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Environmental Enrichment does not Reduce the Rewarding and Neurotoxic Effects of Methamphetamine

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Abstract

Abuse of amphetamine analogues, such as methamphetamine (METH), represents an important health problem because of their powerful addictive and neurotoxic effects. Abuse of METH induces dopamine neuron terminals loss and cell death in the striatum similar to what is found in other neurodegenerative processes. Exposing mice and rats to enriched environments (EE) has been shown to produce significant protective effects against drug-induced reward as well as against neurodegenerative processes. Here, we investigated whether exposure to EE could reduce the METH-induced reward and neurotoxicity. For this, we reared mice for 2 months during early stages of life in standard environments or EE and then, at adulthood, we tested the ability of METH to induce conditioned place preference and neurotoxicity. We found that, contrary to what we found with other drugs such as cocaine and heroin, EE was unable to reduce the rewarding effects of METH. In addition, contrary to what we found with other toxins such as MPTP, EE did not diminish the striatal neurotoxicity induced by METH (4 × 10 mg/kg) as measured by dopamine content, tyrosine hydroxylase protein levels and apoptosis. Our results demonstrate that the rewarding and neurotoxic effects of METH are not reduced by EE and highlight the great risks associated with the increased popularity of this drug amongst the young population.

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References

  • Ahmed SH, Koob GF (1998) Transition from moderate to excessive drug intake: change in hedonic set point. Science 282:298–300

    Article  CAS  PubMed  Google Scholar 

  • Ali SF, Newport GD, Holson RR, Slikker W Jr, Bowyer JF (1994) Low environmental temperatures or pharmacologic agents that produce hypothermia decrease methamphetamine neurotoxicity in mice. Brain Res 658:33–38

    Article  CAS  PubMed  Google Scholar 

  • Anastasia A, Torre L, de Erausquin GA, Masco DH (2009) Enriched environment protects the nigrostriatal dopaminergic system and induces astroglial reaction in the 6-OHDA rat model of Parkinson’s disease. J Neurochem 109:755–765

    Article  CAS  PubMed  Google Scholar 

  • Aron JL, Paulus MP (2007) Location, location: using functional magnetic resonance imaging to pinpoint brain differences relevant to stimulant use. Addiction 102(Suppl 1):33–43

    Article  PubMed  Google Scholar 

  • Barr AM, Panenka WJ, MacEwan GW, Thornton AE, Lang DJ, Honer WG, Lecomte T (2006) The need for speed: an update on methamphetamine addiction. J Psychiatry Neurosci 31:301–313

    PubMed  Google Scholar 

  • Battaglia G, Fornai F, Busceti CL, Aloisi G, Cerrito F, De Blasi A, Melchiorri D, Nicoletti F (2002) Selective blockade of mGlu5 metabotropic glutamate receptors is protective against methamphetamine neurotoxicity. J Neurosci 22:2135–2141

    CAS  PubMed  Google Scholar 

  • Betarbet R, Sherer TB, Greenamyre JT (2002) Animal models of Parkinson’s disease. Bioessays 24:308–318

    Article  CAS  PubMed  Google Scholar 

  • Bezard E, Dovero S, Belin D, Duconger S, Jackson-Lewis V, Przedborski S, Piazza PV, Gross CE, Jaber M (2003) Enriched environment confers resistance to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and cocaine: involvement of dopamine transporter and trophic factors. J Neurosci 23:10999–11007

    CAS  PubMed  Google Scholar 

  • Blandini F, Armentero MT, Martignoni E (2008) The 6-hydroxydopamine model: news from the past. Parkinsonism Relat Disord 14(Suppl 2):S124–S129

    Article  PubMed  Google Scholar 

  • Bowyer JF, Davies DL, Schmued L, Broening HW, Newport GD, Slikker W Jr, Holson RR (1994) Further studies of the role of hyperthermia in methamphetamine neurotoxicity. J Pharmacol Exp Ther 268:1571–1580

    CAS  PubMed  Google Scholar 

  • Brown PL, Wise RA, Kiyatkin EA (2003) Brain hyperthermia is induced by methamphetamine and exacerbated by social interaction. J Neurosci 23:3924–3929

    CAS  PubMed  Google Scholar 

  • Brown JM, Gouty S, Iyer V, Rosenberger J, Cox BM (2006) Differential protection against MPTP or methamphetamine toxicity in dopamine neurons by deletion of ppN/OFQ expression. J Neurochem 98:495–505

