned place preference in adolescent BALB/cJ and C57BL/6J mice. Psychopharmacology 219(3):923–932CrossRefPubMedGoogle Scholar
  38. Koob GF (2006) The neurobiology of addiction: a neuroadaptational view relevant for diagnosis. Addiction 101(Suppl 1):23–30CrossRefPubMedGoogle Scholar
  39. Koob GF, Le Moal M (2001) Drug addiction, dysregulation of reward, and allostasis. Neuropsychopharmacology 24:97–129CrossRefPubMedGoogle Scholar
  40. Lazega D, Driscoll P, Frischknecht HR, Siegfreid B, Waser PG (1986) Opiate receptor binding and behavioural effects of morphine in RHA/Verh and RLA/Verh rats. NIDA Res Monogr 75:485–488PubMedGoogle Scholar
  41. Lecca D, Piras G, Driscoll P, Giorgi O, Corda MG (2004) A differential activation of dopamine output in the shell and core of the nucleus accumbens is associated with the motor responses to addictive drugs: a brain dialysis study in Roman high- and low-avoidance rats. Neuropharmacology 46:688–699CrossRefPubMedGoogle Scholar
  42. Leone P, Di Chiara G (1987) Blockade of D-1 receptors by SCH 23390 antagonizes morphine- and amphetamine-induced place preference conditioning. Eur J Pharmacol 135(2):251–254CrossRefPubMedGoogle Scholar
  43. Marotta R, Fenu S, Scheggi S, Vinci S, Rosas M, Falqui A, Gambarana C, De Montis MG, Acquas E (2014) Acquisition and expression of conditioned taste aversion differentially affects extracellular signal regulated kinase and glutamate receptor phosphorylation in rat prefrontal cortex and nucleus accumbens. Front Behav Neurosci 8:153CrossRefPubMedPubMedCentralGoogle Scholar
  44. Molander AC, Mar A, Norbury A, Steventon S, Moreno M, Caprioli D, Theobald DEH, Belin D, Everitt BJ, Robbins TW, Dalley JW (2011) High impulsivity predicting vulnerability to cocaine addiction in rats: some relationship with novelty preference but not novelty reactivity, anxiety or stress. Psychopharmacology 215:721–731CrossRefPubMedGoogle Scholar
  45. Moreno M, Cardona D, Gomez MJ, Sanchez-Santed F, Tobena A, Fernàndez-Teruel A, Campa L, Sunol C, Escarabajal MD, Torres C, Flores P (2010) Impulsivity characterization in the Roman high- andlow-avoidance rat strains: behavioural and neurochemical differences. Neuropsychopharmacology 35:1198–1208CrossRefPubMedPubMedCentralGoogle Scholar
  46. Mucha RF, van der Kooy D, O'Shaughnessy M, Bucenieks P (1982) Drug reinforcement studied by the use of place conditioning in rat. Brain Res 243(1):91–105CrossRefPubMedGoogle Scholar
  47. Nestler EJ (2001) Molecular neurobiology of addiction. Am J Addict 10:201–217CrossRefPubMedGoogle Scholar
  48. Paxinos G, Watson C (1998) The rat brain in stereotaxic coordinates. Academic Press, SydneyGoogle Scholar
  49. Peana AT, Giugliano V, Rosas M, Sabariego M, Acquas E (2013) Effects of L-cysteine on reinstatement of ethanol-seeking behaviour and on reinstatement-elicited extracellular signal-regulated kinase phosphorylation in the rat nucleus accumbens shell. Alcohol Clin Exp Res 37(Suppl 1):E329–E337CrossRefPubMedGoogle Scholar
  50. Rosas M, Zaru A, Sabariego M, Giugliano V, Carboni E, Colombo G, Acquas E (2014) Differential sensitivity of ethanol-elicited ERK phosphorylation in nucleus accumbens of Sardinian alcohol-preferring and -non preferring rats. Alcohol 48:471–476CrossRefPubMedGoogle Scholar
  51. Rosas M, Porru S, Fenu S, Ruiu S, Peana AT, Papale A, Brambilla R, Di Chiara G, Acquas E (2016) Role of nucleus accumbens μ opioid receptors in the effects of morphine on ERK1/2 phosphorylation. Psychopharmacology 233(15–16):2943–2954CrossRefPubMedGoogle Scholar
  52. Salzmann J, Marie-Claire C, Le Guen S, Roques BP, Noble F (2003) Importance of ERK activation in behavioural and biochemical effects induced by MDMA in mice. Br J Pharmacol 140:831–828CrossRefPubMedPubMedCentralGoogle Scholar
  53. Sanna F, Corda MG, Melis MR, Piludu MA, Giorgi O, Argiolas A (2014) Male Roman high- and low- avoidance rats show different patterns of copulatory behaviour: comparison with Sprague Dawley rats. Physiol Behav 127:27–36CrossRefPubMedGoogle Scholar
  54. Scheggi S, Crociani A, De Montis MG, Tagliamonte A, Gambarana C (2009) Dopamine D1 receptor-dependent modifications in the dopamine and cAMP-regulated phosphoprotein of Mr 32 kDa phosphorylation pattern in striatal areas of morphine-sensitized rats. Neuroscience 163(2):627–639CrossRefPubMedGoogle Scholar
