Original Investigation
Time course of the
effects of the serotonin-selective reuptake inhibitor
sertraline on central and peripheral serotonin neurochemistry
in the rhesus monkey George M. Anderson1  , Christina S. Barr2,
Stephen Lindell2,
Amy C. Durham2,
Ilya Shifrovich1 and
J. Dee Higley2
| (1) |
Departments of Child
Psychiatry and Laboratory Medicine, Yale University
School of Medicine, New Haven, CT,
USA |
| (2) |
Laboratory of Clinical
Studies-Primate Unit, The National Institute of Alcohol
Abuse & Alcoholism (NIAAA), Poolesville, MD,
USA |
Received:
11 June 2004 Accepted:
5 August 2004 Published
online: 25 September 2004
Abstract
Rationale Fundamental
questions remain regarding the actions of the selective
serotonin reuptake inhibitors (SSRIs).
Objectives To examine the
time course of central and peripheral neurochemical effects of
sertraline (SER) in non-human primates.
Methods SER (20 mg/kg,
p.o.) or placebo were administered daily for 4 weeks to two
groups of six young adult male rhesus monkeys. Both groups
received placebo during a 3-week baseline lead-in period and
for 6 weeks after discontinuation. Blood and cisternal
cerebrospinal fluid (cCSF) samples were obtained on days –21,
–14, –7, 0, +3, +7, +14, +21, +28, +35 and +70.
Results In animals receiving
SER, mean (±SD) levels of cCSF serotonin (5-HT) increased from
38.6±9.0 pg/ml at baseline to 128±46.4 pg/ml during
treatment (paired t=4.17, P=0.014).
Concentrations of cCSF 5-HT were 290% of baseline on day 0
(+3 h), ranged from 260% to 436% of baseline during
treatment, and returned to baseline 7 days after
discontinuation. Levels of cCSF 5-hydroxyindoleacetic acid
declined to 51±2.0% of baseline by day +3 and remained at
similarly reduced levels during treatment. Plasma drug levels
and decrements in platelet 5-HT were similar to those seen in
patients.
Conclusions SER rapidly and
substantially increases cCSF levels of 5-HT in primates, the
extent of elevation is relatively constant during prolonged
administration, and values return to baseline shortly after
discontinuation. The results suggest that response latency for
SSRIs in depression is not due to gradually increasing brain
extracellular fluid 5-HT levels and tend not to support
theories that posit SSRI response latency as being due to
autoreceptor desensitization, transporter downregulation, or
drug accumulation.
Keywords Serotonin - Cerebrospinal
fluid - CSF - Rhesus
monkey - Cisternal - Sertraline - Selective
serotonin reuptake
inhibitor - SSRI - 5-Hydroxyindoleacetic
acid
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