The neuronal histaminergic system in cognition

Aim of this review is to outline the relevance of the neuronal histaminergic system in cognition and to suggest potential therapeutic uses of histaminergic ligands for the treatment of cognitive disfunctions that accompany several neural disorders. Recent elegant data have shown that histaminergic neurones are one of the major excitatory sources of cortical activation, and maintain the brain awake allowing it to perform diverse functions such as emotional and cognitive activities. Indeed, both physiological and morphological characteristics of histaminergic neurones are coherent with such a role, as they project profusely to the whole brain and spinal cord and fire according to the behavioural state of the animal. Activation of histaminergic hetero- and/or autoreceptor subtypes modulate neurotransmitter release and neuronal firing frequency, presumably to different degrees and at different times during the elaboration of disparate behavioural responses. Therefore, the histaminergic system may provide a crucial mechanism to fine tuning brain activation for an adequate behavioural response. There is strong evidence of more direct effects of HA on cognitive processes: one of the mechanisms implicated seems to rest on the modulation of the cholinergic function, as systemic or intracerebral administrations of histaminergic compounds modulate acetylcholine release and affect memory. Furthermore, recent evidence suggests that activation of histaminergic receptors subtypes regulate neuronal intracellular signalling pathways such as MAPK cascade, and modulate plastic changes, which are two early cellular mechanisms likely involved in memory consolidation. Not surprisingly, both facilitatory and inhibitory effects of HA on learning and memory have been described, as it is likely that the memory modulating action of HA affects several brain regions differently. Studies of the physiology and function of the histaminergic system would not be possible without the tremendous effort of several investigators to synthesise ever more selective and more potent ligands for the histaminergic receptor subtypes. The recent discovery of constitutively active histaminergic receptors ads a further degree of complexity to the scenario, but at the same time broadens the expectations for new therapeutic approaches for the treatment of CNS dysfunctions.