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Received for publication March 1, 2004.
Revised April 12, 2004.
Accepted for publication April 13, 2004.
7-NICOTINIC ACETYLCHOLINE RECEPTOR-MEDIATED RESPONSES IN XENOPUS OOCYTES
The effects of endogenous and synthetic cannabinoid receptor agonists including 2-arachidonoylglycerol, R-methanandamide, WIN55,212-2, CP55,940 and the psychoactive constituent of marijuana, 
9-THC, on the function of homomeric 
7 nicotinic ACh receptors expressed in Xenopus oocytes was investigated using the two-electrode voltage-clamp technique. The endogenous cannabinoid receptor ligands 2-arachidonoylglycerol and the metabolically stable analogue of anandamide, R-methanandamide, reversibly inhibited currents evoked with ACh (100 µM) in a concentration-dependent manner (IC50 values of 168 nM and 183 nM, respectively). In contrast, the synthetic cannabinoid receptor agonists CP55,940, WIN55,212-2, and the phytochemical 9-THC did not alter 7 nicotinic ACh receptor function. The inhibition of 7-mediated currents by 2-arachidonylglycerol was found to be non-competitive and voltage-independent. Additional experiments using endocannabinoid metabolites suggested that arachidonic acid, but not ethanolamine or glycerol, could also inhibit the 7-nACh receptor function. Whereas the effects of arachidonic acid were also noncompetitive and voltage-independent, its potency was much lower than 2-AG and anandamide. Results of studies with chimeric 7-nACh-5-HT3 receptors that were comprised of the amino-terminal domain of the 7-nACh receptor and the transmembrane and carboxyl-terminal domains of 5-HT3 receptors indicated that the site of interaction of the endocannabinoids with the 7-nAChR was not located on the N-terminal region of the receptor. These data indicate that cannabinoid receptor ligands that are produced in-situ potently inhibit 7-nACh receptor function, whereas the synthetic cannabinoid ligands, and 9-THC, are without effect or are relatively ineffective at inhibiting these receptors.
Key words:
arachidonic acid, cannabinoids, drug abuse, endocannabinoids, nicotinic receptors, xenopus oocytes
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