Histamine and the Global Regulation of Cortico-Striato-Thalamo-Cortical Circuits in Obsessive-Compulsive Disorders

Obsessive–compulsive disorder (OCD) is a disabling psychiatric condition traditionally framed in terms of serotonergic dysfunction and aberrant cortico–striato–thalamo–cortical (CSTC) circuitry. While influential, these models do not fully explain key features of OCD, including cognitive rigidity, exaggerated error monitoring, impaired resolution of uncertainty, and the persistence of compulsive behaviours despite preserved insight. Here, we propose that the brain histamine system represents an under-recognised neuromodulatory contributor to OCD, with the capacity to shape circuit dynamics rather than encode obsessional content.Histaminergic neurons arising from the tuberomammillary nucleus project diffusely across cortical and subcortical regions implicated in OCD, positioning histamine as a regulator of neural gain, arousal, and learning flexibility at the systems level. Integrating evidence from neuroanatomy, receptor pharmacology, circuit neuroscience, genetics, and computational psychiatry, we outline a framework in which histamine influences the stability and adaptability of CSTC loops. Receptor-specific actions, particularly via presynaptic H₃ receptors that regulate histamine and other neuromodulators, provide a mechanism by which histaminergic signalling may bias inhibitory control and habitual responding.From a computational perspective, histamine is well suited to modulate the trade-off between stability and flexibility in learning under uncertainty, a process increasingly implicated in OCD. We conclude by outlining testable hypotheses and experimental strategies to evaluate histaminergic modulation of CSTC dynamics and its relevance for circuit-informed investigation in OCD.