Psychopharmacology

, Volume 201, Issue 2, pp 203–218

Neurochemical, behavioral, and physiological effects of pharmacologically enhanced serotonin levels in serotonin transporter (SERT)-deficient mice

Authors

    • Laboratory of Clinical Science (LCS), National Institute of Mental Health (NIMH), National Institutes of Health (NIH)
  • Catherine L. Jensen
    • Laboratory of Clinical Science (LCS), National Institute of Mental Health (NIMH), National Institutes of Health (NIH)
  • Helen T. French
    • Laboratory of Clinical Science (LCS), National Institute of Mental Health (NIMH), National Institutes of Health (NIH)
  • Alison R. Stein
    • Laboratory of Clinical Science (LCS), National Institute of Mental Health (NIMH), National Institutes of Health (NIH)
  • Su-Jan Huang
    • Laboratory of Clinical Science (LCS), National Institute of Mental Health (NIMH), National Institutes of Health (NIH)
  • Teresa J. Tolliver
    • Laboratory of Clinical Science (LCS), National Institute of Mental Health (NIMH), National Institutes of Health (NIH)
  • Dennis L. Murphy
    • Laboratory of Clinical Science (LCS), National Institute of Mental Health (NIMH), National Institutes of Health (NIH)
Original Investigation

DOI: 10.1007/s00213-008-1268-7

Cite this article as:
Fox, M.A., Jensen, C.L., French, H.T. et al. Psychopharmacology (2008) 201: 203. doi:10.1007/s00213-008-1268-7

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.

Keywords

High-performance liquid chromatography (HPLC)TemperatureSerotonin syndrome behaviorsDopamine 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 269970GBR 12909

Copyright information

© Springer-Verlag 2008