Therefore, our observations showed that the H3R antagonist E169 was capable of counteracting cognitive deficits by simultaneously modulating barin HA and several other brain neurotransmitters by functioning as antagonist on H3 auto- and hetero-receptors and by mitigating disturbances in hippocampal protein levels in the PI3K/AKT/GSK-3β signaling pathway in the context of MK801-induced amnesia in mice, without any modulating effects on locomotor activity or anxiety-like behaviors of tested animals. Here, AKT1 is linked to Cognitive impairment.