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1 The effects of histamine and agents acting at histamine receptors on spontaneous and 100 mM K+-evoked release of acetylcholine, measured by microdialysis from the cortex of freely moving rats, and on cognitive tests are described. 2 Local administration of histamine (0.1-100 pM) failed to affect spontaneous but inhibited 100 mM K+-stimulated release of acetylcholine up to about 50%. The H3 receptor agonists (R)-ca-methylhistamine (RAMH) (0.1-10 yM), imetit (0.01-10 yM) and immepip (0.01-10 yM) mimicked the effect of histamine.3 Neither 2-thiazolylethylamine (TEA), an agonist showing some selectivity for H, receptors, nor the H2 receptor agonist, dimaprit, modified 100 mM K+-evoked release of acetylcholine. 4 The inhibitory effect of 100 pM histamine was completely prevented by the highly selective histamine H3 receptor antagonist, clobenpropit but was resistant to antagonism by triprolidine and cimetidine, antagonists at histamine H, and H2 but not H3 receptors.5 The H3 receptor-induced inhibition of K+-evoked release of acetylcholine was fully sensitive to tetrodotoxin (TTX).6 The effects of intraperitoneal (i.p.) injection of imetit (5 mg kg-') and RAMH (5 mg kg-') were tested on acetylcholine release and short term memory paradigms. Both drugs reduced 100 mM K+-evoked release of cortical acetylcholine, and impaired object recognition and a passive avoidance response.7 These observations provide the first evidence of a regulatory role of histamine H3 receptors on cortical acetylcholine release in vivo. Moreover, they suggest a role for histamine in learning and memory and may have implications for the treatment of degenerative disorders associated with impaired cholinergic function.

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Key factors driving eating behavior are hunger and satiety, which are controlled by a complex interplay of central neurotransmitter systems and peripheral stimuli. The lipid-derived messenger oleoylethanolamide (OEA) is released by enterocytes in response to fat intake and indirectly signals satiety to hypothalamic nuclei. Brain histamine is released during the appetitive phase to provide a high level of arousal in anticipation of feeding, and mediates satiety. However, despite the possible functional overlap of satiety signals, it is not known whether histamine participates in OEA-induced hypophagia. Using different experimental settings and diets, we report that the anorexiant effect of OEA is significantly attenuated in mice deficient in the histamine-synthesizing enzyme histidine decarboxylase (HDC-KO) or acutely depleted of histamine via interocerebroventricular infusion of the HDC blocker α-fluoromethylhistidine (α-FMH). α-FMH abolished OEA-induced early occurrence of satiety onset while increasing histamine release in the CNS with an H 3 receptor antagonist-increased hypophagia. OEA augmented histamine release in the cortex of fasted mice within a time window compatible to its anorexic effects. OEA also increased c-Fos expression in the oxytocin neurons of the paraventricular nuclei of WT but not HDC-KO mice. The density of c-Fos immunoreactive neurons in other brain regions that receive histaminergic innervation and participate in the expression of feeding behavior was comparable in OEA-treated WT and HDC-KO mice. Our results demonstrate that OEA requires the integrity of the brain histamine system to fully exert its hypophagic effect and that the oxytocin neuron-rich nuclei are the likely hypothalamic area where brain histamine influences the central effects of OEA.histamine receptors | behavioral satiety sequence | BSS | paraventricular hypothalamic nuclei | PVN E ating behavior is regulated by central neurotransmitter systems and peripheral stimuli that interact to change the behavioral state and concur to alter homeostatic aspects of appetite and energy expenditure. The fatty acid amide oleoylethanolamide (OEA) is released by the small intestine in a stimulus-dependent manner and suppresses food intake by activating peroxisome proliferator-activated receptor-α (PPAR-α) (1). Systemic administration of OEA induces c-Fos mRNA expression through the vagus nerve to the nucleus of the solitary tract (NST), supraoptic nuclei (SON), and paraventricular hypothalamic nuclei (PVN) and increases the expression of oxytocin (2, 3), which is involved in the central coordination of homeostatic signals and feeding behavior (4). However, it is not known whether OEA recruits other neurotransmitter systems in the brain to reduce food intake. Histaminergic neurons are clustered in the hypothalamic tuberomammillary nuclei (TMN). They send projections organized in functionally distinct circuits impinging on different brain regions (5), and their firing frequency changes according to the behavioral state (6). Brain histamin...