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The effect of active and passive intravenous cocaine administration on the extracellular signal-regulated kinase (ERK) activity in the rat brain

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Abstract

According to a current hypothesis of learning processes, recent papers pointed out to an important role of the extracellular signal-regulated kinase (ERK), in drug addiction. We employed the Western blotting techniques to examine the ERK activity immediately after cocaine iv self-administration and in different drug-free withdrawal periods in rats. To distinguish motivational vs. pharmacological effects of the psychostimulant intake, a “yoked” procedure was used. Animals were decapitated after 14 daily cocaine self-administration sessions or on the 1st, 3rd or 10th extinction days. At each time point the activity of the ERK was assessed in several brain structures, including the prefrontal cortex, hippocampus, dorsal striatum and nucleus accumbens.

Passive, repeated iv cocaine administration resulted in a 45% increase in ERK phosphorylation in the hippocampus while cocaine self-administration did not change brain ERK activity. On the 1st day of extinction, the activity of the ERK in the prefrontal cortex was decreased in rats with a history of cocaine chronic intake: by 66% for “active” cocaine group and by 35% for “yoked” cocaine group. On the 3rd day the reduction in the ERK activity (25–34%) was observed in the hippocampus for both cocaine-treated groups, and also in the nucleus accumbens for “yoked” cocaine group (40%). On the 10th day of extinction there was no significant alteration in ERK activity in any group of rats.

Our findings suggest that cortical ERK is involved in cocaine seeking behavior in rats. They also indicate the time and regional adaptations in this enzyme activity after cocaine withdrawal.

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References

  1. American Psychiatric Association (APA). Diagnostic and statistical manual of mental disorders. 4th ed. Washington, DC: American Psychiatric Press; 1994.

    Google Scholar 

  2. Nestler EJ. Common molecular and cellular substrates of addiction and memory. Neurobiol Learn Mem 2002;78:637–47.

    Article  CAS  PubMed  Google Scholar 

  3. Wolf ME, Sun X, Mangiavacchi S, Chao SZ. Psychomotor stimulants and neuronal plasticity. Neuropharmacology 2004;47(Suppl. 1):61–79.

    Article  CAS  PubMed  Google Scholar 

  4. Everitt BJ, Robbins TW. Neural systems of reinforcement for drug addiction: from actions to habits to compulsion. Nat Neurosci 2005;8:1481–9.

    Article  CAS  PubMed  Google Scholar 

  5. Kalivas PW, O’Brien C. Drug addiction as a pathology of staged neuroplasticity. Neuropsychopharmacology 2008;33:166–80.

    Article  CAS  PubMed  Google Scholar 

  6. Jenab S, Festa ED, Nazarian A, Wu HB, Sun WL, Hazim R, et al. Cocaine induction of ERK proteins in dorsal striatum of Fischer rats. Brain Res Mol Brain Res 2005;142:134–8.

    Article  CAS  PubMed  Google Scholar 

  7. Girault JA, Valjent E, Caboche J, Hervé D. ERK2: a logical AND gate critical for drug-induced plasticity? Curr Opin Pharmacol 2007;7(1):77–85.

    Article  CAS  PubMed  Google Scholar 

  8. Besnard A, Bouveyron N, Kappes V, Pascoli V, Pagès C, Heck N, et al. Alterations of molecular and behavioral responses to cocaine by selective inhibition of Elk-1 phosphorylation. J Neurosci 2011;31(40):14296–307.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Kyosseva SV. Mitogen-activated protein kinase signaling. Int Rev Neurobiol 2004;59:201–20.

    Article  CAS  PubMed  Google Scholar 

  10. Zhai H, Li Y, Wang X, Lu L. Drug-induced alterations in the extracellular signalregulated kinase (ERK) signalling pathway: implications for reinforcement and reinstatement. Cell Mol Neurobiol 2008;28(2):157–72.

