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NEUROPHARMACOLOGY

Additive Effects of Endogenous Cannabinoid Anandamide and Ethanol 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, Baltimore, Maryland (M.O., S.N.J., A.S.W., 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.)

The interaction between the effects of the endogenous cannabinoid receptor agonist anandamide and ethanol on the function of homomeric ₇-nicotinic acetylcholine (nACh) receptors expressed in Xenopus oocytes were investigated using the two-electrode voltage-clamp technique. Anandamide and ethanol reversibly inhibited currents evoked with 100 µM acetylcholine in a concentration-dependent manner. Coapplication of anandamide and ethanol caused a significantly greater inhibition of ₇-nACh receptor function than anandamide or ethanol alone. The IC₅₀ value of 238 ± 34 nM for anandamide inhibition decreased significantly to 104 ± 23 nM in the presence of 30 mM ethanol. The inhibition of ₇-mediated currents by coapplication of anandamide and ethanol was not altered by phenylmethylsulfonyl fluoride, an inhibitor of anandamide hydrolyzing enzyme, or N-(4-hydroxyphenyl)-arachidonylamide, an anandamide transport inhibitor. Analysis of oocytes by matrix-assisted laser desorption/ionization technique indicated that ethanol treatment did not alter the lipid profile of oocytes, and there is negligible, if any, anandamide present in these cells. Results of studies with chimeric ₇-nACh-5-HT₃ receptors comprised of the amino-terminal domain of the ₇-nACh receptor and the transmembrane and carboxyl-terminal domains of 5-HT₃ receptors suggest that although ethanol inhibition of the ₇-nACh receptor is likely to involve the N-terminal region of the receptor, the site of action for anandamide is located in the transmembrane and carboxyl-terminal domains of the receptors. These data indicate that endocannabinoids and ethanol potentiate each other's inhibitory effects on ₇-nACh receptor function through distinct regions of the receptor.

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

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