Skip to main content

Advertisement

SpringerLink
Log in

Single Intranasal Administration of 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine in C57BL/6 Mice Models Early Preclinical Phase of Parkinson’s Disease

  • Published:
Neurotoxicity Research Aims and scope Submit manuscript

Abstract

Many studies have shown that deficits in olfactory and cognitive functions precede the classical motor symptoms seen in Parkinson’s disease (PD) and that olfactory testing may contribute to the early diagnosis of this disorder. Although the primary cause of PD is still unknown, epidemiological studies have revealed that its incidence is increased in consequence of exposure to certain environmental toxins. In this study, most of the impairments presented by C57BL/6 mice infused with a single intranasal (i.n.) administration of the proneurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) (1 mg/nostril) were similar to those observed during the early phase of PD, when a moderate loss of nigral dopamine neurons results in olfactory and memory deficits with no major motor impairments. Such infusion decreased the levels of the enzyme tyrosine hydroxylase in the olfactory bulb, striatum, and substantia nigra by means of apoptotic mechanisms, reducing dopamine concentration in different brain structures such as olfactory bulb, striatum, and prefrontal cortex, but not in the hippocampus. These findings reinforce the notion that the olfactory system represents a particularly sensitive route for the transport of neurotoxins into the central nervous system that may be related to the etiology of PD. These results also provide new insights in experimental models of PD, indicating that the i.n. administration of MPTP represents a valuable mouse model for the study of the early stages of PD and for testing new therapeutic strategies to restore sensorial and cognitive processes in PD.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

References

  • Albanese A, Bentivoglio M (1982) The organization of dopaminergic and nondopaminergic mesencephalocortical neurons in the rat. Brain Res 238:421–425

    Article  CAS  PubMed  Google Scholar 

  • Alexander GE, DeLong MR, Strick PL (1986) Parallel organization of functionally segregated circuits linking basal ganglia and cortex. Annu Rev Neurosci 9:357–381

    Article  CAS  PubMed  Google Scholar 

  • Bezard E, Gross CE, Fournier MC, Dovero S, Bloch B, Jaber M (1999) Absence of MPTP-induced neuronal death in mice lacking the dopamine transporter. Exp Neurol 155:268–273

    Article  CAS  PubMed  Google Scholar 

  • Bondi MW, Kaszniak AW (1991) Implicit and explicit memory in Alzheimer’s disease and Parkinson’s disease. J Clin Exp Neuropsychol 13:339–358

    Article  CAS  PubMed  Google Scholar 

  • Bosboom JL, Stoffers D, Wolters ECh (2004) Cognitive dysfunction and dementia in Parkinson’s disease. J Neural Transm 111:1303–1315

    Article  CAS  PubMed  Google Scholar 

  • Braak H, Ghebremedhin E, Rub U, Bratzke H, Del Tredici K (2004) Stages in the development of Parkinson’s disease-related pathology. Cell Tissue Res 318:121–134

    Article  PubMed  Google Scholar 

  • Bruck A, Aalto S, Nurmi E, Bergman J, Rinne JO (2005) Cortical 6-[18F]fluoro-l-dopa uptake and frontal cognitive functions in early Parkinson’s disease. Neurobiol Aging 26:891–898

    Article  PubMed  CAS  Google Scholar 

  • Chiueh C, Markey SP, Burns RS, Johannessen JN, Pert A, Kopin IJ (1984) Neurochemical and behavioral effects of systemic and intranigral administration of N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in the rat. Eur J Pharmacol 100:189–194

    Article  CAS  PubMed  Google Scholar 

  • Cooper JA, Sagar HJ, Doherty SM, Jordan N, Tidswell P, Sullivan EV (1992) Different effects of dopaminergic and anticholinergic therapies on cognitive and motor function in Parkinson’s disease. A follow-up study of untreated patients. Brain 115:1701–1725

    Article  PubMed  Google Scholar 

  • Coopersmith R, Weihmuller FB, Kirstein CL, Marshall JF, Leon M (1991) Extracellular dopamine increase in neonatal olfactory bulb during odor preference training. Brain Res 564:149–153

    Article  CAS  PubMed  Google Scholar 

  • Da Cunha C, Gevaerd MS, Vital MA, Miyoshi E, Andreatini R, Silveira R, Takahashi RN, Canteras NS (2001) Memory disruption in rats with nigral lesions induced by MPTP: a model for early Parkinson’s disease amnesia. Behav Brain Res 124:9–18

    Article  CAS  PubMed  Google Scholar 

  • Dantzer R, Bluthe RM, Koob GF, Le Moal M (1987) Modulation of social memory in male rats by neurohypophyseal peptides. Psychopharmacology 91:363–368

