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 (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.
Pôle d'Innovation Thérapeutique Neuropsychiatrie Servier, Croissy-sur-Seine and Suresnes, France.
Fany
F
Panayi
Pôle d'Innovation Thérapeutique Neuropsychiatrie Servier, Croissy-sur-Seine and Suresnes, France. Electronic address: aurore.sors@servier.com.
Aurore
A
Sors
Pôle d'Innovation Thérapeutique Neuropsychiatrie Servier, Croissy-sur-Seine and Suresnes, France.
Lionel
L
Bert
Pôle d'Innovation Thérapeutique Neuropsychiatrie Servier, Croissy-sur-Seine and Suresnes, France.
Brigitte
B
Martin
Pôle d'Innovation Thérapeutique Neuropsychiatrie Servier, Croissy-sur-Seine and Suresnes, France.
Gaelle
G
Rollin-Jego
Pôle d'Innovation Thérapeutique Neuropsychiatrie Servier, Croissy-sur-Seine and Suresnes, France.
Rodolphe
R
Billiras
Pôle d'Innovation Thérapeutique Neuropsychiatrie Servier, Croissy-sur-Seine and Suresnes, France.
Isabelle
I
Carrié
Pôle d'Innovation Thérapeutique Neuropsychiatrie Servier, Croissy-sur-Seine and Suresnes, France.
Karine
K
Albinet
Pôle d'Innovation Thérapeutique Neuropsychiatrie Servier, Croissy-sur-Seine and Suresnes, France.
Laurence
L
Danober
Pôle d'Innovation Thérapeutique Neuropsychiatrie Servier, Croissy-sur-Seine and Suresnes, France.
Nathalie
N
Rogez
Pôle d'Innovation Thérapeutique Neuropsychiatrie Servier, Croissy-sur-Seine and Suresnes, France.
Jean-Yves
JY
Thomas
Pharmaness srl, Pula (CA), Italy.
Luigi
L
Pira
Biotrial, Rennes, France.
Valérie
V
Bertaina-Anglade
Pôle d'Innovation Thérapeutique Neuropsychiatrie Servier, Croissy-sur-Seine and Suresnes, France.
Pierre
P
Lestage
D000109:Acetylcholine / Q000378:metabolism; D000818:Animals; D053961:Azabicyclo Compounds / Q000494:pharmacology*; D001549:Benzamides / Q000494:pharmacology*; D003071:Cognition / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D054314:Drug Inverse Agonism; D005110:Extracellular Space / Q000187:drug effects / Q000378:metabolism; D006632:Histamine / Q000378:metabolism; D017442:Histamine Agonists / Q000494:pharmacology*; D054828:Histamine H3 Antagonists / Q000494:pharmacology*; D008297:Male; D017397:Prefrontal Cortex / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D018100:Receptors, Histamine H3 / Q000378:metabolism*; D012890:Sleep / Q000187:drug effects; D012919:Social Behavior; D065853:Spatial Learning / Q000187:drug effects
D053961:Azabicyclo Compounds; D001549:Benzamides; D017442:Histamine Agonists; D054828:Histamine H3 Antagonists; D018100:Receptors, Histamine H3; C000624696:S 38093; D006632:Histamine; D000109:Acetylcholine
Antagonist; Arousal; H3; Inverse agonist; Memory tests; Microdialysis