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Peripubertal Diazepam Administration Prevents the Emergence of Dopamine System Hyperresponsivity in the MAM Developmental Disruption Model of Schizophrenia
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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.
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“Consistent with this view, reducing stress sensitivity in juvenile MAM-treated rats with benzodiazepines prevents the abnormal increase in the activity of dopaminergic neurons and reduces hyperlocomotion in adult rats 71 .”
From Developmental timing and critical windows for the treatment of psychiatric disorders (2016) · cites this paper as [71]
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Intrinsic metabolic and immune impairments in a genetic mouse model of schizophrenia
Belmonte, M., Cardoso, S. L., Pietro, A. A. D., Veigas, F., Pasquini, L. A., & Gelman, D. M. (2025) · Schizophrenia · doi:10.1038/s41537-025-00651-9
Dopamine dysfunction in psychosis
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Metadata
- Authors
- Du, Y., & Grace, A. A.
- Affiliations
- University of Pittsburgh (US)
- Corresponding author
- Du, Yijuan
- Venue
- Neuropsychopharmacology
- Published
- 2013-04-23
- Volume
- 38
- Issue
- 10
- Pages
- 1881-1888
- ISSN
- 0893-133X (ISSN-L)
- 1740-634X
- PMC
- PMC3746684
- OpenAlex
- W1970236655
- Cited by
- 105
- References
- 56
- Citations by year
- 2026: 5 · 2025: 7 · 2024: 5 · 2023: 5 · 2022: 10 · 2021: 8 · 2020: 10 · 2019: 10 · 2018: 10 · 2017: 9 · 2016: 11 · 2015: 6 · 2014: 5 · 2013: 4
- FWCI
- 6.16
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Neuropsychopharmacology (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (2r01mh057440-26a1)
- National Institute of Mental Health (MH-57440, R01-MH057440, R37MH057440)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
- Keywords
- schizophrenia, methylazoxymethanol acetate, diazepam, peripubertal period, anxiety, stress, amphetamine response, psychosis prevention, rat model
- MeSH terms
- Amphetamine, Animals, Anxiety, Diazepam, Female, Male, Methylazoxymethanol Acetate, Motor Activity, Pregnancy, Prenatal Exposure Delayed Effects, Schizophrenia, Ventral Tegmental Area, Maze Learning, Rats, Dopaminergic Neurons, Central Nervous System Sensitization
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