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|Title:||Chronic SSRI treatment exacerbates serotonin deficiency in humanized Tph2 mutant mice|
|Citation:||Siesser, W.B., Sachs, B.D., Ramsey, A.J., Sotnikova, T.D., Beaulieu, J.-M., Zhang, X., Caron, M.G., Gainetdinov, R.R. (2013-01-16). Chronic SSRI treatment exacerbates serotonin deficiency in humanized Tph2 mutant mice. ACS Chemical Neuroscience 4 (1) : 84-88. ScholarBank@NUS Repository. https://doi.org/10.1021/cn300127h|
|Abstract:||Selective serotonin reuptake inhibitors (SSRIs) are a major class of antidepressants that act by blocking inward transport of serotonin (5-HT) into presynaptic neurons mediated by the serotonin transporter (SERT). Both reuptake and ongoing synthesis are essential in supporting intraneuronal serotonin concentrations in serotonergic neurons. A rare mutation in tryptophan hydroxylase 2 (Tph2), the rate limiting enzyme for 5-HT synthesis, was identified in several patients with major depression, and knock-in mice expressing the analogous mutation (R439H Tph2 KI) show 80% reduction in 5-HT synthesis and tissue levels. Chronic treatment with SSRIs (fluoxetine and paroxetine) resulted in a dramatic further depletion of 5-HT tissue levels in R439H Tph2 KI mice (down to 1-3% of wild type levels) while having little effects in wild-type controls. Treatment with the 5-HT precursor 5-hydroxytryptophan (5-HTP) restored 5-HT tissue content in mutant mice, and cotreatment with 5-HTP and fluoxetine essentially prevented the depleting effect of a chronic SSRI. These data demonstrate that chronic SSRI treatment could further exacerbate the 5-HT deficiency in Tph2 mutation carriers, and this can be prevented by 5-HTP supplementation. © 2012 American Chemical Society.|
|Source Title:||ACS Chemical Neuroscience|
|Appears in Collections:||Staff Publications|
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