Cannabinoid CB1 receptor-mediated inhibition of glutamate release from rat hippocampal synaptosomes.
Cannabinoid receptors are widely expressed in the brain and have been shown to regulate synaptic transmission through a presynaptic mechanism. Using synaptosomal preparation, I show here that 2,3-dihydro-5-methyl-3-(4-morpholinyl-methyl)-pyrrolo-1,4-benzoxazin-6-yl-1-naphthalenylmethanone (WIN 55212-2) strongly depressed 4-aminopyridine-evoked glutamate release in a concentration-dependent manner, and this effect was reversed by the selective cannabinoid CB(1) receptor antagonist 1-(2,4-dichlorophenyl)-5-(4-iodophenyl)-4-methyl-N-4-morpholinyl-1H-pyrazole-3-carboxamide (AM 281). The inhibitory modulation by WIN 55212-2 was not due to a decrease in synaptosomal excitability or a direct effect on the release machinery because WIN 55212-2 did not alter 4-aminopyridine-mediated depolarization and ionomycin-induced glutamate release. In addition, the WIN 55212-2-mediated inhibition of glutamate release was blocked by the G(i)/G(o) protein inhibitor pertussis toxin, but not by the protein kinase A inhibitor 2,3,9,10,11,12-Hexahydro-10-hydroxy-9-methyl-1-oxo-9,12-epoxy-1H-diindolo-benzodiazocine-10-carboxylic acid, hexyl ester (KT 5720). Furthermore, this inhibitory effect was associated with a decrease in 4-aminopyridine-evoked Ca(2+) influx, which could be completely prevented in synaptosomes pretreated with the N- and P/Q-type Ca(2+) channel blockers. Together, these observations indicate that activation of cannabinoid CB(1) receptors inhibit 4-aminopyridie-evoked glutamate release from hippocampal synaptosomes through a inhibitory G protein to suppress N- and P/Q-type Ca(2+) channel activity.
Wang
Su-Jane
SJ
School of Medicine, Fu Jen Catholic University, 510, Chung-Cheng Road, Hsin-Chuang, Taipei Hsien, 24205, Taiwan. med003@mails.fju.edu.tw
D000818:Animals; D048588:Benzoxazines; D002186:Cannabinoids / Q000378:metabolism / Q000494:pharmacology; D018698:Glutamic Acid / Q000378:metabolism*; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D009025:Morpholines / Q000494:pharmacology; D009281:Naphthalenes / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism*
D048588:Benzoxazines; D002186:Cannabinoids; D009025:Morpholines; D009281:Naphthalenes; D043884:Receptor, Cannabinoid, CB1; 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