Abstract
Fluoxetine is the foremost prescribed antidepressant. Drugs acting on monoaminergic system may also regulate glutamatergic system. Indeed, the investigation of proteins associated with this system, such as Narp (neuronal activity-dependent pentraxin) and GluA4 subunit of AMPA receptor may reveal poorly explored modulations triggered by conventional antidepressants. This study aimed to uncover neurochemical mechanisms underlying the chronic fluoxetine treatment, mainly by evaluating these protein targets in the prefrontal cortex and in the hippocampus. Mice received a daily administration of fluoxetine (0.1, 1 or 10 mg/kg, p.o.) or potable water (vehicle group) for 21 days. These animals were submitted to the forced swim test (FST) to verify antidepressant-like responses and the open-field test (OFT) to assess locomotor activity. Modulation of signaling proteins was analyzed by western blot. Chronic treatment with fluoxetine (1 and 10 mg/kg) was effective, since it reduced the immobility time in the FST, without altering locomotor activity. Fluoxetine 10 mg/kg increased CREB phosphorylation and BDNF expression in the prefrontal cortex and hippocampus. Noteworthy, in the hippocampus fluoxetine also promoted Akt activation and augmented Narp expression. In the prefrontal cortex, a significant decrease in the expression of the GluA4 subunit and Narp were observed following fluoxetine administration (10 mg/kg). The results provide evidence of novel molecular targets potentially involved in the antidepressant effects of fluoxetine, since in mature rodents Narp and GluA4 are mainly expressed in the GABAergic parvalbumin-positive (PV+) interneurons. This may bring new insights into the molecular elements involved in the mechanisms underlying the antidepressant effects of fluoxetine.
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Acknowledgements
We are also grateful to the Laboratório Multiusuário de Estudos em Biologia at the Federal University of Santa Catarina (LAMEB/UFSC) for technical support and to provide infrastructure for acquisition of western blot data.
Funding
This study was supported by grants from Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) (Project #439601/2018-5 and #309048/2019-2), Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) (CAPES/MINCyT Project #249/14) and Programa de Núcleos de Excelência-NENASC Project (PRONEX) of Fundação de Apoio à Pesquisa Científica e Tecnológica do Estado de Santa Catarina (FAPESC) (Project #1262/2012-9), Brazil. RBL, ALSR and RW are recipients of CNPq Research Productivity Fellowship.
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Study design: Isabella (A) Heinrich, Andiara E. Freitas, Ana Lúcia S. Rodrigues, Rodrigo (B) Leal. Study conduct and data collection: Isabella A. Heinrich, Andiara E. Freitas, Ingrid A.V. Wolin and Ana Paula M. Nascimento. Data analysis: Isabella (A) Heinrich, Andiara E. Freitas, Roger Walz, Ana Lúcia S. Rodrigues, Rodrigo (B) Leal. Drafting manuscript: Isabella A. Heinrich. Wrote the manuscript: Isabella (A) Heinrich, Andiara E. Freitas, Roger Walz, Ana Lúcia S. Rodrigues, Rodrigo (B) Leal. Approving final version of manuscript: all authors.
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Heinrich, I.A., Freitas, A.E., Wolin, I.A.V. et al. Neuronal activity regulated pentraxin (narp) and GluA4 subunit of AMPA receptor may be targets for fluoxetine modulation. Metab Brain Dis 36, 711–722 (2021). https://doi.org/10.1007/s11011-021-00675-x
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DOI: https://doi.org/10.1007/s11011-021-00675-x