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The effect of the endogenous cannabinoid ligand anandamide on the function of the cloned α₇ subunit of the nicotinic acetylcholine (ACh) receptor expressed in Xenopus oocytes was investigated by using the two-electrode voltage-clamp technique. Anandamide reversibly inhibited nicotine (10 μM) induced-currents in a concentration-dependent manner (10 nM to 30 μM), with an IC₅₀ value of 229.7 ± 20.4 nM. The effect of anandamide was neither dependent on the membrane potential nor meditated by endogenous Ca²⁺ dependent Cl^- channels since it was unaffected by intracellularly injected BAPTA and perfusion with Ca²⁺-free bathing solution containing 2 mM Ba²⁺. Anandamide decreased the maximal nicotine-induced responses without significantly affecting its potency, indicating that it acts as a noncompetitive antagonist on nicotinic acetylcholine (nACh) α₇ receptors. This effect was not mediated …