title: Effects of positive modulators of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type glutamate receptors in a benzodiazepine-induced deficit of spatial discrimination in mice.
abstract: Imbalance between GABAergic and glutamatergic neurotransmission has been recently hypothesized to trigger memory decline related either to ageing or to Alzheimer's disease (AD). Thereby, benzodiazepine-induced anterograde amnesia has been construed as a model of hippocampal-related cognitive dysfunctions. Since spatial memory is altered both by ageing and by benzodiazepines such as alprazolam, we investigated the pharmacological sensitivity of alprazolam-induced deficit in a delayed spatial discrimination (SD) task, notably with positive allosteric modulators of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type glutamate receptors. We showed that alprazolam (0.1 mg/kg intraperitoneally) induced memory impairments as compared with vehicle-treated mice. The oral administration of modulators of AMPA receptors (IDRA-21: 10 mg/kg; S18986: 3 and 10 mg/kg) reversed the alprazolam-induced deficits. This study is first to show evidence that reference treatments of AD, such as memantine (a NMDA receptor antagonist) at 3 mg/kg per os (po) and donepezil (an acetylcholinesterase inhibitor) at 1 mg/kg po, also reversed the alprazolam-induced amnesia. Given such results, the SD task emerges as a valuable novel task to screen pro-cognitive compounds. Thus, we highlight the efficacy of modulators of AMPA-type glutamate receptors to counteract alprazolam-induced spatial deficits. These results could be viewed alongside the imbalance between excitation and inhibition observed during normal and pathological ageing.
authors: Institut de Recherches Servier, Croissy-sur-Seine, France. m.vandesquille@cnic.u-bordeaux1.fr
authors: M
authors: M
authors: Vandesquille
authors: I
authors: I
authors: Carrié
authors: C
authors: C
authors: Louis
authors: D
authors: D
authors: Beracochea
authors: P
authors: P
authors: Lestage
mesh_terms: D000525:Alprazolam / Q000494:pharmacology; D000647:Amnesia / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001581:Benzothiadiazines / Q000494:pharmacology*; D003072:Cognition Disorders / Q000139:chemically induced / Q000188:drug therapy*; D004192:Discrimination, Psychological / Q000187:drug effects*; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008568:Memory / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D018091:Receptors, AMPA / Q000378:metabolism*; D017470:Receptors, Glutamate / Q000378:metabolism*; D013037:Spatial Behavior / Q000187:drug effects*
chemical_list: D001581:Benzothiadiazines; D018091:Receptors, AMPA; D017470:Receptors, Glutamate; D000525:Alprazolam