    Article  CAS  PubMed  Google Scholar 

  • Burns RS, LeWitt PA, Ebert MH, Pakkenberg H, Kopin IJ (1985) The clinical syndrome of striatal dopamine deficiency. Parkinsonism induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). N Engl J Med 312:1418–1421

    Article  CAS  PubMed  Google Scholar 

  • Cadet JL, Jayanthi S, Deng (2003) Speed kills: cellular and molecular bases of methamphetamine-induced nerve terminal degeneration and neuronal apoptosis. FASEB J 17:1775–1788

    Article  CAS  PubMed  Google Scholar 

  • Carroll ME, Anker JJ, Perry JL (2009) Modeling risk factors for nicotine and other drug abuse in the preclinical laboratory. Drug Alcohol Depend 104(Suppl 1):S70–S78

    Article  CAS  PubMed  Google Scholar 

  • Chang L, Alicata D, Ernst T, Volkow N (2007) Structural and metabolic brain changes in the striatum associated with methamphetamine abuse. Addiction 102(Suppl 1):16–32

    Article  PubMed  Google Scholar 

  • Davidson C, Gow AJ, Lee TH, Ellinwood EH (2001) Methamphetamine neurotoxicity: necrotic and apoptotic mechanisms and relevance to human abuse and treatment. Brain Res Brain Res Rev 36:1–22

    CAS  PubMed  Google Scholar 

  • Delle Donne KT, Sonsalla PK (1994) Protection against methamphetamine-induced neurotoxicity to neostriatal dopaminergic neurons by adenosine receptor activation. J Pharmacol Exp Ther 271:1320–1326

    CAS  PubMed  Google Scholar 

  • Deng X, Cadet JL (2000) Methamphetamine-induced apoptosis is attenuated in the striata of copper-zinc superoxide dismutase transgenic mice. Brain Res Mol Brain Res 83:121–124

    Article  CAS  PubMed  Google Scholar 

  • Deng X, Ladenheim B, Tsao LI, Cadet JL (1999) Null mutation of c-fos causes exacerbation of methamphetamine-induced neurotoxicity. J Neurosci 19:10107–10115

    CAS  PubMed  Google Scholar 

  • Deng X, Wang Y, Chou J, Cadet JL (2001) Methamphetamine causes widespread apoptosis in the mouse brain: evidence from using an improved TUNEL histochemical method. Brain Res Mol Brain Res 93:64–69

    Article  CAS  PubMed  Google Scholar 

  • Deng X, Jayanthi S, Ladenheim B, Krasnova IN, Cadet JL (2002) Mice with partial deficiency of c-Jun show attenuation of methamphetamine-induced neuronal apoptosis. Mol Pharmacol 62:993–1000

    Article  CAS  PubMed  Google Scholar 

  • Deng X, Ladenheim B, Jayanthi S, Cadet JL (2007) Methamphetamine administration causes death of dopaminergic neurons in the mouse olfactory bulb. Biol Psychiatry 61:1235–1243

    Article  CAS  PubMed  Google Scholar 

  • Deroche-Gamonet V, Belin D, Piazza PV (2004) Evidence for addiction-like behavior in the rat. Science 305:1014–1017

    Article  CAS  PubMed  Google Scholar 

  • Di Chiara G, Imperato A (1988) Drugs abused by humans preferentially increase synaptic dopamine concentrations in the mesolimbic system of freely moving rats. Proc Natl Acad Sci USA 85:5274–5278

    Article  CAS  PubMed  Google Scholar 

  • Diamond MC, Ingham CA, Johnson RE, Bennett EL, Rosenzweig MR (1976) Effects of environment on morphology of rat cerebral cortex and hippocampus. J Neurobiol 7:75–85

    Article  CAS  PubMed  Google Scholar 

  • El Rawas R, Thiriet N, Lardeux V, Jaber M, Solinas M (2009) Environmental enrichment decreases the rewarding but not the activating effects of heroin. Psychopharmacology (Berl) 203:561–570

    Article  CAS  Google Scholar 

  • Fantegrossi WE, Ciullo JR, Wakabayashi KT, De La Garza R II, Traynor JR, Woods JH (2008) A comparison of the physiological, behavioral, neurochemical and microglial effects of methamphetamine and 3,4-methylenedioxymethamphetamine in the mouse. Neuroscience 151:533–543

    Article  CAS  PubMed  Google Scholar 

  • Fleckenstein AE, Gibb JW, Hanson GR (2000) Differential effects of stimulants on monoaminergic transporters: pharmacological consequences and implications for neurotoxicity. Eur J Pharmacol 406:1–13