    Article  CAS  PubMed  Google Scholar 

  11. Pierce RC, Pierce-Bancroft AF, Prasad BM. Neurotrophin-3 contributes to the initiation of behavioral sensitization to cocaine by activating the Ras/Mitogen-activated protein kinase signal transduction cascade. J Neurosci 1999;19: 8685–95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Ferguson SM, Fasano S, Yang P, Brambilla R, Robinson TE. Knockout of ERK1 enhances cocaine-evoked immediate early gene expression and behavioral plasticity. Neuropsychopharmacology 2006;31:2660–8.

    Article  CAS  PubMed  Google Scholar 

  13. Valjent E, Corvol JC, Trzaskos JM, Girault JA, Herve D. Role of the ERK pathway in psychostimulant-induced locomotor sensitization. BMC Neurosci 2006;7: 1–11.

    Article  CAS  Google Scholar 

  14. Valjent E, Corvol JC, Pages C, Besson MJ, Maldonado R, Caboche J. Involvement of the extracellular signal-regulated kinase cascade for cocaine-rewarding properties. J Neurosci 2000;20:8701–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Gerdjikov TV, Ross GM, Beninger RJ. Place preference induced by nucleus accumbens amphetamine is impaired by antagonists of ERK or p38 MAP kinases in rats. Behav Neurosci 2004;118:740–50.

    Article  CAS  PubMed  Google Scholar 

  16. Lu L, Hope BT, Dempsey J, Liu SY, Bossert JM, Shaham Y. Central amygdala ERK signaling pathway is critical to incubation of cocaine craving. Nat Neurosci 2005;8:212–9.

    Article  CAS  PubMed  Google Scholar 

  17. Lu L, Uejima JL, Gray SM, Bossert JM, Shaham Y. Systemic and central amygdala injections of the mGluR(2/3) agonist LY379268 attenuate the expression of incubation of cocaine craving. Biol Psychiatry 2007;61:591–8.

    Article  CAS  PubMed  Google Scholar 

  18. Valjent E, Pages C, Herve D, Girault JA, Caboche J. Addictive and non-addictive drugs induce distinct and specific patterns of ERK activation in mouse brain. Eur J Neurosci 2004;19:1826–36.

    Article  PubMed  Google Scholar 

  19. Zhang L, Lou D, Jiao H, Zhang D, Wang X, **a Y, et al. Cocaine-induced intracellular signaling and gene expression are oppositely regulated by the dopamine D1 and D3 receptors. J Neurosci 2004;24:3344–435.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Valjent E, Pascoli V, Svenningsson P, Paul S, Enslen H, Corvol JC, et al. Regulation of a protein phosphatase cascade allows convergent dopamine and glutamate signals to activate ERK in the striatum. Proc Natl Acad Sci USA 2005;102:491–6.

    Article  CAS  PubMed  Google Scholar 

  21. Corbillé AG, Valjent E, Marsicano G, Ledent C, Lutz B, Hervé D, et al. Role of cannabinoid type 1 receptors in locomotor activity and striatal signaling in response to psychostimulants. J Neurosci 2007;27(26):6937–47.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  22. Radwanska K, Valjent E, Trzaskos J, Caboche J, Kaczmarek L. Regulation of cocaine-induced activator protein 1 transcription factors by the extracellular signal-regulated kinase pathway. Neuroscience 2006;137:253–64.

    Article  CAS  PubMed  Google Scholar 

  23. Zhang J, Xu M. Opposite regulation of cocaine-induced intracellular signaling and gene expression by dopamine D1 and D3 receptors. Ann N Y Acad Sci 2006;1074:1–12.

    Article  CAS  PubMed  Google Scholar 

  24. Berhow MT, Hiroi N, Nestler EJ. Regulation of ERK (extracellular signal regulated kinase), part of the neurotrophin signal transduction cascade, in the rat mesolimbic dopamine system by chronic exposure to morphine or cocaine. J Neurosci 1996;16:4707–15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Radwanska K, Caboche J, Kaczmarek L. Extracellular signal-regulated kinases (ERKs) modulate cocaine-induced gene expression in the mouse amygdala. Eur J Neurosci 2005;22:939–48.

