Chronic SSRI Treatment Exacerbates Serotonin Deficiency in Humanized Tph2 Mutant Mice
详细信息 查看全文
- 作者：William B. Siesser ; Benjamin D. Sachs ; Amy J. Ramsey ; Tatyana D. Sotnikova ; Jean-Martin Beaulieu ; Xiaodong Zhang ; Marc G. Caron ; Raul R. Gainetdinov
- 刊名：ACS Chemical Neuroscience
- 出版年：2013
- 出版时间：January 16, 2013
- 年：2013
- 卷：4
- 期：1
- 页码：84-88
- 全文大小：274K
- 年卷期：v.4,no.1(January 16, 2013)
- ISSN：1948-7193
文摘
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鈥?% 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.<br>