    Article  CAS  PubMed  Google Scholar 

  • Gehrke BJ, Cass WA, Bardo MT (2006) Monoamine-depleting doses of methamphetamine in enriched and isolated rats: consequences for subsequent methamphetamine-induced hyperactivity and reward. Behav Pharmacol 17:499–508

    Article  CAS  PubMed  Google Scholar 

  • Halladay AK, Kusnecov A, Michna L, Kita T, Hara C, Wagner GC (2003) Relationship between methamphetamine-induced dopamine release, hyperthermia, self-injurious behaviour and long term dopamine depletion in BALB/c and C57BL/6 mice. Pharmacol Toxicol 93:33–41

    Article  CAS  PubMed  Google Scholar 

  • Harvey BK, Chou J, Shen H, Hoffer BJ, Wang Y (2009) Diadenosine tetraphosphate reduces toxicity caused by high-dose methamphetamine administration. Neurotoxicology 30:436–444

    Article  CAS  PubMed  Google Scholar 

  • Jaber M, Jones S, Giros B, Caron MG (1997) The dopamine transporter: a crucial component regulating dopamine transmission. Mov Disord 12:629–633

    Article  CAS  PubMed  Google Scholar 

  • Jenner P, Marsden CD (1986) The actions of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in animals as a model of Parkinson’s disease. J Neural Transm Suppl 20:11–39

    CAS  PubMed  Google Scholar 

  • Kalivas PW (2007) Cocaine and amphetamine-like psychostimulants: neurocircuitry and glutamate neuroplasticity. Dialogues Clin Neurosci 9:389–397

    PubMed  Google Scholar 

  • Kempermann G, Kuhn HG, Gage FH (1997) Genetic influence on neurogenesis in the dentate gyrus of adult mice. Proc Natl Acad Sci USA 94:10409–10414

    Article  CAS  PubMed  Google Scholar 

  • Krasnova IN, Cadet JL (2009) Methamphetamine toxicity and messengers of death. Brain Res Rev 60:379–407

    Article  CAS  PubMed  Google Scholar 

  • Laviola G, Hannan AJ, Macri S, Solinas M, Jaber M (2008) Effects of enriched environment on animal models of neurodegenerative diseases and psychiatric disorders. Neurobiol Dis 31:159–168

    Article  PubMed  Google Scholar 

  • Layer RT, Bland LR, Skolnick P (1993) MK-801, but not drugs acting at strychnine-insensitive glycine receptors, attenuate methamphetamine nigrostriatal toxicity. Brain Res 625:38–44

    Article  CAS  PubMed  Google Scholar 

  • Matuszewich L, Yamamoto BK (2004) Chronic stress augments the long-term and acute effects of methamphetamine. Neuroscience 124:637–646

    Article  CAS  PubMed  Google Scholar 

  • Nithianantharajah J, Hannan AJ (2006) Enriched environments, experience-dependent plasticity and disorders of the nervous system. Nat Rev Neurosci 7:697–709

    Article  CAS  PubMed  Google Scholar 

  • Nithianantharajah J, Barkus C, Murphy M, Hannan AJ (2008) Gene-environment interactions modulating cognitive function and molecular correlates of synaptic plasticity in Huntington’s disease transgenic mice. Neurobiol Dis 29:490–504

    Article  CAS  PubMed  Google Scholar 

  • Nordahl TE, Salo R, Leamon M (2003) Neuropsychological effects of chronic methamphetamine use on neurotransmitters and cognition: a review. J Neuropsychiatry Clin Neurosci 15:317–325

    CAS  PubMed  Google Scholar 

  • O’Callaghan JP, Miller DB (1994) Neurotoxicity profiles of substituted amphetamines in the C57BL/6J mouse. J Pharmacol Exp Ther 270:741–751

    PubMed  Google Scholar 

  • Rampon C, Jiang CH, Dong H, Tang YP, Lockhart DJ, Schultz PG, Tsien JZ, Hu Y (2000) Effects of environmental enrichment on gene expression in the brain. Proc Natl Acad Sci USA 97:12880–12884

    Article  CAS  PubMed  Google Scholar 

  • Riddle EL, Fleckenstein AE, Hanson GR (2005) Role of monoamine transporters in mediating psychostimulant effects. AAPS J 7:E847–E851

    Article  CAS  PubMed  Google Scholar 

  • Riddle EL, Fleckenstein AE, Hanson GR (2006) Mechanisms of methamphetamine-induced dopaminergic neurotoxicity. AAPS J 8:E413–E418

