Selective upregulation of histamine H3 receptor expression in postmortem dorsolateral prefrontal cortex tissue in compulsive disorders: a pilot study
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1Department of Clinical Neurosciences and Mental Health, Faculty of Medicine, University of Porto, Portugal; RISE-HEALTH (Neurosciences), Department of Clinical Neurosciences and Mental Health, Faculty of Medicine, University of Porto, Portugal; Department of Neuroimaging, Institute of Psychiatry, Psychology and Neuroscience(,) King's College London, UK.
Background:
Compulsive disorders encompass clinically distinct conditions involving repetitive behaviours and impaired behavioural control, with partially overlapping neurobiological mechanisms. Although prevailing models emphasise cortico-striato-thalamo-cortical circuitry and monoaminergic signalling, their molecular mechanisms remain incompletely understood. The brain histamine system, particularly the histamine H3 receptor (H3R), modulates cortical signalling through presynaptic regulation of histamine and other neurotransmitters but remains underexplored in compulsive disorders.
Methods:
We conducted a hypothesis-driven transcriptomic analysis of postmortem dorsolateral prefrontal cortex (DLPFC) samples from individuals with compulsive disorders, comprising obsessive-compulsive disorder (OCD), obsessive-compulsive personality disorder (OCPD), and tic/Tourette syndrome, and non-psychiatric controls, using publicly available microarray data. Core histamine pathway genes were examined using regression models adjusted for demographic, postmortem, and technical covariates. HRH3 was designated as the primary gene of interest, with multiple-testing correction applied to secondary pathway genes.
Results:
HRH3 expression was increased in the DLPFC of individuals with compulsive disorders relative to controls (η² = 0.035, p = 0.033), with anecdotal Bayesian evidence for a group effect (BF₁₀ = 2.96). No other histamine pathway gene differed significantly after multiple-testing correction. HRH4 nevertheless showed an exploratory signal with anecdotal Bayesian evidence (BF₁₀ = 1.20), while Bayesian analyses of the remaining genes favoured the null model.
Conclusions:
These findings provide preliminary evidence for increased HRH3 expression in the DLPFC in a diagnostically heterogeneous compulsive-disorders sample, alongside an exploratory HRH4 signal. The functional and causal significance of HRH3 upregulation cannot be determined from bulk-tissue transcriptomic data. Independent replication and cell-type-resolved, receptor-level, and functional studies are required to clarify the role of histaminergic mechanisms in compulsive disorders.
