title: Olanzapine treatment of adolescent rats causes enduring specific memory impairments and alters cortical development and function.
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 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.
authors: Dept. of Pharmacology, University of Maryland School of Medicine, Baltimore, Maryland, United States of America.
authors: Jean A
authors: JA
authors: Milstein
authors: Ahmed
authors: A
authors: Elnabawi
authors: Monika
authors: M
authors: Vinish
authors: Thomas
authors: T
authors: Swanson
authors: Jennifer K
authors: JK
authors: Enos
authors: Aileen M
authors: AM
authors: Bailey
authors: Bryan
authors: B
authors: Kolb
authors: Douglas O
authors: DO
authors: Frost
mesh_terms: D000367:Age Factors; D000818:Animals; D014150:Antipsychotic Agents / Q000009:adverse effects*; D001569:Benzodiazepines / Q000009:adverse effects*; D049229:Dendritic Spines / Q000187:drug effects* / Q000473:pathology; D018891:Dentate Gyrus / Q000187:drug effects; D004298:Dopamine / Q000378:metabolism; D005108:Extinction, Psychological / Q000187:drug effects; D008297:Male; D008569:Memory Disorders / Q000139:chemically induced* / Q000503:physiopathology; D008570:Memory, Short-Term / Q000187:drug effects*; D009714:Nucleus Accumbens / Q000187:drug effects; D000077152:Olanzapine; D017397:Prefrontal Cortex / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D044402:Receptor, Serotonin, 5-HT2A / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000378:metabolism; D011963:Receptors, GABA-A / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism; D013995:Time
chemical_list: D014150:Antipsychotic Agents; D044402:Receptor, Serotonin, 5-HT2A; D017448:Receptors, Dopamine D2; D011963:Receptors, GABA-A; D001569:Benzodiazepines; D012701:Serotonin; D000077152:Olanzapine; D004298:Dopamine