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Effects of acute and repeated cocaine on markers for neural plasticity within the mesolimbic system in rats

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Abstract

Rationale

Repeated cocaine is known to induce morphological changes in dopaminergic circuits that are known to participate on cocaine-induced addictive changes.

Objective

The objective of the present study was to discern if acute or repeated regimens of daily cocaine (10 mg/kg) lead to reliable changes in the expression of some protein markers for neural plasticity such as synaptophysin, p21-Arc, alpha-tubulin (α-tubulin), and stathmin, in the mesolimbic dopaminergic circuit. Well-known changes in tyrosine hydroxylase and protein kinase A were used for confirming biochemical effects of repeated cocaine. Animals were subjected to three treatments: acute injection, 3-day injections, or sensitizing cocaine during 3 days followed by challenging doses at days 8 and 18.

Results

The findings revealed that sensitizing regimen of cocaine increases stathmin levels within the nucleus accumbens at day 18 of treatment, not day 8, without changes of synaptophysin, p21-Arc, or α-tubulin. This neural plasticity change seems not to be related to the development of motor sensitization. Other neural regions such as prefrontal cortex, dorsal striatum, and ventral tegmental area were not found to be affected. Repeated cocaine led to well-known short-term augmentation of tyrosine-hydroxylase and protein kinase A expressions in the nucleus accumbens, as well as maintained upregulation of tyrosine hydroxylase in the ventral tegmental area.

Conclusions

As stathmin is an important regulatory protein of microtubule dynamics, this protein change would be linked to morphological changes after repeated cocaine. It was confirmed that upregulation of tyrosine hydroxylase within the ventral tegmental area may participate on the development of motor sensitization.

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References

  • Albertson DN, Pruetz B, Schmidt CJ, Kuhn DM, Kapatos G, Bannon MJ (2004) Gene expression profile of the nucleus accumbens of human cocaine abusers: evidence for dysregulation of myelin. J Neurochem 88:1211–1219

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Boudreau AC, Ferrario CR, Glucksman MJ, Wolf ME (2009) Signaling pathway adaptations and novel protein kinase A substrates related to behavioral sensitization to cocaine. J Neurochem 110(1):363–377

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Fumagalli F, Bedogni F, Frasca A, Di Pasquale L, Racagni G, Riva MA (2006) Corticostriatal up-regulation of activity-regulated cytoskeletal-associated protein expression after repeated exposure to cocaine. Mol Pharmacol 70(5):1726–1734

    Article  CAS  PubMed  Google Scholar 

  • Goldberg DJ, Foley MS, Tang D, Grabham PW (2000) Recruitment of the Arp2/3 complex and mena for the stimulation of actin polymerization in growth cones by nerve growth factor. J Neurosci Res 60(4):458–467

    Article  CAS  PubMed  Google Scholar 

  • Goley ED, Welch MD (2006) The ARP2/3 complex: an actin nucleator comes of age. Nat Rev Mol Cell Biol 13:713–726

    Article  Google Scholar 

  • Henry DJ, Xu XT, White FJ (1998) Adaptations in the mesoaccumbens dopamine system resulting from repeated administration of dopamine D1 and D2 receptor-selective agonists: relevance to cocaine sensitization. Psychopharmacology 140:233–242

    Article  CAS  PubMed  Google Scholar 

  • Jourdain L, Curmi P, Sobel A, Pantaloni D, Carlier MF (1997) Stathmin: a tubulin-sequestering protein which forms a ternary T2S complex with two tubulin molecules. Biochemistry 36(36):10817–10821

    Article  CAS  PubMed  Google Scholar 

  • Karler R, Finnegan KT, Clader LD (1993) Blockade of behavioral sensitization to cocaine and amphetamine by inhibitors of protein synthesis. Brain Res 603:19–24

    Article  CAS  PubMed  Google Scholar 

  • Koob GF, Bloom FE (1988) Cellular and molecular mechanisms of drug dependence. Science 242:715–723

    Article  CAS  PubMed  Google Scholar 

  • Licata SC, Pierce RC (2003) The roles of calcium/calmodulin-dependent and Ras/mitogen-activated protein kinases in the development of psychostimulant-induced behavioral sensitization. J Neurochem 85:14–22

