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Working memory deficits and alterations of ERK and CREB phosphorylation following withdrawal from cocaine self-administration

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Abstract

Background

The mechanisms underlying memory functions during withdrawal from the chronic drug use are poorly understood.

Methods

We assessed learning and spatial working memory using the delayed alternation assay (T-maze) in rats, previously subjected to cocaine self-administration. The T-maze training was conducted 1–5 weeks after cocaine cessation; working memory efficacy was assessed at 5–8 weeks of drug withdrawal. After behavioral training and testing, the rats were sacrificed and the levels of p-CREB/CREB and p-ERK2/ERK2 in several brain areas were measured. The same molecular assessment was performed in rats with cocaine injections, but forced to drug abstinence in home cages.

Results

After 5 weeks of cocaine withdrawal from self-administration, a significant impairment of working memory under increased working memory load (inter-trial delay extended to 30 s), with no changes at baseline conditions (inter-trial delay 10 s), was noticed. Neither acquisition phase nor working memory performance measured 6–8 weeks after the last drug intake differed between cocaine or saline pretreated rats. Upon T-maze training and 8-week withdrawal, cocaine-pretreated rats had higher levels of p-CREB/CREB in prefrontal cortex and dorsal striatum and lower in hippocampus compared to saline rats. Increased levels of p-ERK2/ERK2 were observed in dorsal striatum, hippocampus and decreased in nucleus accumbens. In cocaine-pretreated caged rats no changes in p-CREB/CREB levels were observed, while ERK2 levels either decreased (frontal cortex) or increased (nucleus accumbens).

Conclusion

Our results suggest that cocaine self-administration results in cognitive impairments and alterations in ERK/CREB signaling pathway long after discontinuation of drug use.

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Abbreviations

CREB:

cAMP-response element binding protein

ERK:

extracellular signal-regulated kinase

p-CREB:

phosphorylated cAMP-response element binding protein

p-ERK:

phosphorylated extracellular signal-regulated kinase

References

  1. Nestler EJ. Common molecular and cellular substrates of addiction and memor. Neurobiol Learn Mem 2002;78(3):637–47.

    Article  CAS  PubMed  Google Scholar 

  2. Spiga S, Lintas A, Diana M. Addiction and cognitive functions. Ann N Y Acad Sci 2008;1139:299–306.

    Article  CAS  PubMed  Google Scholar 

  3. Pace-Schott EF, Stickgold R, Muzur A, Wigren PE, Ward AS, Hart CL, et al. Cognitive performance by humans during a smoked cocaine binge-abstinence cycle. Am J Drug Alcohol Abuse 2005;31(4):571–91.

    Article  PubMed  Google Scholar 

  4. Pace-Schott EF, Morgan PT, Malison RT, Hart CL, Edgar C, Walker M, et al. Cocaine users differ from normals on cognitive tasks which show poorer performance during drug abstinence. Am J Drug Alcohol Abuse 2008;34(1): 109–21.

    Article  PubMed  Google Scholar 

  5. van Gorp WG, Wilkins JN, Hinkin CH, Moore LH, Hull J, Horner MD, et al. Declarative and procedural memory functioning in abstinent cocaine abusers. Arch Gen Psychiatry 1999;56(1):85–9.

    Article  PubMed  Google Scholar 

  6. Briand LA, Gross JP, Robinson TE. Impaired object recognition following prolonged withdrawal from extended access cocaine self-administration. Neuroscience 2008;155(1):1–6.

    Article  CAS  PubMed  Google Scholar 

  7. Calu DJ, Stalnaker TA, Franz TM, Singh T, Shaham Y, Schoenbaum G. Withdrawal from cocaine self-administration produces long-lasting deficits in orbitofrontal-dependent reversal learning in rats. Learn Mem 2007;14(5):325–8.

    Article  PubMed  Google Scholar 

  8. George O, Mandyam CD, Wee S, Koob GF. Extended access to cocaine self-administration produces long-lasting prefrontal cortex-dependent working memory impairments. Neuropsychopharmacology 2008;33(10):2474–82.

    Article  CAS  PubMed  Google Scholar 

  9. Vonmoos M, Hulka LM, Preller KH, Minder F, Baumgartner MR, Quednow BB. Cognitive impairment in cocaine users is drug-induced but partially reversible: evidence from a longitudinal study. Neuropsychopharmacology 2014;39(9): 2200–10.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Vonmoos M, Hulka LM, Preller KH, Jenni D, Baumgartner MR, Stohler R, et al. Cognitive dysfunctions in recreational and dependent cocaine users: role of attention-deficit hyperactivity disorder, craving and early age at onset. Br J Psychiatry 2013;203(1):35–43.

