title: 3α5β-Pregnanolone glutamate, a use-dependent NMDA antagonist, reversed spatial learning deficit in an animal model of schizophrenia.
abstract: Neuroactive steroids modulate receptors for neurotransmitters in the brain and thus might be efficacious in the treatment of various diseases of the central nervous system such as schizophrenia. We have designed and synthetized a novel use-dependent NMDA receptor antagonist 3α5β-pregnanolone glutamate (3α5β-P-Glu). In this study, we evaluate procognitive properties of 3α5β-P-Glu in an animal model of schizophrenia induced by systemic application of MK-801. The procognitive properties were evaluated using active place avoidance on a rotating arena (Carousel maze). We evaluated effects of 3α5β-P-Glu on the avoidance, on locomotor activity, and anxiety. 3α5β-P-Glu alone altered neither spatial learning nor locomotor activity in control animals. In the model animals, 3α5β-P-Glu reversed the MK-801-induced cognitive deficit without reducing hyperlocomotion. The highest dose of 3α5β-P-Glu also showed anxiolytic properties. Taken together, 3α5β-P-Glu may participate in the restoration of normal brain functioning and these results may facilitate the development of new promising drugs improving cognitive functioning in schizophrenia.
authors: Institute of Physiology, Academy of Sciences of the Czech Republic, Czech Republic.
authors: Karel
authors: K
authors: Vales
authors: Lukas
authors: L
authors: Rambousek
authors: Kristina
authors: K
authors: Holubova
authors: Jan
authors: J
authors: Svoboda
authors: Vera
authors: V
authors: Bubenikova-Valesova
authors: Hana
authors: H
authors: Chodounska
authors: Ladislav
authors: L
authors: Vyklicky
authors: Ales
authors: A
authors: Stuchlik
mesh_terms: D000818:Animals; D001007:Anxiety / Q000150:complications / Q000188:drug therapy; D001362:Avoidance Learning / Q000187:drug effects; D003072:Cognition Disorders / Q000150:complications / Q000188:drug therapy*; D004195:Disease Models, Animal; D016291:Dizocilpine Maleate; D004305:Dose-Response Relationship, Drug; D005971:Glutamates / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D011280:Pregnanolone / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D020318:Rats, Long-Evans; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*; D012559:Schizophrenia / Q000150:complications / Q000188:drug therapy*; D012565:Schizophrenic Psychology; D014828:Vocalization, Animal / Q000187:drug effects
chemical_list: C571988:20-oxo-5-pregnan-3-yl-glutamyl 1-ester; D005971:Glutamates; D016194:Receptors, N-Methyl-D-Aspartate; D016291:Dizocilpine Maleate; D011280:Pregnanolone