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


OBJECTIVE
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.
Fox
Meredith A
MA
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. mfox@mail.nih.gov
Jensen
Catherine L
CL
French
Helen T
HT
Stein
Alison R
AR
Huang
Su-Jan
SJ
Tolliver
Teresa J
TJ
Murphy
Dennis L
DL
D006916:5-Hydroxytryptophan / Q000494:pharmacology; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000494:pharmacology; D000818:Animals; D001921:Brain / Q000033:anatomy & histology / Q000187:drug effects / Q000378:metabolism; D001923:Brain Chemistry / Q000187:drug effects*; D002395:Catecholamines / Q000037:antagonists & inhibitors / Q000145:classification; D003010:Clorgyline / Q000494:pharmacology; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D005260:Female; D006897:Hydroxyindoleacetic Acid / Q000032:analysis / Q000378:metabolism; D007035:Hypothermia / Q000139:chemically induced; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008996:Monoamine Oxidase Inhibitors / Q000494:pharmacology; D010636:Phenols / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology / Q000633:toxicity; D011725:Pyridines / Q000494:pharmacology; D012701:Serotonin / Q000031:analogs & derivatives / Q000378:metabolism* / Q000494:pharmacology; D058829:Serotonin 5-HT1 Receptor Antagonists; D050486:Serotonin Plasma Membrane Transport Proteins / Q000172:deficiency* / Q000235:genetics; D017366:Serotonin Receptor Agonists / Q000494:pharmacology; D020230:Serotonin Syndrome / Q000139:chemically induced; D013449:Sulfonamides / Q000494:pharmacology; D014191:Tranylcypromine / Q000494:pharmacology
D002395:Catecholamines; D018765:Dopamine Uptake Inhibitors; D008996:Monoamine Oxidase Inhibitors; D010636:Phenols; D010879:Piperazines; D011725:Pyridines; C404922:SB 269970; D058829:Serotonin 5-HT1 Receptor Antagonists; D050486:Serotonin Plasma Membrane Transport Proteins; D017366:Serotonin Receptor Agonists; D013449:Sulfonamides; D012701:Serotonin; D014191:Tranylcypromine; D006897:Hydroxyindoleacetic Acid; C090413:N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; C043425:vanoxerine; C047087:5-carboxamidotryptamine; D006916:5-Hydroxytryptophan; D003010:Clorgyline