The antidepressant-like and glioprotective effects of the Y2 receptor antagonist SF-11 in the astroglial degeneration model of depression in rats: Involvement of glutamatergic inhibition

In this study, we explored the potential antidepressant -like properties of the brain -penetrant Y2 receptor (Y2R) antagonist SF -11 [N-(4-ethoxyphenyl)4-(hydroxydiphenylmethyl)- 1-piperidinecarbothioamide] in the astroglial degeneration model of depression with an emphasis on checking the possible mechanisms implicated in this antidepressant -like effect. The model of depression relies on the loss of astrocytes in the medial prefrontal cortex (mPFC) in Sprague-Dawley rats after administering the gliotoxin L-alpha-aminoadipic acid (L -AAA). SF -11 was administered intraperitoneally (i.p.) once (10 mg/kg) or for three consecutive days (10 mg/kg/day), and the effects of L -AAA and SF -11 injected alone or in combination were investigated using the forced swim test (FST), sucrose intake test (SIT), Western blotting, immunohistochemical staining, and microdialysis. SF -11 produced an antidepressant -like effect after single or three-day administration in rats subjected to astrocyte impairment, as demonstrated by the FST and SIT, respectively. Immunoblotting and immunohistochemical analyses showed that SF -11 reversed the L -AAA -induced astrocyte cell death in the mPFC, suggesting it is glioprotective. Microdialysis studies showed that SF -11 decreased extracellular glutamate (Glu) levels compared to basal value when administered alone and compared to the basal value and control group in LAAA-treated rats. The results from immunoblotting analysis indicated the involvement of Y2Rs in the astrocyte ablation model of depression and the antidepressant -like effect of SF -11. In addition, we observed the participation of the caspase-3 apoptotic pathway in the mechanism of gliotoxin action induced by L -AAA. These findings demonstrate that SF -11, a Y2R antagonist, elicited a rapid antidepressant -like response, possibly linked to its ability to inhibit glutamatergic neurotransmission.