ACUTE INFLAMMATION INDUCED BY ULTRA-LOW DOSE LIPOPOLYSACCHARIDE AND RESTRAINT STRESS IMPROVE POSITIVE SYMPTOM-LIKE BEHAVIOR IN A MOUSE MODEL OF SCHIZOPHRENIA BY DIFFERENT MECHANISMS
Authors: Shinohara *Rikuto Christopher , Ishikawa Shuhei , Ito Koki , Tonosaki Mariko , Hashimoto Naoki , Kusumi Ichiro 
Published: February 2025

Abstract

Background
It has been reported that patients with schizophrenia have increased inflammatory cytokines and activated microglia1,2. These findings support the inflammation hypothesis that inflammation exacerbates schizophrenia symptoms. Brain inflammation has been focused on as a novel therapeutic target. However, the efficacy of anti-inflammatory drugs for schizophrenia has not been established3.

Aims and objectives
The effects of inflammation on schizophrenia may vary based on the intensity, type, and duration. In this study, we aimed to investigate the effects and mechanisms of acute brain inflammation on positive symptoms using an animal model of schizophrenia.

Method
We created a model animal by repeatedly administering 1 mg/kg of methamphetamine (METH) to C57BL/6J male mice. Following a 1-week withdrawal period, METH was readministered to induce behavioral sensitization, manifested as increased locomotor activity, which served as a surrogate behavior of positive symptoms. After behavioral sensitization was induced, changes in behavior and striatal dopamine (DA) concentrations were measured under inflammatory conditions induced by intraperitoneal administration of 1 μ g/kg of lipopolysaccharide (LPS) or 2-hour restraint stress (RS) exposure. The LPS dose was preliminarily determined to be comparable to the blood concentration of tumor necrosis factor (TNF-α) in patients with schizophrenia4. LPS administration and RS exposure were used to simulate peripheral bacterial infection and psychological stress observed in clinical settings, respectively. To identify the mechanisms of behavioral changes, inhibitors of Toll-like receptor 4 (TLR4), TNF-α, and cyclooxygenase (COX)-2 were administered before inflammation was induced. Changes in striatal DA levels were measured using in vivo microdialysis. In addition, tissues were collected and subjected to biochemical and pathological analysis.

Results
Expression of behavioral sensitization was suppressed in both the LPS and RS groups, and this response was reversed by TLR4 inhibitor. In addition, the suppression of behavioral sensitization by LPS administration was reversed by COX-2 inhibitor, and the suppression of behavioral sensitization by RS exposure was reversed by anti-TNF-α antibody. METH re-administration caused an increase in striatal DA level in both the control and LPS groups. However, in the RS group, the increase in striatal DA level was significantly attenuated compared to the control group, and this response was reversed by anti-TNF-α antibody. In biochemical analysis, striatal TNF-α mRNA level was elevated in the RS group but not in the LPS group. In pathological analysis, neither the RS nor the LPS groups showed any change in microglial morphology or expression of activation markers compared to the control group.

Discussions & Conclusion
Mild acute brain inflammation may improve positive symptoms of schizophrenia. Our findings are contrary to the brain inflammation hypothesis but consistent with the well-known clinical observation that acute bacterial infection temporarily alleviates hallucinations and delusions in patients with schizophrenia5,6. Furthermore, the results indicate that the mechanism of action may differ depending on the cause of inflammation. Our findings provide new insight into the inflammation hypothesis and may help identify target patients for whom anti-inflammatory drugs are genuinely effective.

References
Miller, B. J. et al. 2011. Meta-analysis of cytokine alterations in schizophrenia: clinical status and antipsychotic effects. Biol Psychiatry, 70, 663-71.
Bloomfield, P. S. et al. 2016. Microglial Activity in People at Ultra High Risk of Psychosis and in Schizophrenia: An [(11)C]PBR28 PET Brain Imaging Study. Am J Psychiatry, 173, 44-52.
Cakici, N. et al. 2019. An update on the efficacy of anti-inflammatory agents for patients with schizophrenia: a meta-analysis. Psychol Med, 49, 2307-2319.
Di Nicola, M. et al. 2013. Serum and gene expression profile of cytokines in first-episode psychosis. Brain Behav Immun, 31, 90-5.
Sani, G. et al. 2007. A case of resolution of an acute psychotic episode after high fever. CNS Spectr, 12, 447-50.
Zuschlag, Z. D. et al. 2016. Pyrotherapy for the Treatment of Psychosis in the 21st Century: A Case Report and Literature Review. J Psychiatr Pract, 22, 410-5.