  55. Selcher JC, Nekrasova T, Paylor R, Landreth GE, Sweatt JD (2001) Mice lacking the ERK1 isoform of MAP kinase are unimpaired in emotional learning. Learn Mem 8(1):11–19CrossRefPubMedPubMedCentralGoogle Scholar
  56. Shippemberg TS, Herz A (1987) Place preference conditioning reveals the involvement of D1-dopamine receptors in the motivational properties of mu- and kappa-opioid agonists. Brain Res 436(1):169–172CrossRefGoogle Scholar
  57. Solecki W, Turek A, Kubik J, Przewlocki R (2009) Motivational effects of opiates in conditioned place preference and aversion paradigm—a study in three inbred strains of mice. Psychopharmacology 207:245–255CrossRefPubMedGoogle Scholar
  58. Spina L, Longoni R, Vinci S, Ibba F, Peana AT, Muggironi G, Spiga S, Acquas E (2010) Role of dopamine D1 receptors and extracellular signal regulated kinase in the motivational properties of acetaldehyde as assessed by place preference conditioning. Alcohol Clin Exp Res 34(4):607–616CrossRefPubMedGoogle Scholar
  59. Stansfield KH, Kirstein CL (2007) Chronic cocaine or ethanol exposure during adolescence alters novelty-related behaviours in adulthood. Pharmacol Biochem Behav 86(4):637–642CrossRefPubMedGoogle Scholar
  60. Steimer T, Driscoll P (2003) Divergent stress responses and coping styles in psychogenetically selected Roman high-(RHA) and low-(RLA) avoidance rats: behavioural, neuroendocrine and developmental aspects. Stress 6:87–100CrossRefPubMedGoogle Scholar
  61. Steimer T, Driscoll P (2005) Inter-individual vs line/strain differences in psychogenetically selected Roman High-(RHA) and Low-(RLA) Avoidance rats: neuroendocrine and behavioural aspects. Neurosci Biobehav Rev 29(1):99–112Google Scholar
  62. Suzuki T, Tsuda M, Funada M, Misawa M (1995) Blockade of morphine-induced place preference by diazepam in mice. Eur J Pharmacol 280:327–330CrossRefPubMedGoogle Scholar
  63. Tzschentke TM (2007) Measuring reward with the conditioned place preference (CPP) paradigm: update of the last decade. Addict Biol 12:227–462CrossRefPubMedGoogle Scholar
  64. Valjent E, Corvol JC, Pages C, Besson MJ, Maldonado R, Caboche J (2000) Involvement of the extracellular signal-regulated kinase cascade for cocaine-rewarding properties. J Neurosci 20:8701–8709CrossRefPubMedGoogle Scholar
  65. Valjent E, Pages C, Rogard M, Besson MJ, Maldonado R, Caboche J (2001) Delta 9- tetrahydrocannabinol-induced MAPK/ERK and Elk-1 activation in vivo depends on dopaminergic transmission. Eur J Neurosci 14:342–352CrossRefPubMedGoogle Scholar
  66. Valjent E, Pagès C, Hervé D, Girault JA, Caboche J (2004) Addictive and non-addictive drugs induce distinct and specific patterns of ERK activation in mouse brain. Eur J Neurosci 19:1826–1836CrossRefPubMedGoogle Scholar
  67. Verheul R, van den Brink W (2000) The role of personality pathology in the etiology and treatment of substance use disorders. Curr Opin Psychiatry 13:163–169CrossRefGoogle Scholar
  68. Zarrindast MR, Rostami P, Zarei M, Roohbakhsh A (2005) Intracerebroventricular effects of histaminergic agents on morphine-induced anxiolysis in the elevated plus-maze in rats. Basic Clin Pharmacol Toxicol 97(5):276–281CrossRefPubMedGoogle Scholar
  69. Zhai H, Li Y, Wang X, Lu L (2008) Drug-induced alterations in the extracellular signal regulated kinase (ERK) signalling pathway: implications for reinforcement and reinstatement. Cell Mol Neurobiol 28:157–172CrossRefPubMedGoogle Scholar
  70. Zhang L, Lou D, Jiao H, Zhang D, Wang X, Xia Y, Zhang J, Xu M (2004) Cocaine-induced intracellular signaling and gene expression are oppositely regulated by the dopamine D1 and D3 receptors. J Neurosci 24:3344–3354CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany 2017

Authors and Affiliations

  • Michela Rosas
    • 1
  • Simona Porru
    • 1
  • Marta Sabariego
    • 2
  • Maria Antonietta Piludu
    • 1
  • Osvaldo Giorgi
    • 1
  • Maria G. Corda
    • 1
  • Elio Acquas
    • 1
    • 3
  1. 1.Department of Life and Environmental SciencesUniversity of CagliariCagliariItaly
  2. 2.Neurobiology Section and Center for Neural Circuits and Behavior, Division of Biological SciencesUniversity of CaliforniaSan DiegoUSA
  3. 3.Centre of Excellence on Neurobiology of AddictionUniversity of CagliariCagliariItaly

Personalised recommendations