Behavioural Brain Research 149 (2004) 159–181 Research report The prenatal methylazoxymethanol acetate treatment: a neurodevelopmental animal model for schizophrenia? Ana L. Jongen-Rˆ elo 1 , Andreas Leng, Marcel Lüber, Helen H.J. Pothuizen, Liz Weber, Joram Feldon ∗ Behavioural Neurobiology Laboratory, Swiss Federal Institute of Technology, Zurich, Schorenstrasse 16, CH-8603 Schwerzenbach, Switzerland Received 14 April 2003; received in revised form 18 June 2003; accepted 18 June 2003 Abstract The prenatal methylazoxymethanol acetate (MAM) treatment has been proposed as a suitable model for the neurodevelopmental aspects of schizophrenia since the morphological abnormalities it induces in the brain are subtle and in line with most reports of neuropathology in schizophrenic brains. However, the functional aspects of this treatment have not been investigated with behavioural paradigms that are relevant for the psychopathology of the symptoms of schizophrenia. In the present study, we investigated the validity of the prenatal MAM treatment as a developmental model for schizophrenia with a prepulse inhibition of the acoustic startle reflex, latent inhibition, locomotor activity, and cognition and emotionality with freezing in fear conditioning paradigms. We have conducted two studies: in Study I, MAM was injected from E09 to E12, and in Study II, MAM was administered at later stages in the embryonic development, from E12 to E15. Morphologically, the prenatal MAM treatment induced mild to severe reduction in brain weights and in the entorhinal cortex, prefrontal cortex and striatum volumes, the severity of the effects depending on the timing of administration. However, despite the morphological abnormalities induced by the MAM treatments, no behavioural deficits were observed in the MAM-treated animals when compared to Controls in prepulse inhibition, latent inhibition with the two-way active avoidance, and in the freezing paradigms. Therefore, due to the consistent lack of treatment effect observed in the present investigation, we conclude that the prenatal MAM treatment has no validity as a behavioural model for schizophrenia. © 2003 Elsevier B.V. All rights reserved. Keywords: Neuropathology; Schizophrenia; Entorhinal cortex; Latent inhibition; Prepulse inhibition; Fear conditioning 1. Introduction One of the greatest difficulties in the neurobiological research of schizophrenia is the modelling of the patho- physiological aspects of this disease. Although different hy- potheses have been used to model schizophrenia in animals, perhaps the most explored is based on the neurodevelop- mental hypothesis of this disease, which combines its appar- ently early origin and the involvement of the hippocampal formation in its neuropathology [31,36,42,43,66,67,75]. Two major research lines have been used to support the modelling of the pathophysiology according to the neu- rodevelopmental hypothesis of schizophrenia. One research ∗ Corresponding author. Tel.: +41-1-655-7448; fax: +41-1-655-7203. E-mail address: feldon@behav.biol.ethz.ch (J. Feldon). 1 Present address: Abbott GmbH and Co. KG, GGRP, Neuroscience Discovery, Knollstrasse 50, 67061 Ludwigshafen, Germany. Tel.: +49-621-589-2933; fax: +49-621-589-3232. line utilises surgical lesions of the ventral hippocampus in the early postnatal period and monitors the behavioural consequences of these lesions long-term [44–46]. Although these lesions have been shown to induce abnormalities of mesolimbic and nigrostriatally mediated behaviours, where- upon animals become hyper-responsive to dopaminergic drugs and to a variety of experimental stressors [44–46,72], the nature of the neuropathology in this model shows little to no resemblance with the more subtle neuropathological abnormalities reported in the temporal lobe of schizophren- ics. In addition, compensatory mechanisms are likely to occur in the brains of the lesioned animals which could be a confounding factor in the interpretation of the behavioural outcome. A second research line attempts to interfere with the de- velopment of the central nervous system. Here two major approaches have been used. One approach involves prenatal stress, induced either with high glucocorticoid levels and/ or other stressors components [38,63]. Studies have shown 0166-4328/$ – see front matter © 2003 Elsevier B.V. All rights reserved. doi:10.1016/S0166-4328(03)00228-6