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

Abstract

BackgroundThe 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.FindingsTen 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.ConclusionsHigher 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.

Revisiting Preclinical Observations of Several Histamine H3 Receptor Antagonists/Inverse Agonists in Cognitive Impairment, Anxiety, Depression, and Sleep–Wake Cycle Disorder

“…Interestingly, and in agreement with the latter observations, H1R antagonist but not H2R antagonist was found to impair working memory, while H3R antagonist/inverse agonist clobenpropit was reported to improve cognitive functions in preclinical studies in rodents ( Nakazato et al, 2000 ; Huang et al, 2004 ). In addition, and in a clinical study, the density of H3Rs in the dorsolateral prefrontal cortex was inversely correlated with performance in the working memory paradigm ( Ito et al, 2018 ).…”

The histamine system and cognitive function: An in vivo H3 receptor PET imaging study in healthy volunteers and patients with schizophrenia

“…Human studies provide further evidence for a potential role of the H3R in cognitive function and schizophrenia. A multi-modal study combining positron emission tomography (PET) with functional magnetic resonance imaging (fMRI) in healthy controls found a negative correlation between uptake of an H3R-specific tracer and the blood oxygen level dependent signal in the right dorsolateral prefrontal cortex (DLPFC), during a working memory task ( Ito et al, 2018 ). Additionally, a post-mortem study of patients with schizophrenia found an increase in H3R expression in the DLPFC compared to healthy controls and reported a positive correlation between receptor expression and psychotic symptom severity ( Jin et al, 2009 ).…”

Pharmacokinetic Modeling of [11C]GSK-189254, PET Tracer Targeting H3 Receptors, in Rat Brain

“…15 Such neurotransmitters are essential for the normal operation of the brain. 5,16,17 Evidence from animal studies and postmortem human brain analysis suggests that the H 3 receptor is involved in several normal physiological processes and diseases or disorders of the brain, such as cognition, 5,18 anxiety, 19 sleep disorders, 16 obesity, 20 Alzheimer's disease, Parkinson's disease, schizophrenia, attention deficit hyperactive disorder, and epilepsy. 16,21−23 Pharmacological studies have shown that blocking the constitutive activity of H 3 receptors by the administration of an inverse agonist or antagonist enhances the release of histamine and may have therapeutic relevance.…”

“…Histamine release in the mammalian brain shows a diurnal rhythm, with a low rate during sleep and a high rate during waking, active state. , H 3 receptors can also form heteroreceptors, which can modulate the release of other neurotransmitters, including acetylcholine, − dopamine, , noradrenaline, , serotonin, , and gamma-aminobutyric acid . Such neurotransmitters are essential for the normal operation of the brain. ,, …”