    Article  CAS  PubMed  Google Scholar 

  • Dluzen DE (1992) 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) reduces norepinephrine concentrations in the olfactory bulbs of male mice. Brain Res 586:144–147

    Article  CAS  PubMed  Google Scholar 

  • Dluzen DE, Kefalas G (1996) The effects of intranasal infusion of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) upon catecholamine concentrations within olfactory bulbs and corpus striatum of male mice. Brain Res 741:215–219

    Article  CAS  PubMed  Google Scholar 

  • Dluzen DE, Kreutzberg JD (1993) 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) disrupts social memory/recognition processes in the male mouse. Brain Res 609:98–102

    Article  CAS  PubMed  Google Scholar 

  • Dluzen DE, Muraoka S, Landgraf R (1998) Olfactory bulb norepinephrine depletion abolishes vasopressin and oxytocin preservation of social recognition responses in rats. Neurosci Lett 254:161–164

    Article  CAS  PubMed  Google Scholar 

  • Doty RL (2008) The olfactory vector hypothesis of neurodegenerative disease: is it viable? Ann Neurol 63:7–15

    Article  PubMed  Google Scholar 

  • Doty RL, Risser JM (1989) Influence of the D2 dopamine receptor agonist quinpirole on the odor detection performance of rat before and after spiperone administration. Psychopharmacology 98:310–315

    Article  CAS  PubMed  Google Scholar 

  • Doty RL, Deems D, Stellar S (1988a) Olfactory dysfunction in Parkinson’s disease: a general deficit unrelated to neurologic signs, disease state, or disease duration. Neurology 38:1237–1244

    CAS  PubMed  Google Scholar 

  • Doty RL, Fergusson-Segall M, Lucki I, Kreider M (1988b) Effects of intrabulbar injections of 6-hydroxydopamine on ethyl acetate odor detection in castrate and non-castrate male rats. Brain Res 444:95–103

    Article  CAS  PubMed  Google Scholar 

  • Doty RL, Bromley SM, Stern MB (1995) Olfactory testing as an aid in the diagnosis of Parkinson’s disease: development of optimal discrimination criteria. Neurodegeneration 4:93–97

    Article  CAS  PubMed  Google Scholar 

  • Douhou A, Debeir T, Murer MG, Do L, Dufour N, Blanchard V, Moussaoui S, Bohme GA, Agid Y, Raisman-Vozari R (2002) Effect of chronic treatment with riluzole on the nigrostriatal dopaminergic system in weaver mutant mice. Exp Neurol 176:247–253

    Article  CAS  PubMed  Google Scholar 

  • Dubois B, Pillon B (1997) Cognitive deficits in Parkinson’s disease. J Neurol 244:2–8

    Article  CAS  PubMed  Google Scholar 

  • Duvoisin RC (1991) Parkinson’s disease, 3rd edn. Raven Press, New York

    Google Scholar 

  • Espejo EF (1997) Selective dopamine depletion within the medial prefrontal cortex induces anxiogenic-like effects in rats placed on the elevated plus maze. Brain Res 762:281–284

    Article  CAS  PubMed  Google Scholar 

  • Fornai F, Schlüter OM, Lenzi P, Gesi M, Ruffoli R, Ferrucci M, Lazzeri G, Busceti CL, Pontarelli F, Battaglia G, Pellegrini A, Nicoletti F, Ruggieri S, Paparelli A, Südhof TC (2005) Parkinson-like syndrome induced by continuous MPTP infusion: convergent roles of the ubiquitin-proteasome system and alpha-synuclein. Proc Natl Acad Sci USA 102:3413–3418

    Article  CAS  PubMed  Google Scholar 

  • Franco J, Prediger RD, Pandolfo P, Takahashi RN, Farina M, Dafre AL (2007) Antioxidant responses and lipid peroxidation following intranasal 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) administration in rats: increased susceptibility of olfactory bulb. Life Sci 80:1906–1914

    Article  CAS  PubMed  Google Scholar 

  • Franklin KBJ, Paxinos G (1997) The mouse brain in stereotaxic coordinates. Academic Press, San Diego

    Google Scholar 

  • Gall CM, Hendry SH, Seroogy KB, Jones EG, Haycock JW (1987) Evidence of coexistence of GABA and dopamine in neurons of the rat olfactory bulb. J Comp Neurol 266:307–318

    Article  CAS  PubMed  Google Scholar 

  • Gerlach M, Riederer P (1996) Animal models of Parkinson’s disease: an empirical comparison with the phenomenology of the disease in man. J Neural Transm 103:987–1041

