Evaluation of the pro-cognitive effects of the AMPA receptor positive modulator, 5-(1-piperidinylcarbonyl)-2,1,3-benzoxadiazole (CX691), in the rat.
BACKGROUND
Positive allosteric modulators of the glutamatergic alpha-amino-3-hydroxy-5-methyl-4-isoazolepropionic acid (AMPA) receptor do not stimulate AMPA receptors directly but delay deactivation of the receptor and/or slow its desensitisation. This results in increased synaptic responses and enhanced long-term potentiation. Thus, it has been suggested that such compounds may have utility for the treatment of cognitive impairment.


OBJECTIVE
The objective of the study was to investigate the effect of an AMPA positive modulator, CX691, (1) in three rodent models of learning and memory, (2) on neurochemistry in the dorsal hippocampus and medial prefrontal cortex following acute administration, and (3) on brain-derived neurotrophic factor (BDNF) messenger RNA (mRNA) expression in the rat hippocampus following acute and sub-chronic administration.


RESULTS
CX691 attenuated a scopolamine-induced impairment of cued fear conditioning following acute administration (0.1 mg/kg p.o.) and a temporally induced deficit in novel object recognition following both acute (0.1 and 1.0 mg/kg p.o.) and sub-chronic (bi-daily for 7 days) administration (0.01, 0.03, 0.1 mg/kg p.o.). It also improved attentional set-shifting following sub-chronic administration (0.3 mg/kg p.o.). Acute CX691 (0.1, 0.3 and 1.0 mg/kg, p.o.) increased extracellular levels of acetylcholine in the dorsal hippocampus and medial prefrontal cortex and dopamine in the medial prefrontal cortex. Sub-chronic administration of CX691 (0.1 mg/kg, p.o.) elevated BDNF mRNA expression in both the whole and CA(1) sub-region of the hippocampus (P < 0.05).


CONCLUSIONS
Collectively, these data support the pro-cognitive activity reported for AMPA receptor positive modulators and suggest that these compounds may be of benefit in treating disorders characterised by cognitive deficits such as Alzheimer's disease and schizophrenia.
Woolley
M L
ML
Neurosciences Centre of Excellence for Drug Discovery, GlaxoSmithKline plc, New Frontiers Science Park, Third Avenue, Harlow, Essex CM195AW, UK. marie.2.woolley-roberts@gsk.com
Waters
K A
KA
Gartlon
J E
JE
Lacroix
L P
LP
Jennings
C
C
Shaughnessy
F
F
Ong
A
A
Pemberton
D J
DJ
Harries
M H
MH
Southam
E
E
Jones
D N C
DN
Dawson
L A
LA
D000109:Acetylcholine / Q000378:metabolism; D000679:Amygdala / Q000502:physiology; D000818:Animals; D001288:Attention / Q000187:drug effects; D019208:Brain-Derived Neurotrophic Factor / Q000096:biosynthesis; D003071:Cognition / Q000187:drug effects*; D003216:Conditioning, Operant / Q000187:drug effects; D003463:Cues; D004298:Dopamine / Q000378:metabolism; D005239:Fear / Q000187:drug effects / Q000523:psychology; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D017403:In Situ Hybridization; D008297:Male; D018727:Muscarinic Antagonists / Q000494:pharmacology; D018697:Nootropic Agents / Q000494:pharmacology*; D009638:Norepinephrine / Q000378:metabolism; D010069:Oxadiazoles / Q000494:pharmacology*; D010880:Piperidines / Q000494:pharmacology*; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D018091:Receptors, AMPA / Q000187:drug effects*; D021641:Recognition, Psychology / Q000187:drug effects*; D012601:Scopolamine / Q000037:antagonists & inhibitors / Q000494:pharmacology
C521407:1-(benzofurazan-5-ylcarbonyl)piperidine; D019208:Brain-Derived Neurotrophic Factor; D018727:Muscarinic Antagonists; D018697:Nootropic Agents; D010069:Oxadiazoles; D010880:Piperidines; D012333:RNA, Messenger; D018091:Receptors, AMPA; D012601:Scopolamine; D000109:Acetylcholine; D004298:Dopamine; D009638:Norepinephrine
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