    Article  PubMed  Google Scholar 

  11. Sofuoglu M, DeVito EE, Waters AJ, Carroll KM. Cognitive enhancement as a treatment for drug addictions. Neuropharmacology 2013;64:452–63.

    Article  CAS  PubMed  Google Scholar 

  12. Pierce CR, Vanderschuren LJ. Kicking the habit: the neural basis of ingrained behaviors in cocaine addiction. Neurosci Biobehav Rev 2010;35(2):212–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Feil J, Sheppard D, Fitzgerald PB, Yu¨cel M, Lubman DI, Bradshaw JL. Addiction, compulsive drug seeking, and the role of frontostriatal mechanisms in regulating inhibitory control. Neurosci Biobehav Rev 2010;35(2):248–75.

    Article  PubMed  Google Scholar 

  14. Silva AJ, Kogan JH, Frankland PW, Kida S. CREB and memory. Annu Rev Neurosci 1998;21:127–48.

    Article  CAS  PubMed  Google Scholar 

  15. Suzuki A, Fukushima H, Mukawa T, Toyoda H, Wu LJ, Zhao MG, et al. Upregulation of CREB-mediated transcription enhances both short- and long-term memory. J Neurosci 2011;31(24):8786–802.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Sgambato V, Page`s C, Rogard M, Besson MJ, Caboche J. Extracellular signalregulated kinase (Erk) controls immediate early gene induction on corticostriatal stimulation. J Neurosci 1998;18(21):8814–25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Thomas GM, Huganir RL. MAPK cascade signalling and synaptic plasticity. Nat Rev Neurosci 2004;5(3):173–83.

    Article  CAS  PubMed  Google Scholar 

  18. 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 

  19. Wedzony K, Fijał K, Maćkowiak M, Chocyk A, Zajączkowski W. Impact of postnatal blockade of N-methyl-D-aspartate receptors on rat behavior: a search for a new developmental model of schizophrenia. Neuroscience 2008;153(4):1370–9.

    Article  CAS  PubMed  Google Scholar 

  20. Lowry OH, Rosenbrough NJ, Farr AL, Randall RJ. Protein measurement with the Folin phenol reagent. J Biol Chem 1951;193(1):265–75.

    CAS  PubMed  Google Scholar 

  21. Shiflett MW, Balleine BW. Molecular substrates of action control in corticostriatal circuits. Prog Neurobiol 2011;95(1):1–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Shepherd GMG. Corticostriatal connectivity and its role in disease. Nat Rev Neurosci 2013;14(4):278–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Packard MG, Knowlton BJ. Learning and memory functions of the basal ganglia. Annu Rev Neurosci 2002;25:563–93.

    Article  CAS  PubMed  Google Scholar 

  24. Hollerman JR, Tremblay L, Schultz W. Involvement of basal ganglia and orbitofrontal cortex in goal-directed behavior. Prog Brain Res 2000;126: 193–215.

    Article  CAS  PubMed  Google Scholar 

  25. Morita K, Morishima M, Sakai K, Kawaguchi Y. Dopaminergic control of motivation and reinforcement learning: a closed-circuit account for reward-oriented behavior. J Neurosci 2013;33(20):8866–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. 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 U S A 2005;102(2):491–6.

    Article  CAS  PubMed  Google Scholar 

  27. Alberini CA. Transcription factors in long-term memory and synaptic plasticity. Physiol Rev 2009;89(1):121–45.

    Article  CAS  PubMed  Google Scholar 

  28. Brightwell JJ, Smith CA, Neve RL, Colombo PJ. Long-term memory for place learning is facilitated by expression of cAMP response element-binding protein in the dorsal hippocampus. Learn Mem 2007;14(3):195–9.

    Article  PubMed  Google Scholar 

  29. Sakamoto K, Karelina K, Obrietan K. CREB: a multifaceted regulator of neuronal plasticity and protection. J Neurochem 2011;116(1):1–9.

    Article  CAS  PubMed  Google Scholar 

  30. Zhang XH, Liu SS, Yi F, Zhuo M, Li BM. Delay-dependent impairment of spatial working memory with inhibition of NR2B-containing NMDA receptors in hippocampal CA1 region of rats. Mol Brain 2013;6(13). https://doi.org/10.1186/1756-6606-6-13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Sanderson DJ, Bannerman DM. The role of habituation in hippocampusdependent spatial working memory tasks: evidence from GluA1 AMPA receptor subunit knockout mice. Hippocampus 2012;22(5):981–94.

