Raineri, M.; Peskin, V.; Goitia, B.; Taravini, I.R.; Giorgeri, S.; Urbano, F.J.; Bisagno, V. "Attenuated methamphetamine induced neurotoxicity by modafinil administration in mice" (2011) Synapse. 65(10):1087-1098
Estamos trabajando para incorporar este artículo al repositorio
Consulte el artículo en la página del editor
Consulte la política de Acceso Abierto del editor


Methamphetamine (METH) is a highly addictive drug that might induce neurotoxicity. Clinical trials have reported that modafinil, a wake-promoting agent used to treat sleep disorders, may have some efficacy for the treatment of psychostimulant addiction. In this study we tested possible neuroprotective effects of modafinil after toxic METH administration in mice. We evaluated the effect of modafinil (two injections of either 90 or 180 mg/kg) and METH binge (3 × 7 mg/kg i.p. injections, 3-h apart) coadministration on DA striatal content, TH immunoreactivity in striatal areas and spontaneous locomotor activity. We also investigated acute locomotor activity and stereotypy profile in mice treated with a single METH dose (2 and 7 mg/kg) pretreated with modafinil (90 and 180 mg/kg). We found that mice treated with a METH binge showed a marked decrease in DA and dopaminergic metabolites as well as lower levels of TH immunoreactivity in the dorsal striatum. Pretreatment with modafinil (both 90 and 180 mg/kg) attenuated these effects but did not prevent METH induced decrease in locomotion. We also found that groups that received the combination of both modafinil and single dose METH showed a decrease in total distance traveled in an open field compared with METH groups. We observed an increment in the time mice expended doing stereotypic movements (continuous sniffing) in the group that received the combination of both METH and modafinil (i.e., decreasing locomotion). Our results suggest a possible protective role of modafinil against METH acute striatal toxicity. Synapse 2011. © 2011 Wiley-Liss, Inc.


Documento: Artículo
Título:Attenuated methamphetamine induced neurotoxicity by modafinil administration in mice
Autor:Raineri, M.; Peskin, V.; Goitia, B.; Taravini, I.R.; Giorgeri, S.; Urbano, F.J.; Bisagno, V.
Filiación:Instituto de Investigaciones Farmacológicas (ININFA-UBA-CONICET), Junín 956, piso 5 C1113-Buenos Aires, Argentina
Laboratorio de Fisiología y Biología Molecular, Instituto de Fisiología, Biología Molecular y Neurociencias (IFIBYNE), UBA-CONICET, Intendente Guiraldes 2670, pabellón 2, piso 2, Ciudad Universitaria, C1428BGA-Buenos Aires, Argentina
Cátedra de Química Analítica Instrumental, Facultad de Farmacia y Bioquímica, UBA, Junín 956, C1113, Buenos Aires, Argentina
Palabras clave:Behavior; Dopamine (DA); Modafinil; Neurotoxicity; dopamine; methamphetamine; modafinil; tyrosine 3 monooxygenase; animal experiment; animal model; article; controlled study; corpus striatum; drug effect; drug efficacy; locomotion; male; mouse; neuroprotection; neurotoxicity; nonhuman; priority journal; stereotypy; treatment outcome; Amphetamine-Related Disorders; Animals; Benzhydryl Compounds; Central Nervous System Stimulants; Drug Administration Schedule; Drug Interactions; Male; Methamphetamine; Mice; Motor Activity; Neuroprotective Agents; Stereotyped Behavior
Página de inicio:1087
Página de fin:1098
Título revista:Synapse
Título revista abreviado:Synapse
CAS:dopamine, 51-61-6, 62-31-7; methamphetamine, 28297-73-6, 51-57-0, 537-46-2, 7632-10-2; modafinil, 68693-11-8; tyrosine 3 monooxygenase, 9036-22-0; Benzhydryl Compounds; Central Nervous System Stimulants; Methamphetamine, 537-46-2; Neuroprotective Agents; modafinil, 68693-11-8


  • Achat-Mendes, C., Ali, S.F., Itzhak, Y., Differential effects of amphetamines-induced neurotoxicity on appetitive and aversive Pavlovian conditioning in mice (2005) Neuropsychopharmacology, 30, pp. 1128-1137
