Antidepressants of different classes cause distinct behavioral and brain pro- and anti-inflammatory changes in mice submitted to an inflammatory model of depression

•LPS induced despair-like behavior, anhedonia and impaired motivation/self-care.•The ADs, AMI (tricyclic), ESC (SSRI), TCP (MAOI) and VORT (multimodal drug) prevented despair-like behavior.•Only VORT rescued impaired self-care behavior.•All ADs prevented LPS-induced rise of brain pro-inflammatory cytokines (IL-1β and IL-6) and Th1 cytokines (TNFα and IFNγ).•Only VORT increased brain levels of IL-4. Depressed patients present increased plasma levels of lipopolysaccharide (LPS) and neuroinflammatory alterations. Here, we determined the neuroimmune effects of different classes of ADs by using the LPS inflammatory model of depression. Male rats received amitriptyline (AMI) a tricyclic, S-citalopram (ESC) a selective serotonin reuptake inhibitor, tranylcypromine (TCP) a monoamine oxidase inhibitor, vortioxetine (VORT) a multimodal AD or saline for ten days. One-hour after the last AD administration, rats were exposed to LPS 0.83 mg/kg or saline and 24 h later were tested for depressive-like behavior. Plasma corticosterone, brain levels of nitrite, pro- and anti-inflammatory cytokines, phospho-cAMP Response Element-Binding Protein (CREB) and nuclear factor (NF)-kB p 65 were determined. LPS induced despair-like, impaired motivation/self-care behavior and caused anhedonia. All ADs prevented LPS-induced despair-like behavior, but only VORT rescued impaired self-care behavior. All ADs prevented LPS-induced increase in brain pro-inflammatory cytokines [interleukin (IL)-1β and IL-6] and T-helper 1 cytokines [tumor necrosis factor (TNF)-α and interferon-γ]. VORT increased striatal and hypothalamic IL-4 levels. All ADs prevented LPS-induced neuroendocrine alterations represented by increased levels of hypothalamic nitrite and plasma corticosterone response. VORT and ESC prevented LPS-induced increase in NF-kBp65 hippocampal expression, while ESC, TCP and VORT, but not IMI, prevented the alterations in phospho-CREB expression. LPS model helps to understand depression in a subset of depressed patients with immune activation. The levels of neurotransmitters were not determined. This study provides new evidence for the immunomodulatory effects of ADs, and shows a possible superior anti-inflammatory profile of TCP and VORT.