Abstract
Rationale
Prior research has accumulated a substantial amount of evidence on the ability of cocaine to produce short- and long-lasting molecular and structural plasticity in the corticostriatal-limbic circuitry. However, traditionally, the cerebellum has not been included in the addiction circuitry, even though growing evidence supports its involvement in the behavioural changes observed after repeated drug experiences.
Objectives
In the present study, we explored the ability of seven cocaine administrations to alter plasticity in the cerebellar vermis.
Methods
After six cocaine injections, one injection every 48 h, mice remained undisturbed for 1 month in their home cages. Following this withdrawal period, they received a new cocaine injection of a lower dose. Locomotion, behavioural stereotypes and several molecular and structural cerebellar parameters were evaluated.
Results
Cerebellar proBDNF and mature BDNF levels were both enhanced by cocaine. The high BDNF expression was associated with dendritic sprouting and increased terminal size in Purkinje neurons. Additionally, we found a reduction in extracellular matrix components that might facilitate the subsequent remodelling of Purkinje-nuclear neuron synapses.
Conclusions
Although speculative, it is possible that these cocaine-dependent cerebellar changes were incubated during withdrawal and manifested by the last drug injection. Importantly, the present findings indicate that cocaine is able to promote plasticity modifications in the cerebellum of sensitised animals similar to those in the basal ganglia.
Similar content being viewed by others
References
Anderson CM, Maas LC, Frederick BB, Bendor JT, Spencer TJ, Livni E, Lukas SE, Fischman AJ, Madras BK, Renshaw PF, Kaufman MJ (2006) Cerebellar vermis involvement in cocaine-related behaviors. Neuropsychopharmacology 31:1318–1326
Bahi A, Dreyer JL (2008) Overexpression of plasminogen activators in the nucleus accumbens enhances cocaine-, amphetamine- and morphine-induced reward and behavioral sensitization. Genes Brain Behav 7:244–256
Bahi A, Boyer F, Chandrasekar V, Dreyer JL (2008) Role of accumbens BDNF and TrkB in cocaine-induced psychomotor sensitisation, conditioned-place preference, and reinstatement in rats. Psychopharmacology (Berl) 199:169–182
Bostan AC, Dum RP, Strick PL (2013) Cerebellar networks with the cerebral cortex and basal ganglia. Trends Cogn Sci 17:241–254
Boudreau AC, Wolf ME (2005) Behavioral sensitisation to cocaine is associated with increased AMPA receptor surface expression in the nucleus accumbens. J Neurosci 25:9144–9151
Boudreau AC, Reimers JM, Milovanovic M, Wolf ME (2007) Cell surface AMPA receptors in the rat nucleus accumbens increase during cocaine withdrawal but internalise after cocaine challenge in association with altered activation of mitogen activated protein kinases. J Neurosci 27:10621–10635
Brown TE, Forquer MR, Cocking DL, Jansen HT, Harding JW, Sorg BA (2007) Role of matrix metalloproteinases in the acquisition and reconsolidation of cocaine-induced conditioned place preference. Learn Mem 14:214–223
Caldeira MV, Melo CV, Pereira DB, Carvalho R, Correia SS, Backos DS, Carvalho AL, Esteban JA, Duarte CB (2007) Brain-derived neurotrophic factor regulates the expression and synaptic delivery of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor subunits in hippocampal neurons. J Biol Chem 282:12619–12628
Carbo-Gas M, Vazquez-Sanroman D, Aguirre-Manzo L, Coria-Avila GA, Manzo J, Sanchis-Segura C, Miquel M (2014a) Involving the cerebellum in cocaine-induced memory: pattern of cFos expression in mice trained to acquire conditioned preference for cocaine. Addict Biol 19:61–76
Carbo-Gas M, Vazquez-Sanroman D, Gil-Miravet I, De Las Heras-Chanes J, Coria-Avila GA, Manzo J, Sanchis-Segura C, Miquel M (2014b) Cerebellar hallmarks of conditioned preference for cocaine. Physiol Behav 132:24–36
Carulli D, Rhodes KE, Brown DJ, Bonnert TP, Pollack SJ, Oliver K, Strata P, Fawcett JW (2006) Composition of perineuronal nets in the adult rat cerebellum and the cellular origin of their components. J Comp Neurol 494:559–577
Corbit LH, Nie H, Janak PH (2012) Habitual alcohol seeking: time course and the contribution of subregions of the dorsal striatum. Biol Psychiatry 72:389–395
Crooks KR, Kleven DT, Rodriguiz RM, Wetsel WC, McNamara JO (2010) TrkB signaling is required for behavioral sensitisation and conditioned place preference induced by a single injection of cocaine. Neuropharmacology 58:1067–1077
