Fluoxetine administered to juvenile monkeys: Effects on the serotonin transporter and behavior

Stal Saurav Shrestha, Eric E. Nelson, Jeih San Liow, Robert Gladding, Chul Hyoung Lyoo, Pam L. Noble, Cheryl Morse, Ioline D. Henter, Jeremy Kruger, Bo Zhang, Stephen J. Suomi, Per Svenningsson, Victor W. Pike, James T. Winslow, Ellen Leibenluft, Daniel S. Pine, Robert B. Innis

Research output: Contribution to journalArticle

30 Citations (Scopus)

Abstract

Objective: This study examined the longterm 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.

Original languageEnglish
Pages (from-to)323-331
Number of pages9
JournalAmerican Journal of Psychiatry
Volume171
Issue number3
DOIs
Publication statusPublished - 2014 Mar 1

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Serotonin Plasma Membrane Transport Proteins
Fluoxetine
Haplorhini
Receptor, Serotonin, 5-HT1A
Mothers
Macaca mulatta
Brain
Placebos
Parturition
Pharmaceutical Preparations
Neocortex
Gyrus Cinguli
Temporal Lobe
Interpersonal Relations
Drug Interactions
Positron-Emission Tomography
Primates
Young Adult
Hippocampus
Up-Regulation

All Science Journal Classification (ASJC) codes

  • Psychiatry and Mental health

Cite this

Shrestha, Stal Saurav ; Nelson, Eric E. ; Liow, Jeih San ; Gladding, Robert ; Lyoo, Chul Hyoung ; Noble, Pam L. ; Morse, Cheryl ; Henter, Ioline D. ; Kruger, Jeremy ; Zhang, Bo ; Suomi, Stephen J. ; Svenningsson, Per ; Pike, Victor W. ; Winslow, James T. ; Leibenluft, Ellen ; Pine, Daniel S. ; Innis, Robert B. / Fluoxetine administered to juvenile monkeys : Effects on the serotonin transporter and behavior. In: American Journal of Psychiatry. 2014 ; Vol. 171, No. 3. pp. 323-331.
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abstract = "Objective: This study examined the longterm 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.",
author = "Shrestha, {Stal Saurav} and Nelson, {Eric E.} and Liow, {Jeih San} and Robert Gladding and Lyoo, {Chul Hyoung} and Noble, {Pam L.} and Cheryl Morse and Henter, {Ioline D.} and Jeremy Kruger and Bo Zhang and Suomi, {Stephen J.} and Per Svenningsson and Pike, {Victor W.} and Winslow, {James T.} and Ellen Leibenluft and Pine, {Daniel S.} and Innis, {Robert B.}",
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Shrestha, SS, Nelson, EE, Liow, JS, Gladding, R, Lyoo, CH, Noble, PL, Morse, C, Henter, ID, Kruger, J, Zhang, B, Suomi, SJ, Svenningsson, P, Pike, VW, Winslow, JT, Leibenluft, E, Pine, DS & Innis, RB 2014, 'Fluoxetine administered to juvenile monkeys: Effects on the serotonin transporter and behavior', American Journal of Psychiatry, vol. 171, no. 3, pp. 323-331. https://doi.org/10.1176/appi.ajp.2013.13020183

Fluoxetine administered to juvenile monkeys : Effects on the serotonin transporter and behavior. / Shrestha, Stal Saurav; Nelson, Eric E.; Liow, Jeih San; Gladding, Robert; Lyoo, Chul Hyoung; Noble, Pam L.; Morse, Cheryl; Henter, Ioline D.; Kruger, Jeremy; Zhang, Bo; Suomi, Stephen J.; Svenningsson, Per; Pike, Victor W.; Winslow, James T.; Leibenluft, Ellen; Pine, Daniel S.; Innis, Robert B.

In: American Journal of Psychiatry, Vol. 171, No. 3, 01.03.2014, p. 323-331.

Research output: Contribution to journalArticle

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T1 - Fluoxetine administered to juvenile monkeys

T2 - Effects on the serotonin transporter and behavior

AU - Shrestha, Stal Saurav

AU - Nelson, Eric E.

AU - Liow, Jeih San

AU - Gladding, Robert

AU - Lyoo, Chul Hyoung

AU - Noble, Pam L.

AU - Morse, Cheryl

AU - Henter, Ioline D.

AU - Kruger, Jeremy

AU - Zhang, Bo

AU - Suomi, Stephen J.

AU - Svenningsson, Per

AU - Pike, Victor W.

AU - Winslow, James T.

AU - Leibenluft, Ellen

AU - Pine, Daniel S.

AU - Innis, Robert B.

PY - 2014/3/1

Y1 - 2014/3/1

N2 - Objective: This study examined the longterm 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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