Galanin(1-15) Potentiates the Antidepressant-like Effects Induced by Escitalopram in a Rat Model of Depression.

Laura García-Durán,José Ángel Narváez,Noelia Cantero-García,Zaida Díaz-Cabiale,Kjell Fuxe,Antonio Flores-Burgess,Araceli Puigcerver,Carmelo Millón,Luis Santín

doi:10.3390/ijms221910848

Laura García-Durán, José Ángel Narváez + Show 7 more

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https://doi.org/10.3390/ijms221910848

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Abstract

Selective 5-HT reuptake inhibitor antidepressants (SSRIs) are the first choice in major depressive disorder (MDD), but 50% of affected patients do not show improvement. Galanin(1-15) [GAL(1-15)] enhanced Fluoxetine antidepressant-like effects in an animal model of depression, the olfactory bulbectomy (OBX); however, further detailed analysis of GAL(1-15) effects as augmentation treatment in OBX rats are needed. In OBX rats, we analysed the effect of GAL(1–15) on Escitalopram (ESC)-mediated responses in behavioural tests related to despair. We studied whether GAL(1–15) effects involved 5-HT1AR using an in vivo model siRNA 5-HT1A knockdown rats. Moreover, we analysed by immunohistochemistry the expression of the immediate-early gene c-Fos (c-Fos IR) after the administration of GAL(1-15)+ESC in OBX rats in several nuclei involved in MDD. GAL(1-15) enhances the antidepressant-like effects of ESC, and the GALR2 antagonist M871 blocked GAL(1-15) mediated actions. The downregulation of 5-HT1AR by siRNA was sufficient to block GAL(1-15) effects. Our immunohistochemistry and principal component analysis (PCA) analysis suggest that two functional networks are involved in these effects; one includes the lateral (LHb) and medial (mHb) habenula, dorsal raphe (DR) and ventral tegmental area (VTA), and the other consists of the dentate gyrus (DG), and prefrontal cortex (PFC). The results open up the possibility of using GAL(1-15) in combination with SSRIs as a novel strategy for treating MDD.

Highlights

Depression or major depressive disorder (MDD) is one of the most disabling mental disorders
Our immunohistochemistry and principal component analysis (PCA) analysis suggest that two functional networks are involved in these effects; one includes the lateral (LHb) and medial habenula, dorsal raphe (DR) and ventral tegmental area (VTA), and the other consists of the dentate gyrus (DG), and prefrontal cortex (PFC)
In the PFC OBX showed an increase in 5HT1A expression (t9 = 4.08; p = 0.001) and a decreased in Home1A expression (t9 = 3.47; p = 0.003), while the bilateral olfactory bulbectomy rats lacked effect in the mRNA

Summary

Introduction

Depression or major depressive disorder (MDD) is one of the most disabling mental disorders. According to estimates by the World Health Organisation, it affects 350 million people and in 2030 it will become the leading cause of incapacity of the world [1,2]. This complex emotional disorder is often characterised by hopelessness, anhedonia, exacerbated guilt, and painful physical symptoms [3], resulting in suicidal thoughts and attempts [4]. There is a need to develop novel treatments that provide effective, faster and prolonged relief of depressive symptoms in patients with MDD

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