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Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on February 1, 2005; DOI: 10.1124/jpet.104.081315

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Received for publication November 23, 2004.
Revised January 27, 2005.
Accepted for publication January 31, 2005.

ADDITIVE EFFECTS OF ENDOGENOUS CANNABINOID ANANDAMIDE AND ETHANOL ON {alpha}7-NICOTINIC ACETYLCHOLINE RECEPTOR-MEDIATED RESPONSES IN XENOPUS OOCYTES

Murat Oz 1*, Shelley N. Jackson 1, Amina S. Woods 1, Marisela Morales 1, Li Zhang 2

1 NIH/NIDA/IRP, Cellular Neurobiology Branch 2 NIH/NIAAA, Lab. Mol. Cellular Neurobiology

* Address correspondence to: E-mail: moz{at}intra.nida.nih.gov

Abstract

The interaction between the effects of the endogenous cannabinoid receptor agonist anandamide and ethanol on the function of homomeric {alpha}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 ACh (100 ìM) in a concentration-dependent manner. Coapplication of anandamide and ethanol caused a significantly greater inhibition of {alpha}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 {alpha}7-mediated currents by coapplication of anandamide and ethanol was not altered by phenylmethylsulfonyl fluoride, an inhibitor of anandamide hydrolyzing enzyme, or AM404, 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 {alpha}7-nACh-5-HT3 receptors comprised of the amino-terminal domain of the {alpha}7-nACh receptor and the transmembrane and carboxyl-terminal domains of 5-HT3 receptors suggest that while ethanol inhibition of the {alpha}7-nAChR 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 {alpha}7-nACh receptor function through distinct regions of the receptor.


Key words: anandamide, drug abuse, endocannabinoid, ethanol, ligand-gated receptor, nicotinic receptor


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