ParkinsonCanadaV1, Main, Exploration, bibRecord, 001272

Chronic SSRI Treatment Exacerbates Serotonin Deficiency in Humanized Tph2 Mutant Mice

Identifieur interne : 001272 ( Main/Exploration ); précédent : 001271; suivant : 001273

Chronic SSRI Treatment Exacerbates Serotonin Deficiency in Humanized Tph2 Mutant Mice

Auteurs : William X0a B. Siesser [États-Unis] ; Benjamin D. Sachs [États-Unis] ; Amy J. Ramsey [Canada] ; Tatyana D. Sotnikova [Italie] ; Jean-Martin Beaulieu [Canada] ; Xiaodong Zhang [Singapour, États-Unis] ; Marc G. Caron [États-Unis] ; Raul R. Gainetdinov [États-Unis, Italie]

Source :

ACS Chemical Neuroscience [ 1948-7193 ] ; 2012.

RBID : PMC:3547473

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.

Url:

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3547473

DOI: 10.1021/cn300127h
PubMed: 23336047
PubMed Central: 3547473

Affiliations:

Canada, Italie, Singapour, États-Unis

Le document en format XML

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<affiliation wicri:level="1"><nlm:aff id="aff1">Department of Cell Biology,<institution>Duke University</institution>
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<front><div type="abstract" xml:lang="en"><p content-type="toc-graphic"><graphic xlink:href="cn-2012-00127h_0005" id="ab-tgr1"></graphic>
</p>
<p>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 (<italic>Tph2</italic>),
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 <italic>Tph2</italic> 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 <italic>Tph2</italic> 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 <italic>Tph2</italic> mutation carriers,
and this can be prevented by 5-HTP supplementation.</p>
</div>
</front>
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<name sortKey="Gainetdinov, Raul R" sort="Gainetdinov, Raul R" uniqKey="Gainetdinov R" first="Raul R." last="Gainetdinov">Raul R. Gainetdinov</name>
<name sortKey="Sachs, Benjamin D" sort="Sachs, Benjamin D" uniqKey="Sachs B" first="Benjamin D." last="Sachs">Benjamin D. Sachs</name>
<name sortKey="Zhang, Xiaodong" sort="Zhang, Xiaodong" uniqKey="Zhang X" first="Xiaodong" last="Zhang">Xiaodong Zhang</name>
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<country name="Canada"><noRegion><name sortKey="Ramsey, Amy J" sort="Ramsey, Amy J" uniqKey="Ramsey A" first="Amy J." last="Ramsey">Amy J. Ramsey</name>
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<name sortKey="Beaulieu, Jean Martin" sort="Beaulieu, Jean Martin" uniqKey="Beaulieu J" first="Jean-Martin" last="Beaulieu">Jean-Martin Beaulieu</name>
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<country name="Italie"><noRegion><name sortKey="Sotnikova, Tatyana D" sort="Sotnikova, Tatyana D" uniqKey="Sotnikova T" first="Tatyana D." last="Sotnikova">Tatyana D. Sotnikova</name>
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<name sortKey="Gainetdinov, Raul R" sort="Gainetdinov, Raul R" uniqKey="Gainetdinov R" first="Raul R." last="Gainetdinov">Raul R. Gainetdinov</name>
</country>
<country name="Singapour"><noRegion><name sortKey="Zhang, Xiaodong" sort="Zhang, Xiaodong" uniqKey="Zhang X" first="Xiaodong" last="Zhang">Xiaodong Zhang</name>
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<name sortKey="Zhang, Xiaodong" sort="Zhang, Xiaodong" uniqKey="Zhang X" first="Xiaodong" last="Zhang">Xiaodong Zhang</name>
</country>
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La maladie de Parkinson au Canada (serveur d'exploration)

Chronic SSRI Treatment Exacerbates Serotonin Deficiency in Humanized Tph2 Mutant Mice

Chronic SSRI Treatment Exacerbates Serotonin Deficiency in Humanized Tph2 Mutant Mice

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Abstract

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