    Article  PubMed  Google Scholar 

  26. Yoon HS, Kim S, Park HK, Kim JH. Microinjection of CART peptide 55–102 into the nucleus accumbens blocks both the expression of behavioral sensitization and ERK phosphorylation by cocaine. Neuropharmacology 2007;53(2):344–51.

    Article  CAS  PubMed  Google Scholar 

  27. Lee DK, Bian S, Rahman MA, Shim YB, Shim I, Choe ES. Repeated cocaine administration increases N-methyl-d-aspartate NR1 subunit, extracellular signal-regulated kinase and cyclic AMP response element-binding protein phosphorylation and glutamate release in the rat dorsal striatum. Eur J Pharmacol 2008;590(1–3):157–62.

    Article  CAS  PubMed  Google Scholar 

  28. Whitfield Jr TW, Shi X, Sun WL, McGinty JF. The suppressive effect of an intraprefrontal cortical infusion of BDNF on cocaine-seeking is Trk receptor and extracellular signal-regulated protein kinase mitogen-activated protein kinase dependent. J Neurosci 2011;31(3):834–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Fijał K, Pachuta A, McCreary AC, Wydra K, Nowak E, Papp M, et al. Effects of serotonin (5-HT)6 receptor ligands on responding for cocaine reward and seeking in rats. Pharmacol Rep 2010;62(6):1005–14.

    Article  PubMed  Google Scholar 

  30. Pomierny-Chamiolo L, Moniczewski A, Wydra K, Suder A, Filip M. Oxidative stress biomarkers in some rat brain structures and peripheral organs underwent cocaine. Neurotox Res 2013;23:92–102.

    Article  CAS  PubMed  Google Scholar 

  31. Budziszewska B, Szymanska M, Leskiewicz M, Basta-Kaim A, Jaworska-Feil L, Kubera M, et al. The decrease in JNK- and p38-MAP kinase activity is accompanied by the enhancement of PP2A phosphate level in the brain of prenatally stressed rats. J Physiol Pharmacol 2010;61(2):207–15.

    CAS  PubMed  Google Scholar 

  32. Lowry OH, Rosebrough NJ, Farr AL, Randall RJ. Protein measurement with the Folin-Phenol reagents. J Biol Chem 1951;193:265–75.

    CAS  PubMed  Google Scholar 

  33. Edwards S, Graham DL, Bachtell RK, Self DW. Region-specific tolerance to cocaine-regulated cAMP-dependent protein phosphorylation following chronic self-administration. Eur J Neurosci 2007;25(7):2201–13.

    Article  PubMed  Google Scholar 

  34. Morgado-Bernal I. Learning and memory consolidation: linking molecular and behavioral data. Neuroscience 2011;176:12–9.

    Article  CAS  PubMed  Google Scholar 

  35. Twining RC, Bolan M, Grigson PS. Yoked delivery of cocaine is aversive and protects against the motivation for drug in rats. Behav Neurosci 2009;123(4): 913–25.

    Article  CAS  PubMed  Google Scholar 

  36. Fumagalli F, Moro F, Caffino L, Orrù A, Cassina C, Giannotti G, et al. Region-specific effects on BDNF expression after contingent or non-contingent cocaine i.v. self-administration in rats. Int J Neuropsychopharmacol 2013;16(4): 913–8.

    Article  CAS  PubMed  Google Scholar 

  37. Patapoutian A, Reichardt LF. Trk receptors: mediators of neurotrophin action. Curr Opin Neurobiol 2001;11:272–80.

    Article  CAS  PubMed  Google Scholar 

  38. Koya E, Uejima JL, Wihbey KA, Bossert JM, Hope BT, Shaham Y. Role of ventral medial prefrontal cortex in incubation of cocaine craving. Neuropharmacology 2009;56(Suppl. 1):177–85.

    Article  CAS  PubMed  Google Scholar 

  39. Sun WL, Zelek-Molik A, McGinty JF. Short and long access to cocaine self-administration activates tyrosine phosphatase STEP and attenuates GluN expression but differentially regulates GluA expression in the prefrontal cortex. Psychopharmacology (Berl) 2013;229(4):603–13.

