Olanzapine treatment of adolescent rats causes enduring specific memory impairments and alters cortical development and function
Date
2013
Authors
Milstein, Jean A.
Elnabawi, Ahmed
Vinish, Monika
Swanson, Thomas
Enos, Jennifer K.
Bailey, Aileen M.
Kolb, Bryan
Frost, Douglas O.
Journal Title
Journal ISSN
Volume Title
Publisher
Public Library of Science
Abstract
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 orbitaland
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 GABAA receptors with open Cl2 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
Description
Sherpa Romeo green journal: open access
Keywords
Olanzapine , Memory impairment , Cortical development , Cortical function , Antipsychotic drugs , Memory disorders , Adolescent APD treatment , Pediatric APD treatment
Citation
Milstein, J. A., Elnabawi, A., Vinish, M., Swanson, T., Enos, J. K., Bailey, A. M., ... & Frost, D. O. (2013). Olanzapine treatment of adolescent rats causes enduring specific memory impairments and alters cortical development and function. PLoS ONE, 8(2), e57308. doi:10.1371/journal.pone.0057308