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Background: Alterations in the innate immune/inflammatory system have been proposed to underlie the pathophysiology of psychotic disease, but the mechanisms implicated remain elusive. The main agents of the innate immunity are the family of toll-like receptors (TLRs), which detect circulating pathogen-associated molecular patterns and endogenous damage-associated molecular patterns (DAMPS). Current antipsychotics are able to modulate pro- and anti-inflammatory pathways, but their actions on TLRs remain unexplored. Methods: This study was conducted to elucidate the effects of paliperidone (1mg/Kg i.p.) on acute (6 hours) and chronic (6 hours/day during 21 consecutive days) restraint stress–induced TLR-4 pathway activation and neuroinflammation, and the possible mechanism(s) related (bacterial translocation and/or DAMPs activation). The expression of the elements of a TLR-4-dependent proinflammatory pathway was analyzed at the mRNA and protein levels in prefrontal cortex samples. Results: Paliperidone pre-treatment prevented TLR-4 activation and neuroinflammation in the prefrontal cortices of stressed rats. Regarding the possible mechanisms implicated, paliperidone regulated stress-induced increased intestinal inflammation and plasma lipopolysaccharide levels. In addition, paliperidone also prevented the activation of the endogenous activators of TLR-4 HSP70 and HGMB-1. Conclusions: Our results showed a regulatory role of paliperidone on brain TLR-4, which could explain the therapeutic benefits of its use for the treatment of psychotic diseases beyond its effects on dopamine and serotonin neurotransmission. The study of the mechanisms implicated suggests that gut-increased permeability, inflammation, and bacterial translocation of Gram-negative microflora and HSP70 and HGMB1 expression could be potential adjuvant therapeutic targets for the treatment of psychotic and other stress-related psychiatric pathologies. [ABSTRACT FROM AUTHOR]