Genotype-Dependent Activity of Tryptophan Hydroxylase-2 Determines the Response to Citalopram in a Mouse Model of Depression

Cervo, Luigi; Canetta, Alessandro; Calcagno, Eleonora; Burbassi, Silvia; Sacchetti, G.; Caccia, Silvio; Fracasso, Claudia; Albani, Diego; Forloni, Gianluigi; Invernizzi, Roberto William

doi:10.1523/jneurosci.1816-05.2005

Cited by 129 publications

(149 citation statements)

References 52 publications

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“…The different responses to citalopram between BALB/ cJ and A/J mice in the TST appeared similar to differences these strains showed in the effects of the SSRI fluoxetine in the FST, a second antidepressant test (Lucki et al, 2001). However, Cervo et al (2005) reported recently that BALB/c mice responded relatively poorly to citalopram in the FST. This characterization could have resulted from methodological differences between laboratories in conducting and scoring the FST.…”

Section: Discussionmentioning

confidence: 98%

Pharmacogenomic Evaluation of the Antidepressant Citalopram in the Mouse Tail Suspension Test

Crowley

Brodkin

Blendy

et al. 2006

Neuropsychopharmacol

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The identification of genetic variants regulating antidepressant response in human patients would allow for more individualized, rational, and successful drug treatments. We have previously identified the BALB/cJ inbred mouse strain as highly responsive to the selective serotonin reuptake inhibitor (SSRI) citalopram in the tail suspension test (TST), a widely used and well-established screening paradigm for detecting compounds with antidepressant activity. In contrast, A/J mice did not show a significant response to citalopram in this test despite exposure to equivalent plasma levels of the drug. To identify genetic determinants of this differential response, 506 F 2 mice from an intercross between BALB/cJ and A/J mice were phenotyped. Composite interval mapping of 92 mice from the phenotypic extremes revealed three loci on chromosomes 7, 12, and 19 affecting citalopram response in the TST. The quantitative trait locus (QTL) at the telomeric end of chromosome 19 showed the greatest level of significance. Three candidate genes residing in this locus include those for vesicular monoamine transporter 2 (VMAT2, slc18a2), alpha 2A adrenergic receptor (adra2a), and beta 1 adrenergic receptor (adrb1). The protein coding regions of these three genes in BALB/cJ and A/J mice were sequenced and two polymorphisms were found in VMAT2 (Leu117Pro and Ser505Pro), while the transcribed regions of adra2a and adrb1 were of identical sequence between strains. Follow-up studies are needed to determine if the VMAT2 polymorphisms are functional and if they could explain the chromosome 19 QTL. The present quantitative trait study suggests possible candidate genes for human pharmacogenetic studies of therapeutic responses to SSRIs such as citalopram.

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Section: Discussionmentioning

confidence: 98%

Pharmacogenomic Evaluation of the Antidepressant Citalopram in the Mouse Tail Suspension Test

Crowley

Brodkin

Blendy

et al. 2006

Neuropsychopharmacol

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“…This variant results in a reduction of enzyme activity by Ϸ50% when expressed in PC12 cells. Furthermore, expression of this Tph2 variant in these inbred mouse lines is associated with reduced brain 5-HT synthesis (15) and differences in aggressive behavior (45), premRNA editing of the 5-HT 2C receptor (46), as well as responsiveness to SSRIs (47,48). However, these studies can only be viewed as correlative because they were all conducted by comparing different strains of inbred mice and the potential contribution of other genetic variations in these mice cannot be ruled out.…”

