Abstract
RationaleIt has recently been found that chronic treatment with the highly selective, brain-penetrating Y5 receptor antagonist, Lu AA33810 [N-[[trans-4-[(4,5-dihydro [1] benzothiepino[5,4-d] thiazol-2-yl) amino] cyclohexyl]methyl]-methanesulfonamide], produces antidepressant-like effects in the rat chronic mild stress model.ObjectiveIn the present study, we investigated the possible antidepressant-like activity of Lu AA33810 in rats subjected to glial ablation in the prefrontal cortex (PFC) by the gliotoxin L-AAA, which is an astroglial degeneration model of depression.ResultsWe observed that Lu AA33810 administered intraperitoneally at a single dose of 10 mg/kg both reversed depressive-like behavioral changes in the forced swim test (FST) and prevented degeneration of astrocytes in the mPFC. The mechanism of antidepressant and glioprotective effects of Lu AA33810 has not been studied, so far. We demonstrated the contribution of the noradrenergic rather than the serotonergic pathway to the antidepressant-like action of Lu AA33810 in the FST. Moreover, we found that antidepressant-like effect of Lu AA33810 was connected with the influence on brain-derived neurotrophic factor (BDNF) protein expression. We also demonstrated the antidepressant-like effect of Lu AA33810 in the FST in rats which did not receive the gliotoxin. We found that intracerebroventricular injection of the selective MAPK/ERK inhibitor U0126 (5 μg/2 μl) and the selective PI3K inhibitor LY294002 (10 nmol/2 μl) significantly inhibited the anti-immobility effect of Lu AA33810 in the FST in rats, suggesting that MAPK/ERK and PI3K signaling pathways could be involved in the antidepressant-like effect of Lu AA33810.ConclusionOur results indicate that Lu AA33810 exerts an antidepressant-like effect and suggest the Y5 receptors as a promising target for antidepressant therapy.
Highlights
Major depressive disorder (MDD), called major depression, is the commonly occurring mental disease affecting more than 120 million people worldwide (Belmaker and Agam 2008)
Since no studies identified the signaling pathways engaged in the antidepressant-like effect of Lu AA33810, in the present study, we investigated whether its antidepressant-like effect is connected with an influence on brain-derived neurotrophic factor (BDNF) protein expression, as its role in the therapeutic effect of antidepressants has been postulated (Schmidt et al 2008; Autry and Monteggia 2012)
To investigate the possible antidepressant-like activity of Lu AA33810 in rats subjected to glial ablation, we examined the effect of L-alphaaminoadipic acid (L-AAA) and Lu AA33810 in the forced swim test (FST)
Summary
Major depressive disorder (MDD), called major depression, is the commonly occurring mental disease affecting more than 120 million people worldwide (Belmaker and Agam 2008). Despite intensive research in the last 60 years, currently used antidepressant therapies are not efficient enough and depression requires long-term treatment (Thompson et al 2015). 30% of patients with depression fail to respond to currently available therapies, which mainly influence monoaminergic systems, research aimed to find new drugs is still in progress (Prins et al 2011). Studies on depression have shifted from monoamines toward other mechanisms, including glutamatergic neurotransmission (Catena-Dell’Osso et al 2013). It can be suggested that dysregulation of Glu/GABA is involved in the pathogenesis of depression (Wierońska and Pilc 2009; Hashimoto 2009). Several studies have shown that the inhibition of glutamatergic neurotransmission was strongly correlated with the therapeutic action of a majority of antidepressant drugs (Paul and Skolnick 2003)
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