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The Endocannabinoid Anandamide Inhibits the Function of 4β2 Nicotinic Acetylcholine Receptors

United States Department of Health and Human Services, National Institutes of Health, National Institute on Drug Abuse, Intramural Research Program, Cellular Neurobiology Branch, Electrophysiology Research Unit, Baltimore, Maryland

The effects of the endocannabinoid anandamide (arachidonylethanolamide, AEA) on the function of 4β2 nicotinic acetylcholine receptors (nAChR) stably expressed in SH-EP1 cells were investigated using the whole-cell patch-clamp technique. In the concentration range of 200 nM to 2 µM, AEA significantly reduced the maximal amplitudes and increased the desensitization of acetylcholine (ACh)-induced currents. The effects of AEA could be neither replicated by the exogenous cannabinoid ⁹-tetrahydrocannabinol (1 µM) nor reversed by the selective CB1 receptor antagonist 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-N-(piperidin-1-yl)-1H-pyrazole-3-carboxamide (SR-141716A) (1 µM). The actions of AEA were apparent when applied extracellularly but not during intracellular dialysis. Furthermore, the effects of AEA ACh currents were not altered by the calcium chelator 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid. The onset and washout of the AEA effects required several minutes (10–30 min), but the latter was significantly decreased in the presence of lipid-free bovine serum albumin (BSA). Moreover, BSA alone increased peak ACh current amplitudes and diminished desensitization rates in naive cells, suggesting a tonic modulation of 4β2 nAChR function by an endogenous AEA-like lipid. Further analysis of AEA effects on 4β2 nAChR-mediated currents, using a two-stage desensitization model, indicated that the first forward rate constant leading to desensitization, k₁, increased nearly 30-fold as a linear function of the AEA concentration. In contrast, the observation that the other three rate constants were unaltered by AEA suggested that AEA raised the energy of the activated state. These results indicate that AEA directly inhibits the function of 4β2 nAChRs in a CB1 receptor-independent manner.

Address correspondence to: Dr. Charles Spivak, National Institute on Drug Abuse, Intramural Research Program, Cellular Neurobiology Branch, Electrophysiology Unit, 5500 Nathan Shock Drive, Baltimore, MD 21224. E-mail: cspivak{at}intra.nida.nih.gov

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