    Article  CAS  PubMed  Google Scholar 

  • Licata SC, Schmidt HD, Pierce RC (2004) Suppressing calcium/calmodulin-dependent protein kinase II activity in the ventral tegmental area enhances the acute behavioural response to cocaine but attenuates the initiation of cocaine-induced behavioural sensitization in rats. Eur J Neurosci 19:405–414

    Article  PubMed  Google Scholar 

  • Lodge DJ, Grace AA (2011) Divergent activation of ventromedial and ventrolateral dopamine systems in animal models of amphetamine sensitization and schizophrenia. Int J Neuropsychopharmacol 18:1–8

    Google Scholar 

  • Lu H, Cheng PL, Lim BK, Khoshnevisrad N, Poo MM (2010) Elevated BDNF after cocaine withdrawal facilitates LTP in medial prefrontal cortex by suppressing GABA inhibition. Neuron 67(5):821–833

  • Mameli M, Balland B, Luján R, Lüscher C (2007) Rapid synthesis and synaptic insertion of GluR2 for mGluR-LTD in the ventral tegmental area. Science 317(5837):530–533

    Article  CAS  PubMed  Google Scholar 

  • Marquèze-Pouey B, Wisden W, Malosio ML, Betz H (1991) Differential expression of synaptophysin and synaptoporin mRNAs in the postnatal rat central nervous system. J Neurosci 11(11):3388–3397

  • Martel G, Hevi C, Wong A, Zushida K, Uchida S, Shumyatsky GP (2012) Murine GRPR and stathmin control in opposite directions both cued fear extinction and neural activities of the amygdala and prefrontal cortex. PLoS One 7(2):e30942

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Mash DC, Pablo J, Ouyang Q, Hearn WL, Izenwasser S (2002) Dopamine transport function is elevated in cocaine users. J Neurochem 81(2):292–300

    Article  CAS  PubMed  Google Scholar 

  • Mash DC, Ouyang Q, Pablo J, Basile M, Izenwasser S, Lieberman A, Perrin RJ (2003) Cocaine abusers have an overexpression of alpha-synuclein in dopamine neurons. J Neurosci 23(7):2564–2571

    CAS  PubMed  Google Scholar 

  • Miller FD, Naus CC, Durand M, Bloom FE, Milner RJ (1987) Isotypes of alpha-tubulin are differentially regulated durig neuronal maduration. J Cell Biol 105:3065–3073

    Article  CAS  PubMed  Google Scholar 

  • Moussawi K, Pacchioni A, Moran M, Olive MF, Gass JT, Lavin A et al (2009) N-Acetylcysteine reverses cocaine-induced metaplasticity. Nat Neurosci 12(2):182–189

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Nestler EJ (2001) Molecular basis of long-term plasticity underlying addiction. Nat Rev Neurosci 2:119–128

    Article  CAS  PubMed  Google Scholar 

  • Nestler EJ, Aghajanian GK (1997) Molecular and cellular basis of addiction. Science 278:58–63

    Article  CAS  PubMed  Google Scholar 

  • Nestler EJ, Terwilliger RZ, Walker JR, Sevarino KA, Duman RS (1990) Chronic cocaine treatment decreases levels of the G protein subunits Gia and Goa in discrete regions of the rat brain. J Neurochem 55:1079–1082

    Article  CAS  PubMed  Google Scholar 

  • Norrholm SD, Bibb JA, Nestler EJ, Ouimet CC, Taylor JR, Greengard P (2003) Cocaine-induced proliferation of dendritic spines in nucleus accumbens is dependent on the activity of cyclin-dependent kinase-5. Neuroscience 116:19–22

    Article  CAS  PubMed  Google Scholar 

  • Onn SP, Grace AA (2000) Amphetamine withdrawal alters bistable states and cellular coupling in rat prefrontal cortex and nucleus accumbens neurons recorded in vivo. J Neurosci 20(6):2332–2345

    CAS  PubMed  Google Scholar 

  • Paxinos G, Watson C (2005) The rat brain in stereotaxic coordinates. Elsevier Academic Press, Amsterdam

    Google Scholar 

  • Pierce RC, Born B, Adams M, Kalivas PW (1996) Repeated intra-ventral tegmental area administration of SKF-38393 induces behavioral and neurochemical sensitization to a subsequent cocaine challenge. J Pharmacol Exp Ther 278:384–392