Section: Discussionmentioning

confidence: 99%

Role of GSK3β in behavioral abnormalities induced by serotonin deficiency

Beaulieu¹,

Zhang²,

Rodriguiz

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

342

317

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Dysregulation of brain serotonin (5-HT) neurotransmission is thought to underlie mental conditions as diverse as depression, anxiety disorders, bipolar disorder, autism, and schizophrenia. Despite treatment of these conditions with serotonergic drugs, the molecular mechanisms by which 5-HT is involved in the regulation of aberrant emotional behaviors are poorly understood. Here, we generated knockin mice expressing a mutant form of the brain 5-HT synthesis enzyme, tryptophan hydroxylase 2 (Tph2). This mutant is equivalent to a rare human variant (R441H) identified in few individuals with unipolar major depression. Expression of mutant Tph2 in mice results in markedly reduced (Ϸ80%) brain 5-HT production and leads to behavioral abnormalities in tests assessing 5-HT-mediated emotional states. This reduction in brain 5-HT levels is accompanied by activation of glycogen synthase kinase 3␤ (GSK3␤), a signaling molecule modulated by many psychiatric therapeutic agents. Importantly, inactivation of GSK3␤ in Tph2 knockin mice, using pharmacological or genetic approaches, alleviates the aberrant behaviors produced by 5-HT deficiency. These findings establish a critical role of Tph2 in the maintenance of brain serotonin homeostasis and identify GSK3␤ signaling as an important pathway through which brain 5-HT deficiency induces abnormal behaviors. Targeting GSK3␤ and related signaling events may afford therapeutic advantages for the management of certain 5-HT-related psychiatric conditions. GSK-3 ͉ mood disorders ͉ serotonin ͉ Tph2 ͉ functional polymorphism S erotonin (5-HT) is involved in multiple aspects of normal brain functions ranging from the regulation of mood to the control of appetite and social interactions (1-3). Several studies have suggested a contribution of abnormal 5-HT transmission in various human psychiatric conditions and drugs acting on 5-HT neurotransmission are commonly used for the management of major depression, anxiety disorder, obsessive-compulsive disorder, autism, and schizophrenia (1-3). Although drugs that influence the 5-HT system can affect histone acetylation, modulate production of brain-derived neurotrophic factor, increase neural progenitor cell proliferation, and inhibit glycogen synthase kinase 3␤ (GSK3␤) in certain brain areas (4, 5), the mechanisms underlying the regulation of behavior by 5-HT are still obscure.There are indications that pharmacologic manipulations of 5-HT levels by different classes of drugs can affect distinct neuronal signaling mechanisms (6-9). For instance, multiple classes of 5-HT drugs, including selective 5-HT reuptake inhibitors (SSRIs), tricyclic antidepressants, monoamine oxidase inhibitors, and atypical antipsychotics (5, 7, 9), inhibit brain GSK3␤ signaling. GSK3␤ is also inhibited in vivo by lithium (6, 10-12), which is often used in combination with antidepressants for the management of certain mood disorders (13). However, whether these changes in GSK3␤ are incidental or contribute to the regulation of 5-HT-related abnormal behaviors is unexplored (5...

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“…Ambiguous results concerning the sensitivity of DBA/2 mice towards the effects of antidepressants were reported. Some studies found the DBA/2 strain to be antidepressant-sensitive (Lucki et al 2001;Crowley et al 2005), whereas others did not (David et al 2003;Cervo et al 2005). The underlying reasons for this discrepancy still remain to be determined.…”

Section: Slc25a18mentioning

confidence: 95%

Profiling of behavioral changes and hippocampal gene expression in mice chronically treated with the SSRI paroxetine

et al. 2008

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Introduction Monoamine-based antidepressants inhibit neurotransmitter reuptake within short time. However, it commonly takes several weeks until clinical symptoms start to resolve-indicating the involvement of effects distant from reuptake inhibition. Objective To unravel other mechanisms involved in drug action, a "reverse" pharmacological approach was applied to determine antidepressant-induced alterations of hippocampal gene expression. Materials and methodsThe behavioral response to longterm paroxetine administration of male DBA/2Ola mice was assessed by the forced swim test (FST), the modified hole board (mHB), and the dark/light box. Hippocampi of test-naive mice were dissected, and changes in gene expression by paroxetine treatment were investigated by means of microarray technology. Results and discussion Robust effects of paroxetine on passive stress-coping behavior in the FST were observed. Furthermore, anxiolytic properties of long-term antidepressant treatment could be identified in DBA mice in both, the mHB and dark/light box. Analysis of microarray results revealed a list of 60 genes differentially regulated by chronic paroxetine treatment. Preproenkephalin 1 and inhibin beta-A showed the highest level of transcriptional change. Furthermore, a number of candidates involved in neuroplasticity/neurogenesis emerged (e.g., Bdnf, Gfap, Vim, Sox11, Egr1, Stat3). Seven selected candidates were confirmed by in situ hybridization. Additional immunofluorescence colocalization studies of GFAP and vimentin showed more positive cells to be detected in long-term paroxetine-treated DBA mice. Conclusion Candidate genes identified in the current study using a mouse strain validated for its responsiveness to long-term paroxetine treatment add, in our opinion, to unraveling the mechanism of action of paroxetine as a representative for SSRIs.

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Genotype-Dependent Activity of Tryptophan Hydroxylase-2 Determines the Response to Citalopram in a Mouse Model of Depression

Cited by 129 publications

References 52 publications

Pharmacogenomic Evaluation of the Antidepressant Citalopram in the Mouse Tail Suspension Test

Pharmacogenomic Evaluation of the Antidepressant Citalopram in the Mouse Tail Suspension Test

Role of GSK3β in behavioral abnormalities induced by serotonin deficiency

Profiling of behavioral changes and hippocampal gene expression in mice chronically treated with the SSRI paroxetine

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