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

• Published in: European journal of pharmacology 2017-05, Vol.803, p.1-10
• Main Authors: Panayi, Fany, Sors, Aurore, Bert, Lionel, Martin, Brigitte, Rollin-Jego, Gaelle, Billiras, Rodolphe, Carrié, Isabelle, Albinet, Karine, Danober, Laurence, Rogez, Nathalie, Thomas, Jean-Yves, Pira, Luigi, Bertaina-Anglade, Valérie, Lestage, Pierre
• Format: Article
• Language: English
• Subjects: Acetylcholine - metabolism; Animals; Antagonist; Arousal; Azabicyclo Compounds - pharmacology; Benzamides - pharmacology; Cognition - drug effects; Dose-Response Relationship, Drug; Drug Inverse Agonism; Extracellular Space - drug effects; Extracellular Space - metabolism; Histamine - metabolism; Histamine Agonists - pharmacology; Histamine H3 Antagonists - pharmacology; Inverse agonist; Male; Memory tests; Microdialysis; Prefrontal Cortex - cytology; Prefrontal Cortex - drug effects; Prefrontal Cortex - metabolism; Rats; Rats, Wistar; Receptors, Histamine H3 - metabolism; Sleep - drug effects; Social Behavior; Spatial Learning - drug effects
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/j.ejphar.2017.03.008

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 (10mg/kg i.p.). Acute oral administration of S 38093 at 0.1mg/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 1mg/kg p.o. and in a scopolamine-induced memory deficit situation at 3mg/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 1mg/kg i.p. Arousal properties of S 38093 were assessed in freely moving rats by using electroencephalographic recordings: at 3 and 10mg/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 10mg/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.