title: Antidepressant-like activity of the neuropeptide Y Y5 receptor antagonist Lu AA33810: behavioral, molecular, and immunohistochemical evidence.
abstract: It 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.
  
  
  
  In 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.
  
  
  
  We 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.
  
  
  
  O﻿ur results indicate that Lu AA33810 exerts an antidepressant-like effect and suggest the Y5 receptors as a promising target for antidepressant therapy.
authors.affiliation: Institute of Pharmacology, Polish Academy of Sciences, Department of Neurobiology, 31-343 Kraków, Smętna street 12, Poland.
authors.forename: Helena
authors.initials: H
authors.lastname: Domin
authors.affiliation: Institute of Pharmacology, Polish Academy of Sciences, Department of Neurobiology, 31-343 Kraków, Smętna street 12, Poland.
authors.forename: Bernadeta
authors.initials: B
authors.lastname: Szewczyk
authors.affiliation: Institute of Pharmacology, Polish Academy of Sciences, Department of Neurobiology, 31-343 Kraków, Smętna street 12, Poland.
authors.forename: Bartłomiej
authors.initials: B
authors.lastname: Pochwat
authors.affiliation: Institute of Pharmacology, Polish Academy of Sciences, Department of Neurobiology, 31-343 Kraków, Smętna street 12, Poland.
authors.forename: Monika
authors.initials: M
authors.lastname: Woźniak
authors.affiliation: Institute of Pharmacology, Polish Academy of Sciences, Department of Neurobiology, 31-343 Kraków, Smętna street 12, Poland. nfsmialo@cyf-kr.edu.pl.
authors.forename: Maria
authors.initials: M
authors.lastname: Śmiałowska
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001522:Behavior, Animal / Q000187:drug effects; D001582:Benzothiepins / Q000494:pharmacology* / Q000627:therapeutic use; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D002867:Chromones / Q000494:pharmacology; D003863:Depression / Q000188:drug therapy* / Q000378:metabolism; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D008297:Male; D009025:Morpholines / Q000494:pharmacology; D009478:Neuropeptide Y / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects; D013449:Sulfonamides / Q000494:pharmacology* / Q000627:therapeutic use; D013550:Swimming
chemical_list: D000928:Antidepressive Agents; D001582:Benzothiepins; D019208:Brain-Derived Neurotrophic Factor; D002867:Chromones; D004791:Enzyme Inhibitors; D009025:Morpholines; C539254:N-((4-((4,5-dihydro(1)benzothiepino(5,4-d)thiazol-2-yl)amino)cyclohexyl)methyl)methanesulfonamide; D009478:Neuropeptide Y; D000081082:Phosphoinositide-3 Kinase Inhibitors; D013449:Sulfonamides; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
keywords: Antidepressant; Astrocyte; BDNF; Forced swim test; GFAP; Gliotoxin; Lu AA33810; Neuropeptide Y; Prefrontal cortex