Effect of AMPA receptor modulators on hippocampal and cortical function.
Attention has focused on drugs that modulate AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazole proprionic acid) receptors because of their potential for enhancing memory and treating certain pathologies that involve glutamatergic neurotransmission. The aim of this study was to compare and contrast the functionality of positive allosteric modulators of AMPA receptors in the hippocampus and medial prefrontal cortex. Electrically stimulated EPSPs (excitatory postsynaptic potential) in the hippocampus were augmented by CX516 [(1-quinoxaline-6-ylcarbonyl)piperidine], aniracetam and 1-BCP [(1-(1,3-benzodioxol-5-ylcarbonyl)piperidine] and not by cyclothiazide. Using grease gap electrophysiology, it was found that the mode of application dramatically altered the effect of the modulators of AMPA-induced depolarization. When added simultaneously with AMPA, aniracetam, 1-BCP and CX516 augmented the response in the frontal cortex. However, in the hippocampus, only aniracetam and cyclothiazide augmented the response when simultaneously added to AMPA. Therefore, in addition to regional variations, there appears to be differences in modulator response dependent upon whether a response is generated endogenously or exogenously by AMPA.
Black
M D
MD
CNS Research, Aventis Pharmaceuticals, Bridgewater, NJ 08807, USA. marl.black@aventis.com
Wotanis
J
J
Schilp
D E
DE
Hanak
S E
SE
Sorensen
S M
SM
Wettstein
J G
JG
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D002540:Cerebral Cortex / Q000187:drug effects* / Q000502:physiology; D004149:Dioxoles / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D006624:Hippocampus / Q000187:drug effects* / Q000502:physiology; D008297:Male; D010880:Piperidines / Q000494:pharmacology; D011760:Pyrrolidinones / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000187:drug effects* / Q000502:physiology; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000494:pharmacology
C097396:1-(quinoxalin-6-ylcarbonyl)piperidine; D004149:Dioxoles; D010880:Piperidines; D011760:Pyrrolidinones; D018091:Receptors, AMPA; C085415:1-(1,3-benzodioxol-5-ylcarbonyl)piperidine; C036466:aniracetam; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid