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NEUROPHARMACOLOGY

Differential Effects of Endogenous and Synthetic Cannabinoids on ₇-Nicotinic Acetylcholine Receptor-Mediated Responses in Xenopus Oocytes

National Institute on Drug Abuse, National Institutes of Health/Department of Health and Human Services, Intramural Research Program, Cellular Neurobiology Branch (M.O., C.R.L.), Behavioral Neurobiology Branch (M.M.), and National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health/Department of Health and Human Services, Laboratory of Molecular and Cellular Neurobiology, Bethesda, Maryland (L.Z., A.R.)

The effects of endogenous and synthetic cannabinoid receptor agonists, including 2-arachidonoylglycerol (2-AG), R-methanandamide, WIN55,212-2 [4,5-dihydro-2-methyl-4(4-morpholinylmethyl)-1-(1-naphthalenylcarbonyl)-6H-pyrrolo[3,2,1ij]quinolin-6-one], and CP 55,940 [1,2-(R)-5]-(-)-5-(1,1-dimethyl)-2-[5-hydroxy-2-(3-hydroxypropyl) cyclohexyl-phenol], and the psychoactive constituent of marijuana, ⁹-tetrahydrocannabinol (⁹-THC), on the function of homomeric ₇-nicotinic acetylcholine (nACh) receptors expressed in Xenopus oocytes was investigated using the two-electrode voltage-clamp technique. The endogenous cannabinoid receptor ligands 2-AG and the metabolically stable analog of anandamide (arachidonylethanolamide), R-methanandamide, reversibly inhibited currents evoked with ACh (100 µM) in a concentration-dependent manner (IC₅₀ values of 168 and 183 nM, respectively). In contrast, the synthetic cannabinoid receptor agonists CP 55,940, WIN55,212-2, and the phytochemical ⁹-THC did not alter ₇-nACh receptor function. The inhibition of ₇-mediated currents by 2-AG 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-hydroxytryptamine (5-HT)₃ receptors 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.

Address correspondence to: Dr. Murat Oz, National Institute on Drug Abuse/Intramural Research Program, Cellular Neurobiology Branch, 5500 Nathan Shock Dr., Baltimore, MD 21224. E-mail: moz{at}intra.nida.nih.gov

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