    Article  CAS  PubMed  Google Scholar 

  • Gorell JM, Johnson CC, Rybicki BA, Peterson EL, Richardson RJ (1998) The risk of Parkinson’s disease with exposure to pesticides, farming, well water, and rural living. Neurology 50:1346–1350

    CAS  PubMed  Google Scholar 

  • Growdon JH, Kieburtz K, McDermott MP, Panisset M, Friedman JH (1998) Levodopa improves motor function without impairing cognition in mild non-demented Parkinson’s disease patients. Parkinson Study Group. Neurology 50:1327–1331

    CAS  PubMed  Google Scholar 

  • Halasz N, Shepherd GM (1983) Neurochemistry of the vertebrate olfactory bulb. Neuroscience 10:759

    Article  Google Scholar 

  • Hamon M, Fattaccini CM, Adrien J, Gallissot MC, Martin P, Gozlan H (1988) Alterations of central serotonin and dopamine turnover in rats treated with ipsapirone and other 5-hydroxytryptmaine 1A agonists with potential anxiolytic properties. J Pharmacol Exp Ther 246:745–752

    CAS  PubMed  Google Scholar 

  • Hirsch EC, Lejeune O, Colliot G, Corkidi G, Tajani M (1992) Computer methods in nuclei cartography. Methods Neurosci 10:62–79

    Google Scholar 

  • Jenner P (2008) Functional models of Parkinson’s disease: a valuable tool in the development of novel therapies. Ann Neurol Suppl 2:S16–S29

    Google Scholar 

  • Kalaria RN, Mitchell MJ, Harik SI (1987) Correlation of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine neurotoxicity with blood-brain barrier monoamine-oxidase activity. Proc Natl Acad Sci USA 84:3521–3525

    Article  CAS  PubMed  Google Scholar 

  • Kaul S, Kanthasamy A, Kitazawa M, Anantharam V, Kanthasamy AG (2003) Caspase-3 dependent proteolyytic activation of protein kinase C delta mediates and regulates 1-methyl-4-phenylpyridinium (MPP+)-induced apoptotic cell death in dopaminergic cells: relevance to oxidative stress in dopaminergic degeneration. Eur J Neurosci 18:1387–1401

    Article  PubMed  Google Scholar 

  • Kawano T, Margolis FL (1982) Transsynaptic regulation of olfactory bulb catecholamines in mice and rats. J Neurochem 39:342–348

    Article  CAS  PubMed  Google Scholar 

  • Langston JW, Ballard P, Tetrud JW, Irwin I (1983) Chronic Parkinsonism in humans due to a product of meperidine-analog synthesis. Science 219:979–980

    Article  CAS  PubMed  Google Scholar 

  • Lewis SJG, Dove A, Robbins TW, Barker RA, Owen AM (2003) Cognitive impairments in early Parkinson’s disease are accompanied by reductions in activity in frontostriatal neural circuitry. J Neurosci 23:6351–6356

    CAS  PubMed  Google Scholar 

  • Lister RG (1987) The use of a plus-maze to measure anxiety in the mouse. Psychopharmacology 92:180–185

    CAS  PubMed  Google Scholar 

  • Mattson MP (2000) Apoptosis in neurodegenerative disorders. Nat Rev Mol Cell Biol 1:120–129

    Article  CAS  PubMed  Google Scholar 

  • Mayer RA, Kindt MV, Heikkila RE (1986) Prevention of the nigrostriatal toxicity of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine by inhibitors of 3,4-dihydroxyphenylethylamine transport. J Neurochem 47:1073–1079

    Article  CAS  PubMed  Google Scholar 

  • Mitsumoto Y, Mori A, Ohashi S, Nakai M, Moriizumi T (2005) Differential effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in the olfactory bulb and the striatum in mice. Neurosci Res 51:111–115

    Article  CAS  PubMed  Google Scholar 

  • Miyoshi E, Wietzikoski S, Camplessei M, Silveira R, Takahashi RN, Da Cunha C (2002) Impaired learning in a spatial working memory version and in a cued version of the water maze in rats with MPTP-induced mesencephalic dopaminergic lesions. Brain Res Bull 58:41–47

    Article  CAS  PubMed  Google Scholar 

  • Muller A, Reichmann H, Livermore A, Hummel T (2002) Olfactory function in idiopathic Parkinson’s disease (IPD): results from cross-sectional studies in IPD patients and long-term follow-up of de-novo IPD patients. J Neural Transm 109:805–811

    Article  CAS  PubMed  Google Scholar 

  • Passingham D, Sakai K (2004) The prefrontal cortex and working memory: physiology and brain imaging. Curr Opin Neurobiol 14:163–168

