Cannabinoids inhibit the release of [3H]glutamate from rodent hippocampal synaptosomes via a novel CB1 receptor-independent action.
In this study we investigated the effect of cannabinoids on [3H]glutamate release from hippocampal synaptosomes of rat and CB1-null mutant mouse. In the rat, cannabinoid receptor agonists, i.e. CP55,940 (EC50, 0.84 microm), WIN55,212-2 (EC50, 3.47 microm), ACEA (EC50, 17.8 microm), and R-(+)-methanandamide (EC50, 19.8 microm) concentration-dependently inhibited the 25-mm-K+ depolarization-evoked release of [3H]glutamate and, among them, WIN55,212-2 displayed the greatest efficacy. The CB1 receptor antagonists SR141716A (1-5 microm) and AM251 (1 microm) and the VR1 vanilloid receptor antagonist capsazepine (10 microm) did not antagonize the effect of the agonists. SR141716A by itself attenuated the evoked [3H]glutamate release. WIN55,212-2 inhibited the release of [3H]glutamate in CB1 -/- mice as well. These data demonstrate that the action of cannabinoids on glutamate release in the hippocampus is pharmacologically distinct and independent from the cloned CB1 receptor.
Köfalvi
Attila
A
Laboratory of Molecular Pharmacology, Institute of Experimental Medicine, Hungarian Academy of Sciences, H-1083 Budapest, Szigony u. 43., Hungary.
Vizi
E Sylvester
ES
Ledent
Catherine
C
Sperlágh
Beáta
B
D000700:Analgesics / Q000494:pharmacology; D000818:Animals; D001095:Arachidonic Acids / Q000494:pharmacology; D048588:Benzoxazines; D002186:Cannabinoids / Q000494:pharmacology*; D002211:Capsaicin / Q000031:analogs & derivatives* / Q000494:pharmacology; D002851:Chromatography, High Pressure Liquid; D003511:Cyclohexanols / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D018698:Glutamic Acid / Q000378:metabolism*; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D009025:Morpholines / Q000494:pharmacology; D009281:Naphthalenes / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D011851:Radioactivity; D051381:Rats; D017208:Rats, Wistar; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000077285:Rimonabant; D013574:Synaptosomes / Q000187:drug effects* / Q000378:metabolism; D014316:Tritium / Q000378:metabolism
D000700:Analgesics; D001095:Arachidonic Acids; D048588:Benzoxazines; D002186:Cannabinoids; D003511:Cyclohexanols; D009025:Morpholines; D009281:Naphthalenes; D010880:Piperidines; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; C119325:arachidonyl-2-chloroethylamide; D014316:Tritium; C088155:methanandamide; C103505:AM 251; D018698:Glutamic Acid; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone; C054649:3-(2-hydroxy-4-(1,1-dimethylheptyl)phenyl)-4-(3-hydroxypropyl)cyclohexanol; C071423:capsazepine; D000077285:Rimonabant; D002211:Capsaicin