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Fluoxetine Administered to Juvenile Monkeys: Effects on the Serotonin Transporter and Behavior
Stal Saurav Shrestha, B.A.; Eric E. Nelson, Ph.D.; Jeih-San Liow, Ph.D.; Robert Gladding, B.S.; Chul Hyoung Lyoo, M.D., Ph.D.; Pam L. Noble, M.S.; Cheryl Morse, M.S.; Ioline D. Henter, M.A.; Jeremy Kruger, B.S.; Bo Zhang, Ph.D.; Stephen J. Suomi, Ph.D.; Per Svenningsson, M.D., Ph.D.; Victor W. Pike, Ph.D.; James T. Winslow, Ph.D.; Ellen Leibenluft, M.D.; Daniel S. Pine, M.D.; Robert B. Innis, M.D., Ph.D.
Am J Psychiatry 2014;171:323-331. doi:10.1176/appi.ajp.2013.13020183
View Author and Article Information

Mr. Shrestha and Dr. Nelson contributed equally as first authors; Dr. Pine and Dr. Innis contributed equally as last authors.

The authors report no financial relationships with commercial interests.

From the NIMH Intramural Research Program, Bethesda, Md., and the Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.

Address correspondence to Mr. Shrestha (saurav.shrestha@nih.gov).

Copyright © 2014 by the American Psychiatric Association

Received February 09, 2013; Revised April 30, 2013; Revised June 18, 2013; July 19, 2013; Accepted August 29, 2013.

Abstract

Objective  This study examined the long-term effects of fluoxetine administered to juvenile rhesus monkeys who, as young adults, were imaged with positron emission tomography for two serotonergic markers: serotonin transporter (SERT) and serotonin 1A (5-HT1A) receptor. An equal number of monkeys separated from their mothers at birth—an animal model of human childhood stress—were also studied.

Method  At birth, 32 male rhesus monkeys were randomly assigned to either maternal separation or normal rearing conditions. At age 2, half (N=8) of each group was randomly assigned to fluoxetine (3 mg/kg) or placebo for 1 year. To eliminate the confounding effects of residual drug in the brain, monkeys were scanned at least 1.5 years after drug discontinuation. Social interactions were assessed both during and after drug administration.

Results  Fluoxetine persistently upregulated SERT, but not 5-HT1A receptors, in both the neocortex and the hippocampus. Whole-brain voxel-wise analysis revealed that fluoxetine had a significant effect in the lateral temporal and cingulate cortices. In contrast, neither maternal separation by itself nor the rearing-by-drug interaction was significant for either marker. Fluoxetine had no significant effect on the behavioral measures.

Conclusions  Fluoxetine administered to juvenile monkeys upregulates SERT into young adulthood. Implications regarding the efficacy or potential adverse effects of SSRIs in patients cannot be directly drawn from this study. Its purpose was to investigate effects of SSRIs on brain development in nonhuman primates using an experimental approach that randomly assigned long-term SSRI treatment or placebo.

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FIGURE 1. Distribution of [11C]DASB Binding to Serotonin Transporters (SERT) and [11C](R)-RWAY Binding to Serotonin 1A (5-HT1A) Receptors in the Representative Brain of a Normally Reared Monkey That Received Placeboa

a The top row summed images from 30 to 60 minutes show high SERT density in the thalamus, raphe, and caudate. The middle row MRI images show the anatomical structures for the coregistered PET images. The bottom row summed images from 30 to 60 minutes show high 5-HT1A receptor density in hippocampus and cingulate. SUV=standardized uptake value.

FIGURE 2. Effects of Fluoxetine and Maternal Separation on Serotonin Transporter (SERT) in the Neocortexa

a Panel A shows fluoxetine upregulated SERT by 19%. Panel B shows that maternal separation had no statistically significant effect on SERT. BPND=binding potential; bars represent mean±SD.

* p<0.001×2=0.002.

FIGURE 3. Fluoxetine Increased Serotonin Transporter (SERT) Binding in the Lateral Temporal, Cingulate, and Orbitofrontal Cortices as Shown by Whole-Brain Voxel-Wise Analysisa

a The four different colors represent uncorrected p values. The coregistered MRI template is shown in grayscale and is merged with each PET image.

FIGURE 4. Main Effects of Fluoxetine and Maternal Separation on Serotonin 1A (5-HT1A) Receptor Density in the Raphea

a Panel A shows that fluoxetine had no statistically significant effect on 5-HT1A receptor density. Panel B shows that maternal separation increased 5-HT1A receptor density by 23%, which did not reach significance after correction for multiple comparisons across the three regions (p<0.03×3=0.09). BPND=binding potential; bars represent mean±SD.

FIGURE 5. Main Effects of Fluoxetine on Social Behaviors in Monkeysa

a Panel A shows that fluoxetine reduced dominance displays both in the “during treatment” period (between 4 and 8 months after treatment began) and in the “after treatment” period (2–6 months after treatment ceased) but this effect did not survive after statistical correction for eight behavioral measurements (p<0.038×8=0.30). Panel B shows that fluoxetine increased submissive displays only in the after treatment period, which also did not survive correction for multiple comparisons (p<0.049×8=0.39). Bars represent mean±SD.

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What long-term effects on the serotonergic system are seen with fluoxetine administration during the juvenile period?
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While the study found no statistically significant long-term effects of fluoxetine treatment or maternal separation on social behavior, what correlations of interest were reported?
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What implications regarding SSRI use in the pediatric population may be inferred from this study of primates?
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