Acute lipopolysaccharide (LPS) treatment in male mice exacerbates dextroamphetamine-induced hyperlocomotion without...

Immune system activation contributes to the pathophysiology of multiple psychiatric disorders, including schizophrenia. A substantial subgroup of people with schizophrenia are characterised by increased central and peripheral cytokine levels, and a tendency towards more severe symptoms and dopamine-targeting antipsychotic treatment resistance. Previous studies have shown an association between inflammation and increased dopamine turnover as well as increased sensitivity to stimulants such as dextroamphetamine (DEX). However, thus far, no study has demonstrated that increased dopamine release is responsible for stimulant-induced psychosis-relevant behaviour during inflammatory states. This calls the role of dopamine in inflammatory schizophrenia into question. To test whether inflammation-exacerbated behavioural responses are driven by dopaminergic mechanisms, we used a multimodal approach in a mouse model combining intraperitoneally (i.p) administered DEX (0.5 mg kg^-1)-evoked open-field behaviour, in vivo dopamine monitoring, molecular and c-Fos profiling of dopamine-relevant brain regions using qPCR and immunostaining. We measured blood-brain barrier permeability and central DEX exposure in brain after DEX via fluorescein uptake and liquid chromatography-mass spectrometry. To induce inflammation, we administered two doses of lipopolysaccharide (LPS, 0.83 mg kg^-1i.p.) or phosphate-buffered saline (PBS i.p.) to male C57BL/6J mice (n = 158) 24 h apart and measured neuro-behavioural outcomes from 72 to 74 h. Sickness responses, including body mass change, body condition, and inactivity, were assessed longitudinally to confirm resolution of LPS-induced sickness prior to DEX-evoked behavioural testing. In parallel, inflammatory and kynurenine pathway markers were measured in the ventral midbrain and striatum to determine whether persistent neuroinflammatory and metabolic alterations remained after sickness behaviours had subsided and could contribute to exaggerated psychosis-relevant behavioural responses. We found that LPS-treated mice exhibited significantly greater DEX-evoked locomotor activity than PBS-treated controls, despite no differences in whole-brain DEX concentrations. Neuronal activation, indexed by c-Fos⁺ cell density, was significantly increased in both the dorsal and ventral striatum of LPS-treated mice. However, real-time ventral striatal dopamine dynamics assessed using fibre photometry, together with dopamine-related mRNA expression in the ventral midbrain and striatum, did not differ between treatment groups. In contrast, mRNA levels of inflammatory markers (IL-1β, TNF, NF-κB2) were upregulated. To explore alternative pathways through which behaviour may be affected, we measured mRNA levels of enzymes in the inflammation-induced kynurenine pathway. We found that dysregulation of mRNA levels of all three measured kynurenine pathway enzymes (TDO2, KAT II, KMO) was present in the LPS group following behavioural testing. Taken together, our findings suggest that while inflammation augments psychosis-relevant mouse behaviour, dopamine may not be the key driver.