title: Differential and converging molecular mechanisms of antidepressants' action in the hippocampal dentate gyrus.
abstract: Major depression is a highly prevalent, multidimensional disorder. Although several classes of antidepressants (ADs) are currently available, treatment efficacy is limited, and relapse rates are high; thus, there is a need to find better therapeutic strategies. Neuroplastic changes in brain regions such as the hippocampal dentate gyrus (DG) accompany depression and its amelioration with ADs. In this study, the unpredictable chronic mild stress (uCMS) rat model of depression was used to determine the molecular mediators of chronic stress and the targets of four ADs with different pharmacological profiles (fluoxetine, imipramine, tianeptine, and agomelatine) in the hippocampal DG. All ADs, except agomelatine, reversed the depression-like behavior and neuroplastic changes produced by uCMS. Chronic stress induced significant molecular changes that were generally reversed by fluoxetine, imipramine, and tianeptine. Fluoxetine primarily acted on neurons to reduce the expression of pro-inflammatory response genes and increased a set of genes involved in cell metabolism. Similarities were found between the molecular actions and targets of imipramine and tianeptine that activated pathways related to cellular protection. Agomelatine presented a unique profile, with pronounced effects on genes related to Rho-GTPase-related pathways in oligodendrocytes and neurons. These differential molecular signatures of ADs studied contribute to our understanding of the processes implicated in the onset and treatment of depression-like symptoms.
authors.affiliation: 1] Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Braga, Portugal [2] ICVS/3B's-PT Government Associate Laboratory, Braga/Guimarães, Portugal.
authors.forename: Patrícia
authors.initials: P
authors.lastname: Patrício
authors.affiliation: 1] Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Braga, Portugal [2] ICVS/3B's-PT Government Associate Laboratory, Braga/Guimarães, Portugal.
authors.forename: António
authors.initials: A
authors.lastname: Mateus-Pinheiro
authors.affiliation: Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Irmler
authors.affiliation: 1] Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Braga, Portugal [2] ICVS/3B's-PT Government Associate Laboratory, Braga/Guimarães, Portugal.
authors.forename: Nuno D
authors.initials: ND
authors.lastname: Alves
authors.affiliation: 1] Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Braga, Portugal [2] ICVS/3B's-PT Government Associate Laboratory, Braga/Guimarães, Portugal.
authors.forename: Ana R
authors.initials: AR
authors.lastname: Machado-Santos
authors.affiliation: 1] Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Braga, Portugal [2] ICVS/3B's-PT Government Associate Laboratory, Braga/Guimarães, Portugal.
authors.forename: Mónica
authors.initials: M
authors.lastname: Morais
authors.affiliation: 1] Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Braga, Portugal [2] ICVS/3B's-PT Government Associate Laboratory, Braga/Guimarães, Portugal.
authors.forename: Joana S
authors.initials: JS
authors.lastname: Correia
authors.affiliation: Department of Molecular Neuropharmacology, Institute of Pharmacology, Polish Academy of Sciences, Kraków, Poland.
authors.forename: Michal
authors.initials: M
authors.lastname: Korostynski
authors.affiliation: Department of Molecular Neuropharmacology, Institute of Pharmacology, Polish Academy of Sciences, Kraków, Poland.
authors.forename: Marcin
authors.initials: M
authors.lastname: Piechota
authors.affiliation: Max Planck Institute of Psychiatry, Munich, Germany.
authors.forename: Rainer
authors.initials: R
authors.lastname: Stoffel
authors.affiliation: 1] Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany [2] Technical University Munich, Chair of Experimental Genetics, Freising-Weihenstephan, Germany.
authors.forename: Johannes
authors.initials: J
authors.lastname: Beckers
authors.affiliation: 1] Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Braga, Portugal [2] ICVS/3B's-PT Government Associate Laboratory, Braga/Guimarães, Portugal.
authors.forename: João M
authors.initials: JM
authors.lastname: Bessa
authors.affiliation: Max Planck Institute of Psychiatry, Munich, Germany.
authors.forename: Osborne F X
authors.initials: OF
authors.lastname: Almeida
authors.affiliation: 1] Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Braga, Portugal [2] ICVS/3B's-PT Government Associate Laboratory, Braga/Guimarães, Portugal.
authors.forename: Nuno
authors.initials: N
authors.lastname: Sousa
authors.affiliation: 1] Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Braga, Portugal [2] ICVS/3B's-PT Government Associate Laboratory, Braga/Guimarães, Portugal.
authors.forename: Luísa
authors.initials: L
authors.lastname: Pinto
mesh_terms: D000081:Acetamides / Q000494:pharmacology; D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D002908:Chronic Disease; D018891:Dentate Gyrus / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology; D003866:Depressive Disorder / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D005473:Fluoxetine / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects; D007099:Imipramine / Q000494:pharmacology; D008297:Male; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D011897:Random Allocation; D017208:Rats, Wistar; D013315:Stress, Psychological / Q000188:drug therapy / Q000378:metabolism; D013841:Thiazepines / Q000494:pharmacology; D035501:Uncertainty; D009281:Naphthalenes
chemical_list: D000081:Acetamides; D000928:Antidepressive Agents; D005473:Fluoxetine; D007099:Imipramine; D013841:Thiazepines; C050504:tianeptine; C084711:agomelatine; D009281:Naphthalenes