Histamine H₃ receptor density is negatively correlated with neural activity related to working memory in humans

Background: The histamine H₃ receptor is regarded as a drug target for cognitive impairments in psychiatric disorders. H₃ receptors are expressed in neocortical areas, including the prefrontal cortex, the key region of cognitive functions such as working memory. However, the role of prefrontal H₃ receptors in working memory has not yet been clarified. Therefore, using functional magnetic resonance imaging (fMRI) and positron emission tomography (PET) techniques, we aimed to investigate the association between the neural activity of working memory and the density of H₃ receptors in the prefrontal cortex. Findings: Ten healthy volunteers underwent both fMRI and PET scans. The N-back task was used to assess the neural activities related to working memory. H₃ receptor density was measured with the selective PET radioligand [¹¹C] TASP457. The neural activity of the right dorsolateral prefrontal cortex during the performance of the N-back task was negatively correlated with the density of H₃ receptors in this region. Conclusions: Higher neural activity of working memory was associated with lower H₃ receptor density in the right dorsolateral prefrontal cortex. This finding elucidates the role of H₃ receptors in working memory and indicates the potential of H₃ receptors as a therapeutic target for the cognitive impairments associated with neuropsychiatric disorders.