Positive modulation of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors reverses sub-chronic PCP-induced deficits in the novel object recognition task in rats.
Cognitive deficits are a major clinical unmet need in schizophrenia. The psychotomimetic drug phencyclidine (PCP) is widely applied in rodents to mimic symptoms of schizophrenia, including cognitive deficits. Previous studies have shown that sub-chronic PCP induces an enduring episodic memory deficit in female Lister Hooded rats in the novel object recognition (NOR) task. Here we show that positive modulation of AMPA receptor (AMPAR) mediated glutamate transmission alleviates cognitive deficits induced by sub-chronic PCP treatment. Female Lister hooded rats were treated sub-chronically with either vehicle (0.9% saline) or PCP (2mg/kg two doses per day for 7 days), followed by a 7 days washout period. 30 min prior to the acquisition trial of the NOR task animals were dosed with either vehicle, CX546 (10, 40 or 80 mg/kg) or CX516 (0.5, 2.5, 10, 40 or 80 mg/kg). Our results show that sub-chronic PCP treatment induced a significant decrease in the discrimination index (DI) and both ampakines CX546 and CX516 were able to reverse this disruption of object memory in rats in the novel object recognition task. These data suggest that positive AMPAR modulation may represent a mechanism for treatment of cognitive deficits in schizophrenia.
Damgaard
Trine
T
H. Lundbeck A/S, Discovery Pharmacology Research-Cognition, Ottiliavej 9, Valby, Denmark. tdn@lundbeck.com
Larsen
Dorrit Bjerg
DB
Hansen
Suzanne L
SL
Grayson
Ben
B
Neill
Jo C
JC
Plath
Niels
N
D000704:Analysis of Variance; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001923:Brain Chemistry; D004149:Dioxoles / Q000032:analysis / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005106:Exploratory Behavior / Q000187:drug effects*; D005260:Female; D006213:Hallucinogens; D008569:Memory Disorders / Q000139:chemically induced / Q000188:drug therapy*; D009043:Motor Activity / Q000187:drug effects; D010622:Phencyclidine / Q000633:toxicity; D010880:Piperidines / Q000032:analysis / Q000494:pharmacology; D051381:Rats; D018091:Receptors, AMPA / Q000378:metabolism*; D021641:Recognition, Psychology / Q000187:drug effects*; D014741:Video Recording; D014796:Visual Perception / Q000187:drug effects
C443080:1-(1,4-benzodioxan-6-ylcarbonyl)piperidine; C097396:1-(quinoxalin-6-ylcarbonyl)piperidine; D004149:Dioxoles; D006213:Hallucinogens; D010880:Piperidines; D018091:Receptors, AMPA; D010622:Phencyclidine