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

Psychopharmacology
Meredith A FoxDennis L Murphy

Abstract

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. 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. 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 10...Continue Reading

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