    Article  CAS  PubMed  Google Scholar 

  32. Viola H, Furman M, Izquierdo LA, Alonso M, Barros DM, de Souza MM, et al. Phosphorylated cAMP response element-binding protein as a molecular marker of memory processing in rat hippocampus: effect of novelty. J Neurosci 2000;20(23):RC112.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Kenney JW, Poole RL, Adoff MD, Logue SF, Gould TJ. Learning and nicotine interact to increase CREB phosphorylation at the jnk1 promoter in the hippocampus. PLoS ONE 2012;(6):e39939.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Porte Y, Buhot MC, Mons NE. Spatial memory in the Morris water maze and activation of cyclic AMP response element-binding (CREB) protein within the mouse hippocampus. Learn Mem 2008;15(12):885–94.

    Article  PubMed  Google Scholar 

  35. Mizuno M, Yamada K, Maekawa N, Saito K, Seishima M, Nabeshima T. CREB phosphorylation as a molecular marker of memory processing in the hippocampus for spatial learning. Behav Brain Res 2002;133(2):135–41.

    Article  CAS  PubMed  Google Scholar 

  36. McFarland K, Lapish CC, Kalivas PW. Prefrontal glutamate release into the core of the nucleus accumbens mediates cocaine-induced reinstatement of drugseeking behavior. J Neurosci 2003;23(8):3531–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Chauvet C, Lardeux V, Goldberg SR, Jaber M, Solinas M. Environmental enrichment reduces cocaine seeking and reinstatement induced by cues and stress but not by cocaine. Neuropsychopharmacology 2009;34(13): 2767–78.

    Article  PubMed  Google Scholar 

  38. Thiel KJ, Pentkowski NS, Peartree NA, Painter MR, Neisewander JL. Environmental living conditions introduced during forced abstinence alter cocaineseeking behavior and Fos protein expression. Neuroscience 2010;171(4): 1187–96.

    Article  CAS  PubMed  Google Scholar 

  39. Colucci-D’Amato L, Perrone-Capano C, di Porzio U. Chronic activation of ERK and neurodegenerative diseases. Bioessays 2003;25(11):1085–95.

    Article  PubMed  CAS  Google Scholar 

  40. Valor LM, Jancic D, Lujan R, Barco A. Ultrastructural and transcriptional profiling of neuropathological misregulation of CREB function. Cell Death Differ 2010;17(10):1636–44 [See comment in PubMed Commons below].

    Article  CAS  PubMed  Google Scholar 

  41. Johnson BA, Devous Sr MD, Ruiz P, Ait-Daoud N. Treatment advances for cocaine-induced ischemic stroke: focus on dihydropyridine-class calcium channel antagonists. Am J Psychiatry 2001;158(8):1191–8.

    Article  CAS  PubMed  Google Scholar 

  42. Neiman J, Haapaniemi HM, Hillbom M. Neurological complications of drug abuse: pathophysiological mechanisms. Eur J Neurol 2000;7(6):595–606.

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

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

    Katarzyna Fijał, Ewa Nowak & Małgorzata Filip

  2. Department of Toxicology, Faculty of Pharmacy, Jagiellonian University Medical College, Kraków, Poland

    Katarzyna Fijał & Małgorzata Filip

  3. Department of Experimental Neuroendocrinology, Institute of Pharmacology, Polish Academy of Sciences, Kraków, Poland

    Monika Leśkiewicz & Bogusława Budziszewska

  4. Department of Biochemical Toxicology, Faculty of Pharmacy, Jagiellonian University Medical College, Kraków, Poland

    Bogusława Budziszewska

Authors
  1. Katarzyna Fijał
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  2. Ewa Nowak
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  3. Monika Leśkiewicz
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  4. Bogusława Budziszewska
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  5. Małgorzata Filip
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Correspondence to Małgorzata Filip.

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Fijał, K., Nowak, E., Leśkiewicz, M. et al. Working memory deficits and alterations of ERK and CREB phosphorylation following withdrawal from cocaine self-administration. Pharmacol. Rep 67, 881–889 (2015). https://doi.org/10.1016/j.pharep.2015.01.013

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  • DOI: https://doi.org/10.1016/j.pharep.2015.01.013

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