    Article  PubMed  CAS  Google Scholar 

  • Petroske E, Meredith GE, Callen S, Totterdell S, Lau YS (2001) Mouse model of Parkinsonism: a comparison between subacute MPTP and chronic MPTP/probenecid treatment. Neuroscience 106:589–601

    Article  CAS  PubMed  Google Scholar 

  • Pillon B, Dubois B, Bonnet AM, Esteguy M, Guimaraes J, Vigouret JM, Lhermitte F, Agid Y (1989) Cognitive slowing in Parkinson’s disease fails to respond to levodopa treatment: the 15-objects test. Neurology 39:762–768

    CAS  PubMed  Google Scholar 

  • Poewe W, Berger W, Benke T, Schelosky L (1991) High-speed memory scanning in Parkinson’s disease: adverse effects of levodopa. Ann Neurol 29:670–673

    Article  CAS  PubMed  Google Scholar 

  • Prediger RD, Batista LC, Miyoshi E, Takahashi RN (2004) Facilitation of short-term social memory by ethanol in rats is mediated by dopaminergic receptors. Behav Brain Res 153:149–157

    Article  CAS  PubMed  Google Scholar 

  • Prediger RD, Batista LC, Takahashi RN (2005a) Caffeine reverses age-related deficits in olfactory discrimination and social recognition memory in rats. Involvement of adenosine A1 and A2A receptors. Neurobiol Aging 26:957–964

    Article  CAS  PubMed  Google Scholar 

  • Prediger RD, Da Cunha C, Takahashi RN (2005b) Antagonistic interaction between adenosine A2A and dopamine D2 receptors modulates the social recognition memory in reserpine-treated rats. Behav Pharmacol 16:209–218

    Article  CAS  PubMed  Google Scholar 

  • Prediger RD, Batista LC, Medeiros R, Pandolfo P, Florio JC, Takahashi RN (2006) The risk is in the air: intranasal administration of MPTP to rats reproducing clinical features of Parkinson’s disease. Exp Neurol 202:391–403

    Article  CAS  PubMed  Google Scholar 

  • Prediger RD, Rial D, Medeiros R, Figueiredo CP, Doty RL, Takahashi RN (2009) Risk is in the air: an intranasal MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) rat model of Parkinson’s disease. Ann N Y Acad Sci. doi:10.1111/j.1749-6632.2009.03885.x)

  • Przedborski S, Jackson-Lewis V, Naini AB, Jakowec M, Petzinger G, Miller R, Akran M (2001) The parkinsonian toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP): a technical review of its utility and safety. J Neurochem 76:1265–1274

    Article  CAS  PubMed  Google Scholar 

  • Riederer P, Wuketich S (1976) Time course of nigrostriatal degeneration in parkinson’s disease. A detailed study of influential factors in human brain amine analysis. J Neural Transm 38:277–301

    Article  CAS  PubMed  Google Scholar 

  • Rojo AI, Montero C, Salazar M, Close RM, Fernandez-Ruiz J, Sanchez-Gonzalez MA, de Sagarra MR, Jackson-Lewis V, Cavada C, Cuadrado A (2006) Persistent penetration of MPTP through the nasal route induces Parkinson’s disease in mice. Eur J Neurosci 24:1874–1884

    Article  PubMed  Google Scholar 

  • Sallaz M, Jourdan F (1992) Apomorphine disrupts odour-induced patterns of glomerular activation in the olfactory bulb. Neuroreport 3:833–836

    Article  CAS  PubMed  Google Scholar 

  • Saporito MS, Brown EM, Miller MS, Carswell S (1999) CEP-1347/KT-7515, an inhibitor of c-jun N-terminal kinase activation, attenuates the 1-methyl-4-phenyl tetrahydropyridine-mediated loss of nigrostriatal dopaminergic neurons in vivo. J Pharmacol Exp Ther 288:421–427

    CAS  PubMed  Google Scholar 

  • Schintu N, Frau L, Ibba M, Garau A, Carboni E, Carta AR (2009) Progressive dopaminergic degeneration in the chronic MPTPp mouse model of Parkinson’s disease. Neurotox Res 16:127–139

    Article  CAS  PubMed  Google Scholar 

  • Schmidt N, Ferger B (2001) Neurochemical findings in the MPTP model of Parkinson’s disease. J Neural Transm 108:1263–1282

    Article  CAS  PubMed  Google Scholar 

  • Schrag A (2004) Psychiatric aspects of Parkinson’s disease: an update. J Neurol 251:795–804