    CAS  PubMed  Google Scholar 

  • Qin Y, Ouyang Q, Pablo J, Mash DC (2005) Cocaine abuse elevates alpha-synuclein and dopamine transporter levels in the human striatum. Neuroreport 16(13):1489–1493

    Article  CAS  PubMed  Google Scholar 

  • Robinson TE, Gorny G, Mitton E, Kolb B (2001) Cocaine self-administration alters the morphology of dendrites and dendritic spines in the nucleus accumbens and neocortex. Synapse 39:257–266

    Article  CAS  PubMed  Google Scholar 

  • Romanova EV, Lee JE, Kelleher NL, Sweedler JV, Gulley JM (2010) Mass spectrometry screening reveals peptides modulated differentially in the medial prefrontal cortex of rats with disparate initial sensitivity to cocaine. AAPS J 12(3):443–454

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Self DW, Terwilliger RZ, Nestler EJ, Stein L (1994) Inactivation of Gi and G(o) proteins in nucleus accumbens reduces both cocaine and heroin reinforcement. J Neurosci 14(10):6239–6247

    CAS  PubMed  Google Scholar 

  • Stewart J, Vezina P (1989) Microinjections of SCH-23390 into the ventral tegmental area and substantia nigra pars reticulata attenuate the development of sensitization to the locomotor activating effects of systemic amphetamine. Brain Res 495:401–406

    Article  CAS  PubMed  Google Scholar 

  • Sulzer D (2011) How addictive drugs disrupt presynaptic dopamine neurotransmission. Neuron 69(4):628–649

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Terwilliger RZ, Beitner-Johnson D, Sevarino KA, Crain SM, Nestler EJ (1991) A general role for adaptations in G-proteins and the cyclic AMP system in mediating the chronic actions of morphine and cocaine on neuronal function. Brain Res 548:100–110

    Article  CAS  PubMed  Google Scholar 

  • Ujike K, Takaki M, Kodama M, Kuroda S (2002) Gene expression related to synaptogenesis, neuritogenesis, and MAP kinase in behavioral sensitization to psychostimulants. Ann N Y Acad Sci 965:55–67

    Article  CAS  PubMed  Google Scholar 

  • Vezina P (1996) D1 dopamine receptor activation is necessary for the induction of sensitization by amphetamine in the ventral tegmental area. J Neurosci 16:2411–2420

    CAS  PubMed  Google Scholar 

  • Vrana SL, Vrana KE, Koves TR, Smith JE, Dworkin SI (1993) Chronic cocaine administration increases CNS tyrosine hydroxylase enzyme activity and mRNA levels and tryptophan hydroxylase enzyme activity levels. J Neurochem 61:2262–2268

    Article  CAS  PubMed  Google Scholar 

  • Weiss SRB, Post RM, Pert A, Woodward R, Murman D (1989) Context-dependent cocaine sensitization: differential effect of haloperidol on development versus expression. Pharmacol Biochem Behav 34:655–661

    CAS  PubMed  Google Scholar 

  • Wise RA, Rompre PP (1989) Brain dopamine and reward. Annu Rev Psychol 40:191–225

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

This study is supported by grants to EFE from Plan Nacional sobre Drogas (PNSD, ref. 2009I039), Plan Andaluz de Investigacion (BIO127), and Ministerio de Sanidad (RETICS, RD06/001/002, Instituto Carlos III, co-financing with FEDER, European Fund for Regional Development). NRE received a pre-doctoral grant from RETICS RD06/001/002 (Instituto Carlos III). The experiments comply with the current laws of the local ethical committee (University of Seville, PNSD 2009I039).

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The authors declare no conflict of interest.

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Authors and Affiliations

  1. Departamento de Fisiologia Medica y Biofisica, Universidad de Sevilla, Av. Sanchez Pizjuan 4, 41009, Sevilla, Spain

    Nieves Rodriguez-Espinosa & Emilio Fernandez-Espejo

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  1. Nieves Rodriguez-Espinosa
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  2. Emilio Fernandez-Espejo
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Correspondence to Nieves Rodriguez-Espinosa.

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Rodriguez-Espinosa, N., Fernandez-Espejo, E. Effects of acute and repeated cocaine on markers for neural plasticity within the mesolimbic system in rats. Psychopharmacology 232, 57–62 (2015). https://doi.org/10.1007/s00213-014-3632-0

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  • DOI: https://doi.org/10.1007/s00213-014-3632-0

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