In vivo pharmacological profile of S 38093, a novel histamine H3 receptor inverse agonist

S 38093, a novel histamine H3 receptor inverse agonist, was tested in a series of neurochemical and behavioral paradigms designed to evaluate its procognitive and arousal properties.In intracerebral microdialysis studies performed in rats, S 38093 dose-dependently increased histamine extracellular levels in the prefrontal cortex and facilitated cholinergic transmission in the prefrontal cortex and hippocampus of rats after acute and chronic administration (10 mg/kg i.p.).Acute oral administration of S 38093 at 0.1 mg/kg significantly improved spatial working memory in rats in the Morris water maze test. The compound also displayed cognition enhancing properties in the two-trial object recognition task in rats, in a natural forgetting paradigm at 0.3 and 1 mg/kg p.o. and in a scopolamine-induced memory deficit situation at 3 mg/kg p.o. The property of S 38093 to promote episodic memory was confirmed in a social recognition test in rats at 0.3 and 1 mg/kg i.p.Arousal properties of S 38093 were assessed in freely moving rats by using electroencephalographic recordings: at 3 and 10 mg/kg i.p., S 38093 significantly reduced slow wave sleep delta power and induced at the highest dose a delay in sleep latency. S 38093 at 10 mg/kg p.o. also decreased the barbital-induced sleeping time in rats.Taken together these data indicate that S 38093, a novel H3 inverse agonist, displays cognition enhancing at low doses and arousal properties at higher doses in rodents.