    PubMed  Google Scholar 

  • Rosenzweig MR, Bennett EL (1996) Psychobiology of plasticity: effects of training and experience on brain and behavior. Behav Brain Res 78:57–65

    Article  CAS  PubMed  Google Scholar 

  • Scott JC, Woods SP, Matt GE, Meyer RA, Heaton RK, Atkinson JH, Grant I (2007) Neurocognitive effects of methamphetamine: a critical review and meta-analysis. Neuropsychol Rev 17:275–297

    Article  PubMed  Google Scholar 

  • Smeyne RJ, Jackson-Lewis V (2005) The MPTP model of Parkinson’s disease. Brain Res Mol Brain Res 134:57–66

    Article  CAS  PubMed  Google Scholar 

  • Sofuoglu M, Sewell RA (2009) Norepinephrine and stimulant addiction. Addict Biol 14:119–129

    Article  CAS  PubMed  Google Scholar 

  • Solinas M, Chauvet C, Thiriet N, El Rawas R, Jaber M (2008) Reversal of cocaine addiction by environmental enrichment. Proc Natl Acad Sci USA 105:17145–17150

    Article  CAS  PubMed  Google Scholar 

  • Solinas M, Thiriet N, El Rawas R, Lardeux V, Jaber M (2009) Environmental enrichment during early stages of life reduces the behavioral, neurochemical, and molecular effects of cocaine. Neuropsychopharmacology 34:1102–1111

    Article  CAS  PubMed  Google Scholar 

  • Stairs DJ, Bardo MT (2009) Neurobehavioral effects of environmental enrichment and drug abuse vulnerability. Pharmacol Biochem Behav 92:377–382

    Article  CAS  PubMed  Google Scholar 

  • Tata DA, Raudensky J, Yamamoto BK (2007) Augmentation of methamphetamine-induced toxicity in the rat striatum by unpredictable stress: contribution of enhanced hyperthermia. Eur J Neurosci 26:739–748

    Article  PubMed  Google Scholar 

  • Thiriet N, Deng X, Solinas M, Ladenheim B, Curtis W, Goldberg SR, Palmiter RD, Cadet JL (2005) Neuropeptide Y protects against methamphetamine-induced neuronal apoptosis in the mouse striatum. J Neurosci 25:5273–5279

    Article  CAS  PubMed  Google Scholar 

  • Thiriet N, Amar L, Toussay X, Lardeux V, Ladenheim B, Becker KG, Cadet JL, Solinas M, Jaber M (2008) Environmental enrichment during adolescence regulates gene expression in the striatum of mice. Brain Res 1222:31–41

    Article  CAS  PubMed  Google Scholar 

  • van Praag H, Kempermann G, Gage FH (2000) Neural consequences of environmental enrichment. Nat Rev Neurosci 1:191–198

    Article  PubMed  Google Scholar 

  • Vanderschuren LJ, Everitt BJ (2004) Drug seeking becomes compulsive after prolonged cocaine self-administration. Science 305:1017–1019

    Article  CAS  PubMed  Google Scholar 

  • Volz TJ, Fleckenstein AE, Hanson GR (2007) Methamphetamine-induced alterations in monoamine transport: implications for neurotoxicity, neuroprotection and treatment. Addiction 102(Suppl 1):44–48

    Article  PubMed  Google Scholar 

  • Wilson JM, Kalasinsky KS, Levey AI, Bergeron C, Reiber G, Anthony RM, Schmunk GA, Shannak K, Haycock JW, Kish SJ (1996) Striatal dopamine nerve terminal markers in human, chronic methamphetamine users. Nat Med 2:699–703

    Article  CAS  PubMed  Google Scholar 

  • Zhu JP, Xu W, Angulo JA (2005) Disparity in the temporal appearance of methamphetamine-induced apoptosis and depletion of dopamine terminal markers in the striatum of mice. Brain Res 1049:171–181

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank Anne Cantereau for technical assistance with confocal images. We acknowledge the National Institute on Drug Abuse for generous gift of METH. This study was funded by the CNRS, University of Poitiers and the Contrat de Projet Etat Region (CPER) #5.

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Correspondence to Nathalie Thiriet.

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Thiriet, N., Gennequin, B., Lardeux, V. et al. Environmental Enrichment does not Reduce the Rewarding and Neurotoxic Effects of Methamphetamine. Neurotox Res 19, 172–182 (2011). https://doi.org/10.1007/s12640-010-9158-2

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  • DOI: https://doi.org/10.1007/s12640-010-9158-2

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