Abstract
Rationale
Gestational day 17 methylazoxymethanol (MAM) treatment has been shown to reproduce, in rodents, some of the alterations in cortical and mesolimbic circuitries thought to contribute to schizophrenia.
Objective
We characterized the behavior of MAM animals in tasks dependent on these circuitries to see what behavioral aspects of schizophrenia the model captures. We then characterized the integrity of mesolimbic dopamine neurotransmission in a subset of animals used in the behavioral experiments.
Methods
MAM animals’ capacity for working memory, attention, and resilience to distraction was tested with two different paradigms. Cue-reward learning and motivation were assayed with Pavlovian conditioned approach. Measurements of electrically stimulated phasic and tonic DA release in the nucleus accumbens with fast-scan cyclic voltammetry were obtained from the same animals used in the Pavlovian task.
Results
MAM animals’ basic attentional capacities were intact. MAM animals took longer to acquire the working memory task, but once learned, performed at the same level as shams. MAM animals were also slower to develop a Pavlovian conditioned response, but otherwise no different from controls. These same animals showed alterations in terminal DA release that were unmasked by an amphetamine challenge.
Conclusions
The predominant behavioral-cognitive feature of the MAM model is a learning impairment that is evident in acquisition of executive function tasks as well as basic Pavlovian associations. MAM animals also have dysregulated terminal DA release, and this may contribute to observed behavioral differences. The MAM model captures some functional impairments of schizophrenia, particularly those related to acquisition of goal-directed behavior.
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Acknowledgments
The authors thank Dr. Alexandra Difeliceantonio for comments on an earlier draft of this work, and Lauren O’Malley for her assistance in data collection.
Conflict of interest
The research performed here was funded by Pfizer Inc. W.M. Howe, P.L. Tierney, D.A. Young, and R. Kozak work at Pfizer and receive financial compensation for their work.
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Howe, W.M., Tierney, P.L., Young, D.A. et al. MAM (E17) rodent developmental model of neuropsychiatric disease: disruptions in learning and dysregulation of nucleus accumbens dopamine release, but spared executive function. Psychopharmacology 232, 4113–4127 (2015). https://doi.org/10.1007/s00213-015-3955-5
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DOI: https://doi.org/10.1007/s00213-015-3955-5