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

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 administration of the serotonin precursor 5-hydroxy-L-tryptophan (5-HTP) in SERT wildtype (+/+), heterozygous (+/−) and −/− mice.Results-5-HTP increased serotonin in all five brain areas examined, with ~2-5-fold increases in SERT +/+ and +/− mice, and greater 4.5-11.7-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-HT 1A antagonist WAY 100635 decreased 5-HTP-induced hypothermia in SERT +/+ and +/− mice, with no effect in SERT −/− mice, whereas the 5-HT 7 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-HT 7 receptor function in SERT −/− mice, with interesting interactions between 5-HT 1A and 5-HT 7 receptors. As roles for 5-HT 7 receptors in anxiety and depression were recently established, the current findings have implications for understanding the high anxiety and depressivelike phenotype of SERT-deficient mice.

SSRI Augmentation by 5-Hydroxytryptophan Slow Release: Mouse Pharmacodynamic Proof of Concept

“…Diarrhea, tremor, hypothermia, and head twitches are commonly reported to occur in mice following high-dose 5-HTP adjunct to SSRI (Fox et al, 2008;Sanchez et al, 2003). Other typical 5-HT toxicity behaviors, such as backward movement, head-weaving, and hind-limb splaying (Fox et al, 2008;Sanchez et al, 2003), were not observed, and therefore not scored.…”

“…Other typical 5-HT toxicity behaviors, such as backward movement, head-weaving, and hind-limb splaying (Fox et al, 2008;Sanchez et al, 2003), were not observed, and therefore not scored. All mice were treated with fluoxetine for 14 days before adjunct 5-HTP SR or IR.…”

Anxiety and affective disorder comorbidity related to serotonin and other neurotransmitter systems: obsessive–compulsive disorder as an example of overlapping clinical and genetic heterogeneity

“…These changes were discovered in brain imaging studies of healthy and clinical human populations, as well as in studies of human and mouse anxiety-like, depression-like and stress hormone responses, changes in serotonin receptor density and function, in addition to G Â E interactions [57,65,66,[72][73][74][75][76]. Further, genetically engineered mouse and rat models of SERT deficiency and over-expression [72,[77][78][79][80][81][82][83] led to numerous biochemical, pharmacological and anatomical alterations and features related to disease.…”

Methyl Donors Supplementation Attenuates the Adverse Effects of Maternal High Fructose Diet of Offspring Emotional and Cognitive Behaviors

“…In fact, brain developmental period is sensitive to some exogenous factors like mother nutritional programing. It has been showed that high fructose consumption (30%) induces a decrease of the intestinal serotoninergic system by the blockade of serotonin reuptake transpoters [35] [36].…”