    Article  CAS  Google Scholar 

  40. Frankowska M, Gołda A, Wydra K, Gruca P, Papp M, Filip M. Effects of imipramine or GABA(B) receptor ligands on the immobility, swimming and climbing in the forced swim test in rats following discontinuation of cocaine self-administration. Eur J Pharmacol 2010;627(1–3):142–9.

    Article  CAS  PubMed  Google Scholar 

  41. Thiel KJ, Painter MR, Pentkowski NS, Mitroi D, Crawford CA, Neisewander JL. Environmental enrichment counters cocaine abstinence-induced stress and brain reactivity to cocaine cues but fails to prevent the incubation effect. Addict Biol 2012;17(2):365–7.

    Article  CAS  PubMed  Google Scholar 

  42. Marsden WN. Synaptic plasticity in depression: molecular, cellular and functional correlates. Prog Neuropsychopharmacol Biol Psychiatry 2013;43:168–84.

    Article  CAS  PubMed  Google Scholar 

  43. Qi X, Lin W, Li J, Pan Y, Wang W. The depressive-like behaviors are correlated with decreased phosphorylation of mitogen-activated protein kinases in rat brain following chronic forced swim stress. Behav Brain Res 2006;175:233–40.

    Article  CAS  PubMed  Google Scholar 

  44. Gourley SL, Wu FJ, Kiraly DD, Ploski JE, Kedves AT, Duman RS, et al. Regionally specific regulation of ERK MAP kinase in a model of antidepressant-sensitive chronic depression. Biol Psychiatry 2008;63:353–9.

    Article  CAS  PubMed  Google Scholar 

  45. Qi X, Lin W, Li J, Li H, Wang W, Wang D, et al. Fluoxetine increases the activity of the ERK-CREB signal system and alleviates the depressive-like behavior in rats exposed to chronic forced swim stress. Neurobiol Dis 2008;31:278–85.

    Article  CAS  PubMed  Google Scholar 

  46. Duric V, Banasr M, Stockmeier CA, Simen AA, Newton SS, Overholser JC, et al. Altered expression of synapse and glutamate related genes in post-mortem hippocampus of depressed subjects. Int J Neuropsychopharmacol 2012;16(1): 69–82.

    Article  PubMed  CAS  Google Scholar 

  47. First M, Gil-Ad I, Taler M, Tarasenko I, Novak N, Weizman A. The effects of fluoxetine treatment in a chronic mild stress rat model on depression-related behavior, brain neurotrophins and ERK expression. J Mol Neurosci 2011;45: 246–55.

    Article  CAS  PubMed  Google Scholar 

  48. **ong Z, Jiang B, Wu PF, Tian J, Shi LL, Gu J, et al. Antidepressant effects of a plant-derived flavonoid baicalein involving extracellular signal-regulated kinases cascade. Biol Pharm Bull 2011;34:253–9.

    Article  CAS  PubMed  Google Scholar 

  49. O’Malley D, Julio-Pieper M, Dinan TG, Cryan JF. Strain differences in stress-induced changes in central CRF1 receptor expression. Neurosci Lett 2014 [Epub ahead of print].

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Authors and Affiliations

  1. Laboratory of Drug Addiction Pharmacology, Department of Pharmacology, Institute of Pharmacology, Polish Academy of Sciences, Kraków, Poland

    Joanna Miszkiel, Jan Detka, Joanna Cholewa, Małgorzata Frankowska, Ewa Nowak, Bogusława Budziszewska, Edmund Przegaliński & Małgorzata Filip

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  1. Joanna Miszkiel
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Correspondence to Małgorzata Filip.

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Miszkiel, J., Detka, J., Cholewa, J. et al. The effect of active and passive intravenous cocaine administration on the extracellular signal-regulated kinase (ERK) activity in the rat brain. Pharmacol. Rep 66, 630–637 (2014). https://doi.org/10.1016/j.pharep.2014.02.001

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