title: Clozapine and glycinamide prevent MK-801-induced deficits in the novel object recognition (NOR) test in the domestic rabbit (Oryctolagus cuniculus).
abstract: Studies in humans indicate that acute administration of sub-anesthetic doses of ketamine, an NMDA receptor antagonist, provokes schizophrenic-like symptoms in healthy volunteers, and exacerbates existing symptoms in individuals with schizophrenia. These and other findings suggest that NMDA receptor hypofunction might participate in the pathophysiology of schizophrenia, and have prompted the development of rodent pharmacological models for this disorder based on acute or subchronic treatment with NMDA receptor antagonists, as well as the development of novel pharmacotherapies based on increasing extrasynaptic glycine concentrations. In the present study, we tested whether acute hyperlocomotory behavior and/or deficits in the novel object recognition (NOR) task, induced in male rabbits by the acute subcutaneous (s.c.) administration of MK-801 (0.025 and 0.037 mg/kg s.c., respectively), were prevented by prior administration of the atypcial antipsychotic, clozapine (0.2mg/kg, s.c.), or the glycine pro-drug glycinamide (56 mg/kg, s.c.). We found that clozapine fully prevented the MK-801-induced hyperlocomotion, and both clozapine and glycinamide prevented MK-801-induced deficits in the NOR task. The present results show that MK-801-induced hyperlocomotion and deficits in the NOR task in the domestic rabbit demonstrate predictive validity as an alternative animal model for symptoms of schizophrenia. Moreover, these results indicate that glycinamide should be investigated in pre-clinical models of neuropsychiatric disorders such as schizophrenia, obsessive compulsive disorder and anxiety disorders, where augmentation of extrasynaptic glycine concentrations may have therapeutic utility.
authors.affiliation: Centro de Investigación en Reproducción Animal (CIRA), Universidad Autónoma de Tlaxcala - CINVESTAV, Tlaxcala, Mexico. Electronic address: rexvitro@hotmail.com.
authors.forename: Kurt L
authors.initials: KL
authors.lastname: Hoffman
authors.affiliation: Centro de Investigación en Reproducción Animal (CIRA), Universidad Autónoma de Tlaxcala - CINVESTAV, Tlaxcala, Mexico.
authors.forename: Enrique
authors.initials: E
authors.lastname: Basurto
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology; D003024:Clozapine / Q000494:pharmacology*; D004195:Disease Models, Animal; D016291:Dizocilpine Maleate / Q000008:administration & dosage / Q000494:pharmacology*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005106:Exploratory Behavior; D005998:Glycine / Q000031:analogs & derivatives* / Q000494:pharmacology; D008124:Locomotion / Q000187:drug effects; D008297:Male; D011817:Rabbits; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors; D021641:Recognition, Psychology / Q000187:drug effects*; D012559:Schizophrenia / Q000139:chemically induced / Q000188:drug therapy*; D012565:Schizophrenic Psychology; D016896:Treatment Outcome; D014796:Visual Perception / Q000187:drug effects
chemical_list: D014150:Antipsychotic Agents; D018691:Excitatory Amino Acid Antagonists; D016194:Receptors, N-Methyl-D-Aspartate; C018556:glycine amide; D016291:Dizocilpine Maleate; D003024:Clozapine; D005998:Glycine
keywords: Clozapine; Glycinamide; MK-801; Object recognition; Rabbit; Schizophrenia