An increasing number of studies show that selective serotonin reuptake inhibitors (SSRIs) exert their therapeutic action, at least in part, by amplifying the influence of the living environment on mood. As a consequence, when administered in a favorable environment, SSRIs lead to a reduction of symptoms, but in stressful conditions, they show limited efficacy. Therefore, novel therapeutic approaches able to neutralize the influence of the stressful environment on treatment are needed. The aim of our study was to test whether, in a mouse model of depression, the combined administration of SSRI fluoxetine and metformin, a drug able to improve the metabolic profile, counteracts the limited efficacy of fluoxetine alone when administered in stressful conditions. Indeed, metabolic alterations are associated to both the onset of major depression and the antidepressant efficacy. To this goal, adult C57BL/6 male mice were exposed to stress for 6 weeks; the first two weeks was aimed at generating a mouse model of depression. During the remaining 4 weeks, mice received one of the following treatments: vehicle, fluoxetine, metformin, or a combination of fluoxetine and metformin. We measured liking- and wanting-type anhedonia as behavioral phenotypes of depression and assessed the expression levels of selected genes involved in major depressive disorder and antidepressant response in the dorsal and ventral hippocampus, which are differently involved in the depressive symptomatology. The combined treatment was more effective than fluoxetine alone in ameliorating the depressive phenotype after one week of treatment. This was associated to an increase in IGF2 mRNA expression and enhanced long-term potentiation, specifically in the dorsal hippocampus, at the end of treatment. Overall, the present results show that, when administered in stressful conditions, the combined fluoxetine and metformin treatment may represent a more effective approach than fluoxetine alone in a short term. Finally, our findings highlight the relevance of polypharmacological strategy as effective interventions to increase the efficacy of the antidepressant drugs currently available.

Combined fluoxetine and metformin treatment potentiates antidepressant efficacy increasing IGF2 expression in the dorsal hippocampus / Poggini, S.; Golia, M. T.; Alboni, S.; Milior, G.; Sciarria, L. P.; Viglione, A.; Bon, G. M.; Brunello, N.; Puglisi-Allegra, S.; Limatola, C.; Maggi, L.; Branchi, I.. - In: NEURAL PLASTICITY. - ISSN 2090-5904. - 2019:(2019), pp. 1-12. [10.1155/2019/4651031]

Combined fluoxetine and metformin treatment potentiates antidepressant efficacy increasing IGF2 expression in the dorsal hippocampus

Alboni S.
Membro del Collaboration Group
;
Brunello N.;
2019

Abstract

An increasing number of studies show that selective serotonin reuptake inhibitors (SSRIs) exert their therapeutic action, at least in part, by amplifying the influence of the living environment on mood. As a consequence, when administered in a favorable environment, SSRIs lead to a reduction of symptoms, but in stressful conditions, they show limited efficacy. Therefore, novel therapeutic approaches able to neutralize the influence of the stressful environment on treatment are needed. The aim of our study was to test whether, in a mouse model of depression, the combined administration of SSRI fluoxetine and metformin, a drug able to improve the metabolic profile, counteracts the limited efficacy of fluoxetine alone when administered in stressful conditions. Indeed, metabolic alterations are associated to both the onset of major depression and the antidepressant efficacy. To this goal, adult C57BL/6 male mice were exposed to stress for 6 weeks; the first two weeks was aimed at generating a mouse model of depression. During the remaining 4 weeks, mice received one of the following treatments: vehicle, fluoxetine, metformin, or a combination of fluoxetine and metformin. We measured liking- and wanting-type anhedonia as behavioral phenotypes of depression and assessed the expression levels of selected genes involved in major depressive disorder and antidepressant response in the dorsal and ventral hippocampus, which are differently involved in the depressive symptomatology. The combined treatment was more effective than fluoxetine alone in ameliorating the depressive phenotype after one week of treatment. This was associated to an increase in IGF2 mRNA expression and enhanced long-term potentiation, specifically in the dorsal hippocampus, at the end of treatment. Overall, the present results show that, when administered in stressful conditions, the combined fluoxetine and metformin treatment may represent a more effective approach than fluoxetine alone in a short term. Finally, our findings highlight the relevance of polypharmacological strategy as effective interventions to increase the efficacy of the antidepressant drugs currently available.
2019
1
12
Combined fluoxetine and metformin treatment potentiates antidepressant efficacy increasing IGF2 expression in the dorsal hippocampus / Poggini, S.; Golia, M. T.; Alboni, S.; Milior, G.; Sciarria, L. P.; Viglione, A.; Bon, G. M.; Brunello, N.; Puglisi-Allegra, S.; Limatola, C.; Maggi, L.; Branchi, I.. - In: NEURAL PLASTICITY. - ISSN 2090-5904. - 2019:(2019), pp. 1-12. [10.1155/2019/4651031]
Poggini, S.; Golia, M. T.; Alboni, S.; Milior, G.; Sciarria, L. P.; Viglione, A.; Bon, G. M.; Brunello, N.; Puglisi-Allegra, S.; Limatola, C.; Maggi, L.; Branchi, I.
File in questo prodotto:
File Dimensione Formato  
4651031 (1).pdf

accesso aperto

Tipologia: Versione dell'editore (versione pubblicata)
Dimensione 1.93 MB
Formato Adobe PDF
1.93 MB Adobe PDF Visualizza/Apri
Pubblicazioni consigliate

Caricamento pubblicazioni consigliate

Licenza Creative Commons
I metadati presenti in IRIS UNIMORE sono rilasciati con licenza Creative Commons CC0 1.0 Universal, mentre i file delle pubblicazioni sono rilasciati con licenza Attribuzione 4.0 Internazionale (CC BY 4.0), salvo diversa indicazione.
In caso di violazione di copyright, contattare Supporto Iris

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11380/1201694
Citazioni
  • ???jsp.display-item.citation.pmc??? 8
  • Scopus 26
  • ???jsp.display-item.citation.isi??? 27
social impact