Neurochemical,behavioral, and physiological effects of pharmacologically enhanced serotonin levels in serotonin transporter (SERT)-deficient mice |
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Authors: | Meredith A Fox Catherine L Jensen Helen T French Alison R Stein Su-Jan Huang Teresa J Tolliver Dennis L Murphy |
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Institution: | (1) Laboratory of Clinical Science (LCS), National Institute of Mental Health (NIMH), National Institutes of Health (NIH), 10 Center Drive, Building 10-3D41, MSC 1264, Bethesda, MD 20892-1264, USA |
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Abstract: | Rationale Serotonin transporter (SERT) knockout (−/−) mice have an altered phenotype in adulthood, including high baseline anxiety and
depressive-like behaviors, associated with increased baseline extracellular serotonin levels throughout life.
Objectives To examine the effects of increases in serotonin following the administration of the serotonin precursor 5-hydroxy-l-tryptophan (5-HTP) in SERT wild-type (+/+), heterozygous (+/−), and −/− mice.
Results 5-HTP increased serotonin in all five brain areas examined with approximately 2- to 5-fold increases in SERT+/+ and +/− mice,
and with greater 4.5- to 11.7-fold increases in SERT−/− mice. Behaviorally, 5-HTP induced exaggerated serotonin syndrome behaviors
in SERT−/−, mice with similar effects in male and female mice. Studies suggest promiscuous serotonin uptake by the dopamine
transporter (DAT) in SERT−/− mice, and here, the DAT blocker GBR 12909 enhanced 5-HTP-induced behaviors in SERT−/− mice. Physiologically,
5-HTP induced exaggerated temperature effects in SERT-deficient mice. The 5-HT1A antagonist WAY 100635 decreased 5-HTP-induced hypothermia in SERT+/+ and +/− mice with no effect in SERT−/− mice, whereas
the 5-HT7 antagonist SB 269970 decreased this exaggerated response in SERT−/− mice only. WAY 100635 and SB 269970 together completely
blocked 5-HTP-induced hypothermia in SERT+/− and −/− mice.
Conclusions These studies demonstrate that SERT−/− mice have exaggerated neurochemical, behavioral, and physiological responses to further
increases in serotonin, and provide the first evidence of intact 5-HT7 receptor function in SERT−/− mice, with interesting interactions between 5-HT1A and 5-HT7 receptors. As roles for 5-HT7 receptors in anxiety and depression were recently established, the current findings have implications for understanding the
high anxiety and depressive-like phenotype of SERT-deficient mice. |
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Keywords: | High-performance liquid chromatography (HPLC) Temperature Serotonin syndrome behaviors Dopamine transporter (DAT) 5-hydroxy-L-tryptophan (5-HTP) 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-2-pyridinylcyclohexanecarboxamide maleate salt (WAY 100635) 5-carboxamidotryptamine maleate (5-CT) SB 269970 GBR 12909 |
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