title: Stress-induced anhedonia is associated with the activation of the inflammatory system in the rat brain: Restorative effect of pharmacological intervention.
abstract: Major depression is a complex disease that originates from the interaction between a genetic background of susceptibility and environmental factors such as stress. At molecular level, it is characterized by dysfunctions of multiple systems including neurotransmitters, hormones, signalling pathways, neurotrophic and neuroplastic molecules and - more recently - inflammatory mediators. Accordingly, in the present study we used the chronic mild stress (CMS) paradigm in the rat to elucidate to what extent brain inflammation may contribute to the development and/or the maintenance of an anhedonic phenotype and how pharmacological intervention may interfere with such behavioral and molecular stress-induced alterations. To this aim, adult male rats were exposed to CMS for 2 weeks and the cerebral expression of several mediators of the inflammatory system was evaluated in the hippocampus and prefrontal cortex of both stressed and control animals in parallel with the sucrose intake. Next, the animals that showed a decreased sucrose consumption were exposed to five further weeks of CMS and treated with the antidepressants imipramine or agomelatine, or the antipsychotic lurasidone. Our results demonstrate that only the stressed animals that were characterized by a deficit in sucrose intake showed increased expression of the pro-inflammatory cytokines IL-1β, IL-6 and up-regulation of markers and mediators of microglia activation such as CD11b, CX3CL1 and its receptor CX3CR1 in comparison with stress-resilient animals. Some of these molecular alterations persisted also after longer stress exposure and were modulated, similarly to the behavioral effects of CMS, by chronic pharmacological treatment. These data suggest that neuroinflammation may have a key role in the pathological consequences of stress exposure, thus contributing to the subject's vulnerability for depression.
authors.affiliation: Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Milan, Italy. Electronic address: andreacarlo.rossetti@unimi.it.
authors.forename: Andrea C
authors.initials: AC
authors.lastname: Rossetti
authors.affiliation: Institute of Pharmacology, Polish Academy of Sciences, Kracow, Poland. Electronic address: nfpapp@cyfronet.pl.
authors.forename: Mariusz
authors.initials: M
authors.lastname: Papp
authors.affiliation: Institute of Pharmacology, Polish Academy of Sciences, Kracow, Poland. Electronic address: gruca@if-pan.krakow.pl.
authors.forename: Piotr
authors.initials: P
authors.lastname: Gruca
authors.affiliation: Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Milan, Italy. Electronic address: mariaserena.paladini@studenti.unimi.it.
authors.forename: Maria Serena
authors.initials: MS
authors.lastname: Paladini
authors.affiliation: Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Milan, Italy. Electronic address: giorgio.racagni@unimi.it.
authors.forename: Giorgio
authors.initials: G
authors.lastname: Racagni
authors.affiliation: Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Milan, Italy. Electronic address: m.riva@unimi.it.
authors.forename: Marco A
authors.initials: MA
authors.lastname: Riva
authors.affiliation: Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Milan, Italy. Electronic address: raffaella.molteni@unimi.it.
authors.forename: Raffaella
authors.initials: R
authors.lastname: Molteni
mesh_terms: D000081:Acetamides / Q000494:pharmacology; D059445:Anhedonia / Q000502:physiology*; D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology; D014150:Antipsychotic Agents / Q000494:pharmacology; D001921:Brain / Q000378:metabolism*; D039481:CD11b Antigen / Q000235:genetics / Q000378:metabolism; D000073883:CX3C Chemokine Receptor 1; D054428:Chemokine CX3CL1 / Q000235:genetics; D020869:Gene Expression Profiling; D006624:Hippocampus / Q000378:metabolism; D007099:Imipramine / Q000494:pharmacology; D053583:Interleukin-1beta / Q000235:genetics; D015850:Interleukin-6 / Q000235:genetics; D000069056:Lurasidone Hydrochloride / Q000494:pharmacology; D008297:Male; D017397:Prefrontal Cortex / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D017208:Rats, Wistar; D019707:Receptors, Chemokine / Q000235:genetics; D013312:Stress, Physiological / Q000502:physiology*; D016212:Transforming Growth Factor beta / Q000235:genetics; D009281:Naphthalenes
chemical_list: D000081:Acetamides; D000928:Antidepressive Agents; D014150:Antipsychotic Agents; D039481:CD11b Antigen; D000073883:CX3C Chemokine Receptor 1; D054428:Chemokine CX3CL1; D007099:Imipramine; D053583:Interleukin-1beta; D015850:Interleukin-6; D000069056:Lurasidone Hydrochloride; D012333:RNA, Messenger; D019707:Receptors, Chemokine; D016212:Transforming Growth Factor beta; C516305:CX3CR1 protein, rat; C515540:Cx3cl1 protein, rat; C000594089:IL1B protein, rat; C577686:interleukin-6, mouse; C084711:agomelatine; D009281:Naphthalenes
keywords: Agomelatine: N-[2-(7-methoxynaphthalen-1-yl) ethyl]acetamide; Antidepressant; Chronic mild stress; Cytokines; Differential susceptibility; Imipramine: 3-(10,11-dihydro-5H-dibenzo[b,f]azepin-5-yl)-N,N-dimethylpropan-1-amine; Lurasidone: (3aR,4S,7R,7aS)-2-{(1R,2R)-2-[4-(1,2-benzisothiazol-3-yl) piperazin-1-ylmethyl] cyclohexylmethyl} hexahydro-4,7-methano-2H-isoindole-1,3-dione; Microglia activation; Sucrose intake