The biomedical literature has documented increasing use of psychoactive drugs in childhood behavior disorders and there is public concern over this issue. This application uses the rhesus monkey (1 to 4 years of age) as a juvenile animal model to: 1. test the hypothesis that the serotonin reuptake inhibitor fluoxetine influences activity and affective behavior during dosing at the juvenile stage of brain development. Information to identify a fluoxetine dose similar to human therapy will be provided by an initial pharmacokinetic study of plasma fluoxetine/norfluoxetine with a pharmacodynamics component to quantify serotonin in cerebrospinal fluid, a sensitive index in previous human and nonhuman primate studies. The affective behavior tests include some used in children (reward delay) as well as behaviors regulated by the serotonin system in monkeys (social intruder). Activity monitoring will conducted with actimeters. 2. identify alterations in brain morphology that could signal interference with normal juvenile brain development, specifically the proliferation and pruning of dendritic spine synapses. Daily oral fluoxetine will be given from 1 to 3 years of age (approximately 4 to 12 years of age in children). A placebo will be administered exclusively to a separate control group. Potential long-term effects will be assessed in all monkeys after discontinuation of dosing using an automated cognitive test battery. Dendritic spine synapse numbers in hippocampus (CA1, CA3, dentate gyrus) and prefrontal cortex (Walker area 46) will be studied at 4 years of age, one year after termination of dosing. This assessment is relevant to one of the most important components of childhood brain development, synaptic pruning. 3. determine whether some children may be more sensitive to these changes than others based on their genetic makeup. Colony-wide genetic screening at our primate center (CNPRC) allows selection of subgroups of monkeys with low and high activity MAOA gene polymorphisms. MAOA metabolizes serotonin, as well as other monoamines, and human populations have a similar distribution of low and high activity polymorphisms. Findings from this study, integrated with clinical studies and experience, can help guide safe use of fluoxetine in children.

Public Health Relevance

This project studies fluoxetine, a drug approved for use in children for depression and obsessive-compulsive disease, in a juvenile animal model. We will determine whether fluoxetine changes affective (emotional) behavior and late childhood brain development, and determine whether some children may be more sensitive than others based on their genetic makeup. This study will help guide safe use of fluoxetine in children.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD065826-04
Application #
8651928
Study Section
Biobehavioral Regulation, Learning and Ethology Study Section (BRLE)
Program Officer
Zajicek, Anne
Project Start
2011-04-01
Project End
2016-03-31
Budget Start
2014-04-01
Budget End
2015-03-31
Support Year
4
Fiscal Year
2014
Total Cost
$420,463
Indirect Cost
$146,546
Name
University of California Davis
Department
Veterinary Sciences
Type
Other Domestic Higher Education
DUNS #
047120084
City
Davis
State
CA
Country
United States
Zip Code
95618
Lien, Espen; Andersen, Guro L; Bao, Yongde et al. (2014) Gene sequences regulating the production of apoE and cerebral palsy of variable severity. Eur J Paediatr Neurol 18:591-6
Golub, Mari S; Hogrefe, Casey E (2014) Fluoxetine: juvenile pharmacokinetics in a nonhuman primate model. Psychopharmacology (Berl) 231:4041-7
He, Y; Hogrefe, C E; Grapov, D et al. (2014) Identifying individual differences of fluoxetine response in juvenile rhesus monkeys by metabolite profiling. Transl Psychiatry 4:e478
Lien, Espen; Andersen, Guro L; Bao, Yongde et al. (2013) Apolipoprotein E polymorphisms and severity of cerebral palsy: a cross-sectional study in 255 children in Norway. Dev Med Child Neurol 55:372-7