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.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Project (R01)
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Study Section
Biobehavioral Regulation, Learning and Ethology Study Section (BRLE)
Program Officer
Zajicek, Anne
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University of California Davis
Veterinary Sciences
Other Domestic Higher Education
United States
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Golub, Mari S; Hogrefe, Casey E; Sherwood, Richard J et al. (2018) Fluoxetine Administration in Juvenile Monkeys: Implications for Pharmacotherapy in Children. Front Pediatr 6:21
Golub, Mari S; Hackett, Edward P; Hogrefe, Casey E et al. (2017) Cognitive performance of juvenile monkeys after chronic fluoxetine treatment. Dev Cogn Neurosci 26:52-61
Golub, Mari S; Hogrefe, Casey E (2016) Sleep disturbance as detected by actigraphy in pre-pubertal juvenile monkeys receiving therapeutic doses of fluoxetine. Neurotoxicol Teratol 55:1-7
Golub, M S; Hogrefe, C E; Bulleri, A M (2016) Regulation of emotional response in juvenile monkeys treated with fluoxetine: MAOA interactions. Eur Neuropsychopharmacol 26:1920-1929
Golub, Mari S; Hogrefe, Casey E; Bulleri, Alicia M (2016) Peer social interaction is facilitated in juvenile rhesus monkeys treated with fluoxetine. Neuropharmacology 105:553-560
Su, Shu-Yi; Hogrefe-Phi, Casey E; Asara, John M et al. (2016) Peripheral fibroblast metabolic pathway alterations in juvenile rhesus monkeys undergoing long-term fluoxetine administration. Eur Neuropsychopharmacol 26:1110-8
Lien, Espen; Andersen, Guro; Bao, Yongde et al. (2015) Genes determining the severity of cerebral palsy: the role of single nucleotide polymorphisms on the amount and structure of apolipoprotein E. Acta Paediatr 104:701-6
Franklin, Ashanti L; Said, Mariam; Cappiello, Clint D et al. (2015) Are Immune Modulating Single Nucleotide Polymorphisms Associated with Necrotizing Enterocolitis? Sci Rep 5:18369
Golub, Mari S; Bulleri, Alicia M; Hogrefe, Casey E et al. (2015) Bone growth in juvenile rhesus monkeys is influenced by 5HTTLPR polymorphisms and interactions between 5HTTLPR polymorphisms and fluoxetine. Bone 79:162-9
Golub, Mari S; Hogrefe, Casey E (2014) Fluoxetine: juvenile pharmacokinetics in a nonhuman primate model. Psychopharmacology (Berl) 231:4041-7

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