Dataset Information

Effect of clinically relevant doses of vortioxetine and citalopram on serotonergic PET markers in the nonhuman primate brain.

ABSTRACT: Vortioxetine is a multimodal antidepressant approved for treatment of major depressive disorder. Preclinical studies have demonstrated that the mechanism of action of vortioxetine might be different from selective serotonin reuptake inhibitors (SSRIs), including larger serotonin (5-HT) release and direct modulation of several 5-HT receptors. In the current positron emission tomography (PET) study, we evaluated the mechanism of action of vortioxetine by comparing its effect to the SSRI citalopram on the binding of [¹¹C]AZ10419369 to the 5-HT_1B receptor in the nonhuman primate brain. Initially, the 5-HT transporter (5-HTT) binding of vortioxetine was determined by [¹¹C]MADAM PET measurements before and after administration of vortioxetine (0.1-3.0?mg/kg) and data were used to confirm clinically relevant dosing in subsequent PET measurements with [¹¹C]AZ10419369. The 5-HT_1B receptor binding was significantly decreased after 0.3?mg/kg of citalopram in the dorsal raphe nucleus (5%), as well as after 0.3?mg/kg of vortioxetine in six brain regions (~25%) or 1.0?mg/kg of vortioxetine in all 12 examined regions (~48%). Moreover, there was no effect of 1.0?mg/kg of vortioxetine on the binding of [¹¹C]Cimbi-36 to the 5-HT_2A receptor, which has comparable sensitivity to 5-HT release as [¹¹C]AZ10419369 binding. In conclusion, at clinically relevant doses, vortioxetine induced larger reductions in [¹¹C]AZ10419369 binding than citalopram. These observations suggest that vortioxetine binds to the 5-HT_1B receptor at clinically relevant doses. Future studies are warranted to evaluate the role of the 5-HT_1B receptor in the therapeutic effects of vortioxetine and as a potential target for the development of novel antidepressant drugs.

SUBMITTER: Yang KC

PROVIDER: S-EPMC6784989 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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Effect of clinically relevant doses of vortioxetine and citalopram on serotonergic PET markers in the nonhuman primate brain.

Yang Kai-Chun KC Stepanov Vladimir V Amini Nahid N Martinsson Stefan S Takano Akihiro A Bundgaard Christoffer C Bang-Andersen Benny B Sanchez Connie C Halldin Christer C Farde Lars L Finnema Sjoerd J SJ

Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 20190619 10

Vortioxetine is a multimodal antidepressant approved for treatment of major depressive disorder. Preclinical studies have demonstrated that the mechanism of action of vortioxetine might be different from selective serotonin reuptake inhibitors (SSRIs), including larger serotonin (5-HT) release and direct modulation of several 5-HT receptors. In the current positron emission tomography (PET) study, we evaluated the mechanism of action of vortioxetine by comparing its effect to the SSRI citalopram ...[more]

PMID: 31216565

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Project description:Parthenogenesis is the biological phenomenon by which embryonic development is initiated without male contribution. Whereas parthenogenesis is a common mode of reproduction in lower organisms, the mammalian parthenote fails to produce a successful pregnancy. We herein describe in vitro parthenogenetic development of monkey (Macaca fascicularis) eggs to the blastocyst stage, and their use to create a pluripotent line of stem cells. These monkey stem cells (Cyno-1 cells) are positive for telomerase activity and are immunoreactive for alkaline phosphatase, octamer-binding transcription factor 4 (Oct-4), stage-specific embryonic antigen 4 (SSEA-4), tumor rejection antigen 1-60 (TRA 1-60), and tumor rejection antigen 1-81 (TRA 1-81) (traditional markers of human embryonic stem cells). They have a normal chromosome karyotype (40 + 2) and can be maintained in vitro in an undifferentiated state for extended periods of time. Cyno-1 cells can be differentiated in vitro into dopaminergic and serotonergic neurons, contractile cardiomyocyte-like cells, smooth muscle, ciliated epithelia, and adipocytes. When Cyno-1 cells were injected into severe combined immunodeficient mice, teratomas with derivatives from all three embryonic germ layers were obtained. When grown on fibronectin/laminin-coated plates and in neural progenitor medium, Cyno-1 cells assume a neural precursor phenotype (immunoreactive for nestin). However, these cells remain proliferative and express no functional ion channels. When transferred to differentiation conditions, the nestin-positive precursors assume neuronal and epithelial morphologies. Over time, these cells acquire electrophysiological characteristics of functional neurons (appearance of tetrodotoxin-sensitive, voltage-dependent sodium channels). These results suggest that stem cells derived from the parthenogenetically activated nonhuman primate egg provide a potential source for autologous cell therapy in the female and bypass the need for creating a competent embryo.

Dataset Information

Effect of clinically relevant doses of vortioxetine and citalopram on serotonergic PET markers in the nonhuman primate brain.

Publications

Effect of clinically relevant doses of vortioxetine and citalopram on serotonergic PET markers in the nonhuman primate brain.

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