Background: The histamine-3 receptor (H3R) may have a role in cognitive processes through its action as a presynaptic heteroreceptor inhibiting the release of glutamate in the brain. To explore this, we examined anterior cingulate cortex (ACC) and striatum H3R availability in patients with schizophrenia and characterized their relationships with glutamate levels in corresponding brain regions. Methods: We employed a cross-sectional study, recruiting 12 patients with schizophrenia and 12 healthy volunteers. Participants underwent positron emission tomography using the H3R-specific radio ligand [11C]MK-8278, followed by proton magnetic resonance spectroscopy to measure glutamate levels, recorded as Glu and Glx. Based on existing literature, the ACC and striatum were selected as regions of interest. Results: We found significant inverse relationships between tracer uptake and Glu (r = -0.66, P =. 02) and Glx (r = -0.62, P =. 04) levels in the ACC of patients, which were absent in healthy volunteers (Glu: r = -0.19, P =. 56, Glx: r = 0.10, P =. 75). We also found a significant difference in striatal (F1,20 = 6.00, P =. 02) and ACC (F1,19 = 4.75, P =. 04) Glx levels between groups. Conclusions: These results provide evidence of a regionally specific relationship between H3Rs and glutamate levels, which builds on existing preclinical literature. Our findings add to a growing literature indicating H3Rs may be a promising treatment target in schizophrenia, particularly for cognitive impairment, which has been associated with altered glutamate signaling.

Original languageEnglish
Article numberpyae011
JournalInternational Journal of Neuropsychopharmacology
Issue number3
Publication statusPublished - 1 Mar 2024


  • glutamate
  • histamine-3 receptor
  • neuroimaging
  • Schizophrenia


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