Functional studies have recently demonstrated that activation of the central histaminergic system alters CNS functions in both behavioral and homeostatic contexts, which include sleep and wakefulness, learning and memory, anxiety, locomotion, feeding and drinking, and neuroendocrine regulation. These actions are achieved through interactions with other neurotransmitter systems, and the interplay between histaminergic neurons and other neurotransmitter systems are becoming clear. Endocannabinoids and histaminergic neurons exert complex actions on neurotransmitter networks involved in cognitive processes, locomotion, appetite and, interestingly, they command several, similar behavioural states. Until recently, though, no information was available on the possible interactions between these two systems. Recently we demonstrated that agonists of the cannabinoid receptor (CB)1 augment histamine release in rat brain regions of freely moving animals involved in the acquisition and consolidation of memories and in the control of locomotion. In these areas, augmented histamine release improves rats performance in cognitive tests whereas cannabinoids have deleterious effects on cognitive processes. These results are apparently counterintuitive, because augmented histamine release is also an indicator of stress and it is conceivable that protracted occupancy of CB1 receptors, as produced by administering cannabinoid agonists, disrupts the spatiotemporal specificity of histamine release in different brain regions, contributing to maladaptive behavioral responses. The hyperhistaminergic state produced by cannabinoids, though, may have relevance in controlling food related behavior. Brain histamine is involved in feeding physiology by integrating inputs from neurotransmitters and hormones that drive or inhibit feeding. Endogenous cannabinoids regulate satiety and body weight and recent evidence indicates that histamine drives the appetitive rather than the consummatory phase of feeding. In this regard, preliminary data in our laboratory indicate that oleylethanolamide, a peripherally generated endocannabinoid that signals satiety, decreases histamine release from the hypothalamus. These results are better reconciled with the hypothesis of a histaminergic system engaged in the preparatory phases of food condumption.

Hence, understanding in what circumstances endocannabinoids are released and activate histaminergic cells warrants further investigations and may provide interesting hints to develop new therapeutic strategies in the treatment of food intake disorders.