Pitolisant disrupts memory consolidation and hippocampal synaptic plasticity: Impaired excitability and long-term potentiation in the CA1 area

Articles in Press

Document Type : Original Article

Authors

1 Department of Plant and Animal Biology, Faculty of Biological Science and Technology, University of Isfahan, Isfahan, Iran

2 Department of Animal Biology, Faculty of Biological Sciences, Kharazmi University, Tehran, Iran

3 Department of Psychology, Faculty of Arts and Science, University of Toronto, St. George Street, Toronto, Ontario, M5S3G3, Canada

10.22038/ijbms.2026.90953.19621

Abstract

Objective(s): The histaminergic system plays a vital role in memory function, but the underlying cellular and circuit mechanisms remain poorly understood. Pitolisant, an inverse agonist of the histamine H3 receptor (H3R), is widely used in the treatment of narcolepsy and has shown potential anti-seizure effects. However, its impact on memory and synaptic plasticity is unclear. This study investigated the effects of intracerebroventricular administration of pitolisant on passive avoidance memory consolidation. Meanwhile, the impact of pitolisant on synaptic excitability, short-term plasticity, and long-term potentiation (LTP) in the hippocampus was investigated. 
Materials and Methods: Adult male Wistar rats received pitolisant (10 or 100 µg/rat; ICV) or saline immediately after training in the passive avoidance apparatus to test memory consolidation. Meanwhile, pitolisant was microinjected into the CA1 region to assess its targeted effects. Subsequently, field potentials were recorded to measure fundamental synaptic properties: input-output (I/O) function, paired-pulse facilitation, and LTP function. 
Results: Pitolisant significantly impaired memory consolidation. It also reduced the fEPSP slope in I/O function and paired-pulse facilitation, suggesting impaired synaptic excitability and increased presynaptic inhibition. Additionally, LTP was reduced in pitolisant-treated groups, indicating disrupted long-term plasticity. 
Conclusion: These findings highlight a potential inhibitory effect of pitolisant on passive-avoidance memory consolidation in healthy rats and on hippocampal synaptic function, raising concerns about its use in neurological disorders.

Keywords

Main Subjects

References

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Iranian Journal of Basic Medical Sciences

Articles in Press, Accepted Manuscript
Available Online from 06 January 2026

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