  • Anderson, A.L., Reid, M.S., Li, S.H., Holmes, T., Shemanski, L., Slee, A., Smith, E.V., Elkashef, A.M., Modafinil for the treatment of cocaine dependence (2009) Drug Alcohol Depend, 104 (1-2), pp. 133-139
  • Ballon, J.F., Feifel, D., A systematic review of modafinil: Potential clinical uses and mechanisms of action (2006) J Clin Psychiatry, 67, pp. 554-566
  • Beck, P., Odle, A., Wallace-Huitt, T., Skinner, R.D., Garcia-Rill, E., Modafinil increases arousal determined by P13 potential amplitude: An effect blocked by gap junction antagonists (2008) Sleep, 31, pp. 1647-1654
  • Berridge, C.W., Neural substrates of psychostimulant-induced arousal (2006) Neuropsychopharmacology, 11, pp. 2332-2340. , Epub 2006 Jul 19
  • Bisagno, V., Ferguson, D., Luine, V.N., Short toxic methamphetamine schedule impairs object recognition task in male rats (2002) Brain Research, 940, pp. 95-101
  • Chartoff, E.H., Marck, B.T., Matsumoto, A.M., Dorsa, D.M., Palmiter, R.D., Induction of stereotypy in dopamine-deficient mice requires striatal D1 receptor activation (2001) Proc Natl Acad Sci USA, 98, pp. 10451-10456
  • Creese, I., Iversen, S.D., Blockage of amphetamine induced motor stimulation and stereotypy in the adult rat following neonatal treatment with 6-hydroxydopamine (1973) Brain Res, 55, pp. 369-382
  • Dackis, C.A., Kampman, K.M., Lynch, K.G., Pettinati, H.M., O'Brien, C.P., A double-blind, placebo-controlled trial of modafinil for cocaine dependence (2005) Neuropsychopharmacology, 30, pp. 205-211
  • Davidson, C., Gow, A.J., Lee, T.H., Ellinwood, E.H., Methamphetamine neurotoxicity: Necrotic and apoptotic mechanisms and relevance to human abuse and treatment (2001) Brain Res Brain Res Rev, 36, pp. 1-22
  • Fog, J.U., Khoshbouei, H., Holy, M., Owens, W.A., Vaegter, C.B., Sen, N., Nikandrova, Y., Gether, U., Calmodulin kinase II interacts with the dopamine transporter C terminus to regulate amphetamine-induced reverse transport (2006) Neuron, 51, pp. 417-429
  • Garcia-Rill, E., Heister, D.S., Ye, M., Charlesworth, A., Hayar, A., Electrical coupling: Novel mechanism for sleep-wake control (2007) Sleep, 30, pp. 1405-1414. , Subject of an Editorial
  • Ghahremani, D.G., Tabibnia, G., Monterosso, J., Hellemann, G., Poldrack, R.A., London, E.D., Effect of modafinil on learning and task-related brain activity in methamphetamine-dependent and healthy individuals (2011) Neuropsychopharmacology, 36, pp. 950-959
  • Hart, C.L., Haney, M., Vosburg, S.K., Rubin, E., Foltin, R.W., Smoked cocaine self-administration is decreased by modafinil (2008) Neuropsychopharmacology, 33, pp. 761-768
  • Kalechstein, A.D., De La Garza 2nd, R., Newton, T.F., Modafinil administration improves working memory in methamphetamine-dependent individuals who demonstrate baseline impairment (2010) Am J Addict, 19, pp. 340-344
  • Kelly, P.H., Iversen, S.D., Selective 6OHDA-induced destruction of mesolimbic dopamine neurons: Abolition of psychostimulant-induced locomotor activity in rats (1976) Eur J Pharmacol, 40, pp. 45-56
  • Myrick, H., Malcolm, R., Taylor, B., LaRowe, S., Modafinil: Preclinical, clinical, and post-marketing surveillance-A review of abuse liability issues (2004) Ann Clin Psychiatry, 16, pp. 101-109
  • Padmanabhan, S., Lambert, N.A., Prasad, B.M., Activity-dependent regulation of the dopamine transporter is mediated by Ca(2+)/calmodulin-dependent protein kinase signaling (2008) Eur J Neurosci, 28, pp. 2017-2027
  • Paxinos, G., Franklin, K.B.J., (2001) The mouse brain in stereotaxic coordinates, , 2nd ed. London: Academic
  • Picconi, B., Gardoni, F., Centonze, D., Mauceri, D., Cenci, M.A., Bernardi, G., Calabresi, P., Di Luca, M., Abnormal Ca2+-calmodulin-dependent protein kinase II function mediates synaptic and motor deficits in experimental parkinsonism (2004) J Neurosci, 24 (23), pp. 5283-5291
