- Acute low-dose LPS (1 μg·kg−1) and single 2-hour restraint stress significantly attenuate methamphetamine (1 mg·kg−1) behavioural sensitisation without other behavioural abnormalities.
- Attenuation depends on TLR4 signalling; LPS effect requires COX-2, whereas restraint stress involves microglial TNF-α, whose intrastriatal administration reproduces attenuation.
- Restraint stress, but not LPS, reduced striatal extracellular dopamine, supporting acute inflammation's modulation of methamphetamine-relevant processes and implicating TNF-α as candidate.
Br J Pharmacol. 2026 Oct 5. doi: 10.1111/bph.70697. Online ahead of print.
ABSTRACT
BACKGROUND AND PURPOSE: Clinical observations suggest that acute inflammatory states transiently modulate psychotic symptoms. However, animal models often use relatively strong inflammatory stimuli, and the effects of low-intensity acute inflammation on psychostimulant-induced behavioural sensitisation remain unclear.
EXPERIMENTAL APPROACH: We examined whether relatively low-intensity acute inflammatory stimuli attenuate behavioural sensitisation in methamphetamine (METH)-sensitised male mice, a model of psychostimulant-induced psychosis. We used a repeated METH (1 mg·kg-1)-sensitised model to evaluate the effects of acute inflammation on behavioural sensitisation. Acute inflammation was induced via two methods: lipopolysaccharides (LPS; 1 μg·kg-1) to mimic peripheral immune activation and restraint stress (RS; single 2-h exposure) to induce an acute stress-related neuroimmune response. LPS doses were adjusted with reference to the magnitude of peripheral cytokine elevation reported in patients, and RS was applied in short single sessions to avoid excessive inflammation.
KEY RESULTS: LPS and RS significantly attenuated behavioural sensitisation, without inducing other detectable behavioural abnormalities. The behavioural effects of both LPS and RS were sensitive to toll-like receptor 4 (TLR4) inhibition. LPS-mediated attenuation was sensitive to cyclooxygenase-2 (COX-2) inhibition, whereas RS-mediated attenuation involved tumour necrosis factor-α (TNF-α). TNF-α expression was increased in brain-isolated microglia following RS, and intrastriatal TNF-α reproduced the attenuation of behavioural sensitisation. RS, but not LPS, significantly reduced the striatal extracellular dopamine levels.
CONCLUSIONS AND IMPLICATIONS: Acute inflammation attenuated METH-induced behavioural sensitisation following low-dose LPS and acute RS. These findings suggest that acute inflammation may modulate processes relevant to METH-induced psychosis and highlight TNF-α as a candidate for further investigation.
PMID:42833884 | DOI:10.1111/bph.70697
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