Olanzapine treatment of adolescent rats causes enduring specific memory impairments and alters cortical development and function
Open accessAbstract
Antipsychotic drugs are increasingly used in children and adolescents to treat a variety of psychiatric disorders. However, little is known about the long-term effects of early life antipsychotic drug treatment. Most antipsychotic drugs are potent antagonists or partial agonists of dopamine D2 receptors; atypical antipsychotic drugs also antagonize type 2A serotonin receptors. Dopamine and serotonin regulate many neurodevelopmental processes. Thus, early life antipsychotic drug treatment can, potentially, perturb these processes, causing long-term behavioral- and neurobiological impairments. Here, we treated adolescent, male rats with olanzapine on post-natal days 28-49. As adults, they exhibited impaired working memory, but normal spatial memory, as compared to vehicle-treated control rats. They also showed a deficit in extinction of fear conditioning. Measures of motor activity and skill, habituation to an open field, and affect were normal. In the orbital- and medial prefrontal cortices, parietal cortex, nucleus accumbens core and dentate gyrus, adolescent olanzapine treatment altered the developmental dynamics and mature values of dendritic spine density in a region-specific manner. Measures of motor activity and skill, habituation to an open field, and affect were normal. In the orbital- and medial prefrontal cortices, D1 binding was reduced and binding of GABA(A) receptors with open Cl(-) channels was increased. In medial prefrontal cortex, D2 binding was also increased. The persistence of these changes underscores the importance of improved understanding of the enduring sequelae of pediatric APD treatment as a basis for weighing the benefits and risks of adolescent antipsychotic drug therapy, especially prophylactic treatment in high risk, asymptomatic patients. The long-term changes in neurotransmitter receptor binding and neural circuitry induced by adolescent APD treatment may also cause enduring changes in behavioral- and neurobiological responses to other therapeutic- or illicit psychotropic drugs.
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Animal studies support clinical observations that biological changes during adolescence increase addiction vulnerability.
“Animal studies support clinical observations that biological changes during adolescence increase addiction vulnerability.”
From Impact of Sleep and Circadian Rhythms on Addiction Vulnerability in Adolescents (2018) · cites this paper as [20]
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- Authors
- Milstein, J. A., Elnabawi, A., Vinish, M., Swanson, T., Enos, J. K., Bailey, A. M., Kolb, B., & Frost, D. O.
- Affiliations
- University of Maryland, Baltimore (US)
- St. Mary's College of Maryland (US)
- University of Lethbridge (CA)
- Corresponding author
- Frost, Douglas O.
- Venue
- PLoS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2013-02-20
- Volume
- 8
- Issue
- 2
- Pages
- e57308
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC3577739
- OpenAlex
- W1972460604
- Cited by
- 57
- References
- 118
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 6 · 2023: 3 · 2022: 3 · 2021: 2 · 2020: 3 · 2019: 4 · 2018: 5 · 2017: 6 · 2016: 9 · 2015: 3 · 2014: 4 · 2013: 6
- FWCI
- 5.20
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- PLoS ONE (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Figshare (submittedVersion, cc-by)
- Open ULeth Scholarship (OPUS) (University of Lethbridge) (submittedVersion)
- Funders
- Eli Lilly and Company
- Canadian Institutes of Health Research
- National Institute of Mental Health (MH07083)
- National Institute of Neurological Disorders and Stroke (T32NS007375)
- 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 › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- olanzapine, antipsychotic effects, working memory impairment, fear extinction, dendritic spine density, prefrontal cortex, nucleus accumbens, dopamine D1 receptor, dopamine D2 receptor, GABAA receptor, serotonin receptors, brain development, long-term drug effects
- MeSH terms
- Olanzapine, Age Factors, Animals, Benzodiazepines, Dopamine, Extinction, Psychological, Male, Memory Disorders, Memory, Short-Term, Nucleus Accumbens, Receptors, GABA-A, Serotonin, Time, Antipsychotic Agents, Rats, Sprague-Dawley, Prefrontal Cortex, Receptors, Dopamine D2, Dentate Gyrus, Receptor, Serotonin, 5-HT2A, Dendritic Spines, Rats
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