De Zeeuw CI, Wylie DR, DiGiorgi PL, Simpson JI (1994) Projections of individual Purkinje cells of identified zones in the flocculus to the vestibular and cerebellar nuclei in the rabbit. J Comp Neurol 15:428–447
Everitt BJ, Robbins TW (2005) Neural systems of reinforcement for drug addiction: from actions to habits to compulsion. Nat Neurosci 8:1481–1489
Foscarin S, Ponchione D, Pajaj E, Leto K, Gawlak M, Wilczynski GM, Rossi F, Carulli D (2011) Experience dependent plasticity and modulation of growth regulatory molecules at central synapses. PLoS One 6:e16666
Ghasemzadeh MB, Mueller C, Vasudevan P (2009) Behavioral sensitisation to cocaine is associated with increased glutamate receptor trafficking to the postsynaptic density after extended withdrawal period. Neuroscience 159:414–426
Grant S, London ED, Newlin DB, Villemagne VL, Liu X, Contoreggi C, Phillips RL, Kimes AS, Margolin A (1996) Activation of memory circuits during cue elicited cocaine craving. Proc Natl Acad Sci U S A 93:12040–12045
Grimm JW, Lu L, Hayashi T, Hope BT, Su TP, Shaham Y (2003) Time-dependent increases in brain-derived neurotrophic factor protein levels within the mesolimbic dopamine system after withdrawal from cocaine: implications for incubation of cocaine craving. J Neurosci 23:742–747
Hansel C (2005) When the B-team runs plasticity: GluR2 receptor trafficking in cerebellar long-term potentiation. Proc Natl Acad Sci U S A 102:18245–18246
Huang CC, Yeh CM, Wu MY, Chang AY, Chan JY, Chan SH, Hsu KS (2011) Cocaine withdrawal impairs metabotropic glutamate receptor-dependent long-term depression in the nucleus accumbens. J Neurosci 31:4194–4203
Jeanneteau F, Deinhardt K, Miyoshi G, Bennett AM, Chao MV (2010) The MAP kinase phosphatase MKP-1 regulates BDNF-induced axon branching. Nat Neurosci 13:1373–1379
Kafitz KW, Rose CR, Thoenen H, Konnerth A (1999) Neurotrophin-evoked rapid excitation through TrkB receptors. Nature 401:918–921
Kakegawa W, Yuzaki M (2005) A mechanism underlying AMPA receptor trafficking during cerebellar long-term potentiation. Proc Natl Acad Sci U S A 102:17846–17851
Kovalchuk Y, Hanse E, Kafitz KW, Konnerth A (2002) Postsynaptic induction of BDNF-mediated long-term potentiation. Science 295:1729–1734
Lau AG, Irier HA, Gu J, Tian D, Ku L, Liu G, Xia M, Fritsch B, Zheng JQ, Dingledine R, Xu B, Lu B, Feng Y (2010) Distinct 3′UTRs differentially regulate activity-dependent translation of brain-derived neurotrophic factor (BDNF). Proc Natl Acad Sci U S A 107:15945–15950
Li X, Wolf ME (2014) Multiple faces of BDNF in cocaine addiction. Behav Brain Res 279:240–254
Li X, DeJoseph MR, Urban JH, Bahi A, Dreyer JL, Meredith GE, Ford KA, Ferrario CR, Loweth JA, Wolf ME (2013) Different roles of BDNF in nucleus accumbens core versus shell during the incubation of cue-induced cocaine craving and its long-term maintenance. J Neurosci 33:1130–1142
Loweth JA, Tseng KY, Wolf ME (2014) Adaptations in AMPA receptor transmission in the nucleus accumbens contributing to incubation of cocaine craving. Neuropharmacology 76:287–300
Lu B, Figurov A (1997) Role of neurotrophins in synapse development and plasticity. Rev Neurosci 8:1–12
Maiya R, Zhou Y, Norris EH, Kreek MJ, Strickland S (2009) Tissue plasminogen activator modulates the cellular and behavioral response to cocaine. Proc Natl Acad Sci U S A 106:1983–1988
Mash DC, Ffrench-Mullen J, Adi N, Qin Y, Buck A, Pablo J (2007) Gene expression in human hippocampus from cocaine abusers identifies genes which regulate extracellular matrix remodeling. PLoS One 2(11):e1187
McGinty JF, Whitfield TW Jr, Berglind WJ (2010) Brain-derived neurotrophic factor and cocaine addiction. Brain Res 1314:183–193
Miquel M, Font L, Sanchis-Segura C, Aragon CMG (2003) Neonatal administration of monosodium glutamate prevents the development of ethanol-, but not psychostimulant-induced, sensitization: a putative role of the arcuate nucleus. Eur J Neurosci 17:2163–2170
Miquel M, Toledo R, García LI, Coria-Avila GA, Manzo J (2009) Why should we keep the cerebellum in mind when thinking about addiction? Curr Drug Abuse Rev 2:26–40
Moulton EA, Elman I, Becerra LR, Goldstein RZ, Borsook D (2014) The cerebellum and addiction: insights gained from neuroimaging research. Addict Biol 19:317–331
Murray JE, Dilleen R, Pelloux Y, Economidou D, Dalley JW, Belin D, Everitt BJ (2013) Increased impulsivity retards the transition to dorsolateral striatal dopamine control of cocaine seeking. Biol Psychiatry 76:15–22
