Peripubertal diazepam administration prevents the emergence of dopamine system hyperresponsivity in the MAM developmental disruption model of schizophrenia

Yijuan Du, Anthony A. Grace

Research output: Contribution to journalArticlepeer-review

62 Scopus citations

Abstract

Schizophrenia is believed to arise from an interaction of genetic predisposition and adverse environmental factors, with stress being a primary variable. We propose that alleviating anxiety produced in response to stress during a sensitive developmental period may circumvent the dopamine (DA) system alterations that may correspond to psychosis in adults. This was tested in a developmental rat model of schizophrenia based on prenatal administration of the mitotoxin methyl azoxymethanol acetate (MAM). MAM administration leads to a hyperdopaminergic state consisting of an increase in the number of DA neurons firing spontaneously, which correlates with an increased behavioral response to amphetamine. MAM-treated rats exhibited a heightened level of anxiety during adolescence. Peripubertal administration of the antianxiety agent diazepam was found to prevent the increase in DA neuron activity and blunt the behavioral hyperresponsivity to amphetamine in these rats. These data suggest that the pathophysiological factors leading to the onset of psychosis in early adulthood may be circumvented by controlling the response to stress during the peripubertal period.

Original languageEnglish (US)
Pages (from-to)1881-1888
Number of pages8
JournalNeuropsychopharmacology
Volume38
Issue number10
DOIs
StatePublished - Sep 2013
Externally publishedYes

Bibliographical note

Funding Information:
This work was supported by the US Public Health Service Grants MH57440 (AAG). We thank Niki MacMurdo for her technical assistance.

Keywords

  • MAM
  • diazepam
  • dopamine
  • prevention
  • schizophrenia

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