    Article  PubMed  Google Scholar 

  • Sedelis M, Hofele K, Auburger GW, Morgan S, Huston JP, Schwarting RK (2000) MPTP susceptibility in the mouse: behavioral, nurochemical, and histological analysis of gender and strain differences. Behav Genet 30:171–182

    Article  CAS  PubMed  Google Scholar 

  • Shipley MT, Halloran FJ, de la Torre J (1985) Surprisingly rich projection from locus coeruleus to the olfactory bulb in the rat. Brain Res 329:294–299

    Article  CAS  PubMed  Google Scholar 

  • Stebbins GT, Gabrieli JD, Masciari F, Monti L, Goetz CG (1999) Delayed recognition memory in Parkinson’s disease: a role for working memory? Neuropsychologia 37:503–510

    Article  CAS  PubMed  Google Scholar 

  • Tadaiesky MT, Dombrowski PA, Figueiredo CP, Cargnin-Ferreira E, Da Cunha C, Takahashi RN (2008) Emotional, cognitive and neurochemical alterations in a premotor stage model of Parkinson’s disease. Neuroscience 156:830–840

    Article  CAS  PubMed  Google Scholar 

  • Weldon DA, Travis ML, Kennedy DA (1991) Posttraining D1 receptor blockade impairs odor conditioning in neonatal rats. Behav Neurosci 105:450–458

    Article  CAS  PubMed  Google Scholar 

  • Xikota JC, Rial D, Ruthes D, Pereira R, Figueiredo CP, Prediger RD, Walz R (2008) Mild cognitive deficits associated to neocortical microgyria in mice with genetic deletion of cellular prion protein. Brain Res 1241:148–156

    Article  CAS  PubMed  Google Scholar 

  • Zgaljardic DJ, Borod JC, Foldi NS, Mattis P (2003) A review of the cognitive and behavioral sequelae of Parkinson’s disease: relationship to frontostriatal circuitry. Cogn Behav Neurol 16:193–210

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported by grants from the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), the Coordenacão de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), the Programa de Apoio aos Núcleos de Excelência (PRONEX), and the Fundação de Apoio a Pesquisa do Estado de Santa Catarina (FAPESC), all of Brazil. ASA Jr is supported by scholarship from CAPES-Brazil. AERM is supported by CONACYT (México cod.76101, 93485). RDSP and EDB are supported by research fellowships from CNPq-Brazil. RDSP, EDB, and RRV are supported by CAPES-COFECUB (France/Brazil; 491/2005) and FAPESP-INSERM (08/55092-9).

Author information

Authors and Affiliations

  1. Departamento de Farmacologia, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, UFSC, Florianópolis, SC, 88049-900, Brazil

    Rui D. S. Prediger, Aderbal S. Aguiar Jr., Claudia P. Figueiredo & Filipe C. Matheus

  2. Université Pierre et Marie Curie-Paris 6, Centre de Recherche de l’Institut du Cerveau et de la Moelle epiniere, UMR-S975, Paris, France

    Argelia Esperanza Rojas-Mayorquin, Laure Ginestet & Rita Raisman-Vozari

  3. INSERM, U975, Paris, France

    Argelia Esperanza Rojas-Mayorquin, Laure Ginestet & Rita Raisman-Vozari

  4. CNRS, UMR 7225, Paris, France

    Argelia Esperanza Rojas-Mayorquin, Laure Ginestet & Rita Raisman-Vozari

  5. Neuropsychopharmacologie, INSERM, UMR 677, Paris, 75013, France

    Caroline Chevarin, Raymond Mongeau, Michel Hamon & Laurence Lanfumey

  6. Departamento MEF-Fisiologia, Faculdade de Odontologia de Ribeirão Preto, Universidade de São Paulo, USP, Ribeirão Preto, SP, Brazil

    Elaine Del Bel

Authors
  1. Rui D. S. Prediger
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Aderbal S. Aguiar Jr.
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Argelia Esperanza Rojas-Mayorquin
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Claudia P. Figueiredo
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Filipe C. Matheus
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Laure Ginestet
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Caroline Chevarin
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Elaine Del Bel
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Raymond Mongeau
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Michel Hamon
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Laurence Lanfumey
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Rita Raisman-Vozari
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Rui D. S. Prediger.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Prediger, R.D.S., Aguiar, A.S., Rojas-Mayorquin, A.E. et al. Single Intranasal Administration of 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine in C57BL/6 Mice Models Early Preclinical Phase of Parkinson’s Disease. Neurotox Res 17, 114–129 (2010). https://doi.org/10.1007/s12640-009-9087-0

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12640-009-9087-0

Keywords

Search

Navigation