Pitolisant disrupts memory consolidation and hippocampal synaptic plasticity: Impaired excitability and long-term...

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.

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.

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.

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.