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

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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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Acknowledgements

This research was supported by the NIMH Intramural Research program.

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  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

    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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  1. Meredith A. Fox
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  2. Catherine L. Jensen
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Correspondence to Meredith A. Fox.

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Fox, M.A., Jensen, C.L., French, H.T. et al. Neurochemical, behavioral, and physiological effects of pharmacologically enhanced serotonin levels in serotonin transporter (SERT)-deficient mice. Psychopharmacology 201, 203–218 (2008). https://doi.org/10.1007/s00213-008-1268-7

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