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Anti-inflammatory drugs prevent memory and hippocampal plasticity deficits following initial binge-like alcohol exposure in adolescent male rats

Abstract

Rationale

Binge drinking during adolescence impairs learning and memory on the long term, and many studies suggest a role of neuroinflammation. However, whether neuroinflammation occurs after the very first exposures to alcohol remains unclear, while initial alcohol exposure impairs learning for several days in male rats.

Objectives

To investigate the role of neuroinflammation in the effects of only two binge-like episodes on learning and on neuronal plasticity in adolescent male rat hippocampus.

Methods

Animals received two ethanol i.p. injections (3 g/kg) 9 h apart. Forty-eight hours later, we recorded long-term depression (LTD) and potentiation (LTP) in CA1 area of hippocampus slices. In isolated CA1, we measured immunolabelings for microglial activation and Toll-like receptor 4 (TLR4) and mRNA levels for several cytokines.

Results

Forty-eight hours after the two binges, rats performed worse than control rats in novel object recognition, LTD was reduced, LTP was increased, and excitatory neurotransmission was more sensitive to an antagonist of the GluN2B subunit of the NMDA receptor. Exposure to ethanol with minocycline or indomethacin, two anti-inflammatory drugs, or with a TLR4 antagonist, prevented all effects of ethanol. Immunolabelings at 48 h showed a reduction of neuronal TLR4 that was prevented by minocycline pretreatment, while microglial reactivity was undetected and inflammatory cytokines mRNA levels were unchanged.

Conclusion

Two binge-like ethanol exposures during adolescence in rat involved neuroinflammation leading to changes in TLR4 expression and in GluN2B functioning inducing disturbances in synaptic plasticity and cognitive deficits. Anti-inflammatory drugs are good candidates to prevent brain function and memory deficits induced by few binge-drinking episodes.

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Acknowledgements

CD and CM are PhD students supported by the Région Hauts-de-France, University of Picardy Jules Verne and the Ministry of French Research and Education. GF is supported by ERA-NET program: Psi-Alc (FKZ: 01EW1908)

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Correspondence to Olivier Pierrefiche.

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Deschamps, C., Uyttersprot, F., Debris, M. et al. Anti-inflammatory drugs prevent memory and hippocampal plasticity deficits following initial binge-like alcohol exposure in adolescent male rats. Psychopharmacology 239, 2245–2262 (2022). https://doi.org/10.1007/s00213-022-06112-w

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  • DOI: https://doi.org/10.1007/s00213-022-06112-w

Keywords

  • Minocycline
  • Indomethacin
  • Ethanol
  • Long-term depression
  • TLR4
  • TAK-242
  • GluN2B