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


METHODS
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.
Stal Saurav
SS
Shrestha
Eric E
EE
Nelson
Jeih-San
JS
Liow
Robert
R
Gladding
Chul Hyoung
CH
Lyoo
Pam L
PL
Noble
Cheryl
C
Morse
Ioline D
ID
Henter
Jeremy
J
Kruger
Bo
B
Zhang
Stephen J
SJ
Suomi
Per
P
Svenningsson
Victor W
VW
Pike
James T
JT
Winslow
Ellen
E
Leibenluft
Daniel S
DS
Pine
Robert B
RB
Innis
D000367:Age Factors; D000818:Animals; D005473:Fluoxetine / Q000494:pharmacology*; D059907:Functional Neuroimaging; D006624:Hippocampus / Q000000981:diagnostic imaging / Q000378:metabolism*; D007398:Interpersonal Relations; D008253:Macaca mulatta; D008297:Male; D008426:Maternal Deprivation; D019579:Neocortex / Q000000981:diagnostic imaging / Q000187:drug effects / Q000378:metabolism*; D011877:Radionuclide Imaging; D044282:Receptor, Serotonin, 5-HT1A / Q000378:metabolism; D050486:Serotonin Plasma Membrane Transport Proteins / Q000378:metabolism*; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology; D015854:Up-Regulation
D005473:Fluoxetine; D044282:Receptor, Serotonin, 5-HT1A; D050486:Serotonin Plasma Membrane Transport Proteins; D017367:Selective Serotonin Reuptake Inhibitors