POSTISCHEMIC RECOVERY OF ACETYLCHOLINE-RELEASE IN-VITRO - INFLUENCE OF DIFFERENT EXCITATORY AMINO-ACID RECEPTOR SUBTYPE ANTAGONISTS

The release of endogenous acetylcholine was measured in electrically ( 5-20 Hz) stimulated guinea pig cerebral cortex and caudate nucleus sli ces under ischemic (hypoxic and glucose-free) conditions. Ischemia red uced acetylcholine release by 40-90%; the inhibition depended on the d uration of ischemia (10-30 min) while the extent of post-ischemic reco very was inversely related to it. Caudate nucleus slices displayed a h igher sensitivity to ischemia than did cortical slices. To test the ef fects of excitatory amino acid receptor antagonists on the ischemia-in duced reduction of acetylcoline release and on its post-ischemic recov ery, the following drugs were used: 1-dihydro-5-H-dibenzo-[a,b]-cycloh epten-5,10-imine (MK-801, a blocker of the N-methyl-D-aspartate [NMDA] receptor-linked channel), 7-chloro-kynurenic acid (7-Cl-KYN) and carb amoyl)ethenyl]-4,6-dichloroindole-2-carboxylic acid sodium salt (GV150 526A, blockers of the glycine site of the NMDA receptor), eliprodil, ( an antagonist at the polyamine site of the NMDA receptor), and 6-cyano -7-nitro-quinoxalin-2,3-dione (CNQX, a D,L-alpha-amino-3-hydroxy-5-met hyl-4-isoxalone propionic acid [AMPA] receptor antagonist). These did not modify the time-course and the extent of ischemia-induced inhibiti on but improved post-ischemic recovery in a concentration dependent ma nner. GV 150526A and CNQX appeared to be more effective in the cerebra l cortex. Only eliprodil was devoid of any effect in both areas. The e valuation of acetylcholine release from brain slices represents a suit able in vitro model to quantify the effectiveness of drugs in favourin g recovery from the cholinergic presynaptic failure induced by ischemi c conditions. The different effects of the excitatory amino acid recep tor antagonists cited above, depending on the brain areas considered a nd the receptor subtypes involved, may be of interest in view of their therapeutic potential. (C) 1997 Elsevier Science Ltd. All rights rese rved.