The MAM Rodent Model of Schizophrenia

Daniel J. Lodge1

1 Department of Pharmacology and Center for Biomedical Neuroscience, University of Texas Health Science Center at San Antonio, San Antonio, Texas
Publication Name:  Current Protocols in Neuroscience
Unit Number:  Unit 9.43
DOI:  10.1002/0471142301.ns0943s63
Online Posting Date:  April, 2013
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Rodent models of human disease are essential to obtain a better understanding of disease pathology, the mechanism of action underlying conventional treatments, as well as for the generation of novel therapeutic approaches. There are a number of rodent models of schizophrenia based on either genetic manipulations, acute or sub‐chronic drug administration, or developmental disturbances. The prenatal methylazoxymethanol acetate (MAM) rodent model is a developmental disruption model gaining increased attention because it displays a number of histological, neurophysiological, and behavioral deficits analogous to those observed in schizophrenia patients. This unit describes the procedures required to safely induce the MAM phenotype in rats. In addition, we describe a simple behavioral procedure, amphetamine‐induced hyperlocomotion, which can be utilized to verify the MAM phenotype. Curr. Protoc. Neurosci. 63:9.43.1‐9.43.7. © 2013 by John Wiley & Sons, Inc.

Keywords: methylazoxymethanol acetate; rodent model; schizophrenia; amphetamine; locomotor activity

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Table of Contents

  • Introduction
  • Basic Protocol 1: Generation of MAM Phenotype
  • Basic Protocol 2: Amphetamine‐Induced Hyper‐Locomotion
  • Commentary
  • Literature Cited
  • Figures
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Basic Protocol 1: Generation of MAM Phenotype

  • Rats: female, pregnant Sprague‐Dawley rats—timed to be gestational day (GD)17 on a Friday (Harlan)
  • Methylazoxymethanol acetate (MRI Global Chemical Carcinogen Repository, cat. no. 213)
  • Sterile saline
  • Standard rat chow softened with tap water
  • 10% (v/v) bleach in water
  • Cavicide disinfectant (Metrix Research)
  • Standard housing cages for rats
  • Housing room separated from colony with limited access
  • Personal protective equipment, including latex gloves, nitrile gloves, laboratory coat, eye protection, and mask
  • 1.5‐ml microcentrifuge tubes
  • Biohazard bags
  • 1‐ml luer‐lock syringes
  • 25‐G needles
  • Biohazard sharps container
NOTE: Female rats should be weighed in advance on a standard laboratory balance to determine the required volume of MAM to be administered.

Basic Protocol 2: Amphetamine‐Induced Hyper‐Locomotion

  • Rats: adult rats treated prenatally (GD 17) with either MAM or saline (see protocol 1)
  • D‐amphetamine sulfate (Sigma‐Aldrich)
  • Saline
  • Laboratory‐grade balance
  • Med Associates rodent locomotor chamber (or equivalent)
  • 1‐ml luer‐lock syringes
  • 25‐G needles
NOTE: All experiments following prenatal MAM or saline administration should be performed on rats spanning a number of different litters. Ten to twelve rats per group is typically required.NOTE: Adult rats should be used, as differences in locomotor activity to low dose amphetamine are typically only observed following puberty in MAM‐treated rats.
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Literature Cited

   Abi‐Dargham, A., van de Giessen, E., Slifstein, M., Kegeles, L.S., and Laruelle, M. 2009. Baseline and amphetamine‐stimulated dopamine activity are related in drug‐naive schizophrenic subjects. Biol. Psychiatry 65:1091‐1093.
   Bayer, S.A. and Altman, J. 1995. Neurogenesis and neuronal migration. In The Rat Nervous System (G. Paxinos, ed.) pp. 1041‐1078. Academic Press, San Diego.
   Flagstad, P., Mork, A., Glenthoj, B.Y., van Beek, J., Michael‐Titus, A.T., and Didriksen, M. 2004. Disruption of neurogenesis on gestational day 17 in the rat causes behavioral changes relevant to positive and negative schizophrenia symptoms and alters amphetamine‐induced dopamine release in nucleus accumbens. Neuropsychopharmacology 29:2052‐2064.
   Ganote, C.E. and Rosenthal, A.S. 1968. Characteristic lesions of methylazoxymethanol‐induced liver damage. A comparative ultrastructural study with dimethylnitrosamine, hydrazine sulfate, and carbon tetrachloride. Lab. Invest. 19:382‐398.
   Gastambide, F., Cotel, M.C., Gilmour, G., O'Neill, M.J., Robbins, T.W., and Tricklebank, M.D. 2011. Selective remediation of reversal learning deficits in the neurodevelopmental MAM model of schizophrenia by a novel mGlu5 positive allosteric modulator. Neuropsychopharmacology 37:1057‐1066.
   Gill, K.M., Lodge, D.J., Cook, J.M., Aras, S., and Grace, A.A. 2011. A novel α5GABAAR‐positive allosteric modulator reverses hyperactivation of the dopamine system in the MAM model of schizophrenia. Neuropsychopharmacology 36:1903‐1911.
   Lavin, A., Moore, H.M., and Grace, A.A. 2005. Prenatal disruption of neocortical development alters prefrontal cortical neuron responses to dopamine in adult rats. Neuropsychopharmacology 30:1426‐1435.
   Le Pen, G., Gourevitch, R., Hazane, F., Hoareau, C., Jay, T.M., and Krebs, M.O. 2006. Peri‐pubertal maturation after developmental disturbance: A model for psychosis onset in the rat. Neuroscience 143:395‐405.
   Lieberman, J.A., Kane, J.M., and Alvir, J. 1987. Provocative tests with psychostimulant drugs in schizophrenia. Psychopharmacology 91:415‐433.
   Lodge, D.J. and Grace, A.A. 2007. Aberrant hippocampal activity underlies the dopamine dysregulation in an animal model of schizophrenia. J. Neurosci. 27:11424‐11430.
   Lodge, D.J. and Grace, A.A. 2009. Gestational methylazoxymethanol acetate administration: A developmental disruption model of schizophrenia. Behav. Brain Res. 204:306‐312.
   Lodge, D.J. and Grace, A.A. 2011. Hippocampal dysregulation of dopamine system function and the pathophysiology of schizophrenia. Trends Pharmacol. Sci. 32:507‐513.
   Lodge, D.J., Behrens, M.M., and Grace, A.A. 2009. A loss of parvalbumin‐containing interneurons is associated with diminished oscillatory activity in an animal model of schizophrenia. J. Neurosci. 29:2344‐2354.
   Moore, H., Jentsch, J.D., Ghajarnia, M., Geyer, M.A., and Grace, A.A. 2006. A neurobehavioral systems analysis of adult rats exposed to methylazoxymethanol acetate on E17: Implications for the neuropathology of schizophrenia. Biol. Psychiatry 60:253‐264.
   Penschuck, S., Flagstad, P., Didriksen, M., Leist, M., and Michael‐Titus, A.T. 2006. Decrease in parvalbumin‐expressing neurons in the hippocampus and increased phencyclidine‐induced locomotor activity in the rat methylazoxymethanol (MAM) model of schizophrenia. Eur. J. Neurosci. 23:279‐284.
   Perez, S.M. and Lodge, D.J. 2012. Aberrant dopamine D2‐like receptor function in a rodent model of schizophrenia. J. Pharmacol. Exp. Ther. 343:288‐295.
   Perez, S.M., Shah, A., Asher, A., and Lodge, D.J. 2012. Hippocampal deep brain stimulation reverses physiological and behavioral deficits in a rodent model of schizophrenia. Int. J. Neuropsychopharmacol. 28:1‐9.
   Schobel, S.A., Lewandowski, N.M., Corcoran, C.M., Moore, H., Brown, T., Malaspina, D., and Small, S.A. 2009. Differential targeting of the CA1 subfield of the hippocampal formation by schizophrenia and related psychotic disorders. Arch. Gen. Psychiatry 66:938‐946.
   Smith, D.W.E. 1966. Mutagenicity of cycasin aglycone (methylazoxymethanol), a naturally occurring carcinogen. Science 152:1273‐1274.
   Talamini, L.M., Ellenbroek, B., Koch, T., and Korf, J. 2000. Impaired sensory gating and attention in rats with developmental abnormalities of the mesocortex. Implications for schizophrenia. Ann. N.Y. Acad. Sci. 911:486‐494.
   Valenti, O., Cifelli, P., Gill, K.M., and Grace, A.A. 2011. Antipsychotic drugs rapidly induce dopamine neuron depolarization block in a developmental rat model of schizophrenia. J. Neurosci. 31:12330‐12338.
   Zedeck, M.S., Sternberg, S.S., Poynter, R.W., and McGowan, J. 1970. Biochemical and pathological effects of methylazoxymethanol acetate, a potent carcinogen. Cancer Res. 30:801‐812.
Key Reference
   Moore et al., 2006. See above.
  This seminal paper provides the first characterization of the MAM phenotype and its relevance to schizophrenia when administered at gestational day 17.
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