As recently reviewed, SERT-deficient slc6a4 +/- and -/- mice have gene-proportionate increases in extracellular fluid serotonin (5-HT) concentrations. i.e., 3- or 6-fold excesses respectively over +/+ mice, with the slc6a4 deficiency present since conception (Murphy & Lesch 2008). ? These mice also have significantly increased 5-HT synthesis and turnover across all five brain regions investigated in slc6a4 -/- mice.? Dopaminergic neurons in substantia nigra accumulate excess serotonin in slc6a4 -/- mice and expression of organic cation transporters, OCT1 and OCT3, which are low affinity transporters of monoamines is increased, both findings indicative of some partial but inefficient attempts at compensation for the loss of SERT function via heterologous transporters. ? Slc6a4 +/- mice with decreased SERT binding sites, decreased 5-HT clearance and elevated ECF 5-HT nonetheless have unchanged tissue 5-HT concentrations in the brain and periphery and unchanged brain 5-HT synthesis and turnover. Thus, the loss of one slc6a4 allele leads to a decrease in transporter function, but a single copy of slc6a4 is adequate to maintain overall 5-HT tissue homeostasis.? In models of anxiety, the slc6a4 deficient mice exhibit markedly greater anxiety-like behaviors. Similarly, these mice have substantially greater activation of the HPA and 36sympathoadrenal systems in responses to minor stressful stimuli. ? Genetic vulnerability to exaggerated, serotonin syndrome behaviors and physiology are present in slc6a4 +/- and -/- mice with a targeted disruption of SERT. This has potential implications for similar SRI side effects in humans with polymorphisms that reduce SERT gene function to as much as that found in slc6a4 mice. Of special note, it is likely that relatively mild serotonin syndrome occurrence may contribute to early discontinuation of SRIs and side effects during SRI treatment associated with the SERT gene polymorphisms.? Thus, SERT provides an interesting example of likely mouse-human congruence in genetic vulnerability to many common disorders. Additional examples likely exist and might be modeled in gene-targeted mice that have been created for other serotonin genes and for some of the double knockout models constructed, all examples of the projected, soon-to-come personalized medicine.
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