  • Pu, C., Fisher, J.E., Cappon, G.D., Vorhees, C.V., The effects of amfonelic acid, a dopamine uptake inhibitor, on methamphetamine-induced dopaminergic terminal degeneration and astrocytic response in rat striatum (1994) Brain Res, 649 (1-2), pp. 217-224
  • Reichel, C.M., See, R.E., Modafinil effects on reinstatement of methamphetamine seeking in a rat model of relapse (2010) Psychopharmacology (Berl), 210, pp. 337-346
  • Ridley, R.M., The psychology of perserverative and stereotyped behaviour (1994) Prog Neurobiol, 44, pp. 221-231
  • Robinson, T.E., Becker, J.B., Enduring changes in brain and behavior produced by chronic amphetamine administration: A review and evaluation of animal models of amphetamine psychosis (1986) Brain Res, 396, pp. 157-198
  • Schmidt, C.J., Gibb, J.W., Role of the dopamine uptake carrier in the neurochemical response to methamphetamine: Effects of amfonelic acid (1985) Eur J Pharmacol, 109, pp. 73-80
  • Segal, D.S., Kuczenski, R., Repeated binge exposures to amphetamine and methamphetamine: Behavioral and neurochemical characterization (1997) J Pharmacol Exp Ther, 282, pp. 561-573
  • Suemaru, J., Akiyama, K., Tanabe, Y., Kuroda, S., Methamphetamine decreases calcium-calmodulin dependent protein kinase II activity in discrete rat brain regions (2000) Synapse, 36, pp. 155-166
  • Thomas, D.M., Francescutti-Verbeem, D.M., Kuhn, D.M., The newly synthesized pool of dopamine determines the severity of methamphetamine-induced neurotoxicity (2008) J Neurochem, 105, pp. 605-616
  • van Vliet, S.A., Blezer, E.L., Jongsma, M.J., Vanwersch, R.A., Olivier, B., Philippens, I.H., Exploring the neuroprotective effects of modafinil in a marmoset Parkinson model with immunohistochemistry, magnetic resonance imaging and spectroscopy (2008) Brain Res, 16 (1189), pp. 219-228
  • Volkow, N.D., Fowler, J.S., Logan, J., Alexoff, D., Zhu, W., Telang, F., Wang, G.J., Apelskog-Torres, K., Effects of modafinil on dopamine and dopamine transporters in the male human brain: Clinical implications (2009) JAMA, 301, pp. 1148-1154
  • Volz, T.J., Hanson, G.R., Fleckenstein, A.E., The role of the plasmalemmal dopamine and vesicular monoamine transporters in methamphetamine-induced dopaminergic deficits (2007) J Neurochem, 101, pp. 883-888
  • Urbano, F.J., Leznik, E., Llinás, R.R., Modafinil enhances thalamocortical activity by increasing neuronal electrotonic coupling (2007) Proc Natl Acad Sci USA, 104, pp. 12554-12559
  • Zolkowska, D., Jain, R., Rothman, R.B., Partilla, J.S., Roth, B.L., Setola, V., Prisinzano, T.E., Baumann, M.H., Evidence for the involvement of dopamine transporters in behavioral stimulant effects of modafinil (2009) J Pharmacol Exp Ther, 329, pp. 738-746


---------- APA ----------
Raineri, M., Peskin, V., Goitia, B., Taravini, I.R., Giorgeri, S., Urbano, F.J. & Bisagno, V. (2011) . Attenuated methamphetamine induced neurotoxicity by modafinil administration in mice. Synapse, 65(10), 1087-1098.
---------- CHICAGO ----------
Raineri, M., Peskin, V., Goitia, B., Taravini, I.R., Giorgeri, S., Urbano, F.J., et al. "Attenuated methamphetamine induced neurotoxicity by modafinil administration in mice" . Synapse 65, no. 10 (2011) : 1087-1098.
---------- MLA ----------
Raineri, M., Peskin, V., Goitia, B., Taravini, I.R., Giorgeri, S., Urbano, F.J., et al. "Attenuated methamphetamine induced neurotoxicity by modafinil administration in mice" . Synapse, vol. 65, no. 10, 2011, pp. 1087-1098.
---------- VANCOUVER ----------
Raineri, M., Peskin, V., Goitia, B., Taravini, I.R., Giorgeri, S., Urbano, F.J., et al. Attenuated methamphetamine induced neurotoxicity by modafinil administration in mice. Synapse. 2011;65(10):1087-1098.