Narisawa-Saito M, Iwakura Y, Kawamura M, Araki K, Kozaki S, Takei N, Nawa H (2002) Brain-derived neurotrophic factor regulates surface expression of alpha-amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid receptors by enhancing the N-ethylmaleimide-sensitive factor/GluR2 interaction in devel- oping neocortical neurons. J Biol Chem 277:40901–40910
Nestler EJ (2004) Molecular mechanisms of drug addiction. Neuropharmacology 47:24–32
Ng T, Chand D, Song L, Al Chawaf A, Watson JD, Boutros PC, Belsham DD, Lovejoy DA (2012) Identification of a novel brain derived neurotrophic factor (BDNF)-inhibitory factor: regulation of BDNF by teneurin C-terminal associated peptide (TCAP)-1 in immortalised embryonic mouse hypothalamic cells. Regul Pept 10:79–89
Petralia RS, Wang YX, Mayat E, Wenthold RJ (1997) Glutamate receptor subunit 2-selective antibody shows a differential distribution of calcium-impermeable AMPA receptors among populations of neurons. J Comp Neurol 385:456–476
Piazza PV, Deroche-Gamonet V (2013) A multistep general theory of transition to addiction. Psychopharmacology (Berl) 229:387–413
Ripley TL, Rocha BA, Oglesby MW, Stephens DN (1999) Increased sensitivity to cocaine, and over-responding during cocaine self-administration in tPA knockout mice. Brain Res 826:117–127
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
Slaker M, Churchill L, Todd RP, Blacktop JM, Zuloaga DG, Raber J, Darling RA, Brown TE, Sorg BA (2015) Removal of perineuronal nets in the medial prefrontal cortex impairs the acquisition and reconsolidation of a cocaine-induced conditioned place preference memory. J Neurosci 35:4190–4202
Stamenkovic I (2003) Extracellular matrix remodelling: the role of matrix metalloproteinases. J Pathol 200:448–464
Strata P, Scelfo B, Sacchetti B (2011) Involvement of cerebellum in emotional behavior. Physiol Res 60:S39–S48
Suzuki L, Coulon P, Sabel-Goedknegt EH, Ruigrok TMH (2012) Organization of cerebral projections to identified cerebellar zones in the posterior cerebellum of the rat. J Neurosci 32:10854–10869
Tanaka J, Horiike Y, Matsuzaki M, Miyazaki T, Ellis-Davies GC, Kasai H (2008) Protein synthesis and neurotrophin-dependent structural plasticity of single dendritic spines. Science 319:1683–1687
Van den Oever MC, Lubbers BR, Goriounova NA, Li KW, Van der Schors RC, Loos M, Riga D, Wiskerke J, Binnekade R, Stegeman M, Schoffelmeer AN, Mansvelder HD, Smit AB, De Vries TJ, Spijker S (2010) Extracellular matrix plasticity and GABAergic inhibition of prefrontal cortex pyramidal cells facilitates relapse to heroin seeking. Neuropsychopharmacology 35:2120–2133
Vazquez-Sanroman D, Letto K, Cerezo-Garcia M, Carbo-Gas M, Sanchis-Segura C, Carulli D, Rossi F, Miquel M (2015) The cerebellum on cocaine: the cerebellum on cocaine: plasticity and metaplasticity. Addict Biol. doi:10.1111/adb.12223
Willuhn I, Burgeno LM, Everitt BJ, Phillips PE (2012) Hierarchical recruitment of phasic dopamine signalling in the striatum during the progression of cocaine use. Proc Natl Acad Sci U S A 109:20703–20708
Wright JW, Harding JW (2009) Contributions of matrix metalloproteinases to neural plasticity, habituation, associative learning and drug addiction. Neural Plast. doi:10.1155/2009/579382
Xue YX, Xue LF, Liu JF, He J, Deng JH, Sun SC, Han HB, Luo YX, Xu LZ, Wu P, Lu L (2014) Depletion of perineuronal nets in the amygdala to enhance the erasure of drug memories. J Neurosci 34:6647–6658
Yalachkov Y, Kaiser J, Naumer MJ (2010) Sensory and motor aspects of addiction. Behav Brain Res 207:215–222
Acknowledgments
This work was supported by grants and fellowships: Ministerio de Economía y Competitividad [PSI2011- 29181], FPI-PREDOC2009/05, FPU12/04059, PPF 2013 (13I087.01/1) and UJI (P1.1B2011-42).
Conflict of interest
The authors of the present manuscript declare no conflict of interest.
Author information
Authors and Affiliations
Corresponding author
Additional information
In memoriam of Ferdinando Rossi.
Electronic supplementary material
Below is the link to the electronic supplementary material.
ESM 1
(DOC 606 kb)
Rights and permissions
About this article
Cite this article
Vazquez-Sanroman, D., Carbo-Gas, M., Leto, K. et al. Cocaine-induced plasticity in the cerebellum of sensitised mice. Psychopharmacology 232, 4455–4467 (2015). https://doi.org/10.1007/s00213-015-4072-1
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00213-015-4072-1