4.7 Article

Anandamide transport inhibitor AM404 and structurally related compounds inhibit synaptic transmission between rat hippocampal neurons in culture independent of cannabinoid CB1 receptors

Journal

EUROPEAN JOURNAL OF PHARMACOLOGY
Volume 496, Issue 1-3, Pages 33-39

Publisher

ELSEVIER SCIENCE BV
DOI: 10.1016/j.ejphar.2004.06.011

Keywords

AM404; excitatory synaptic transmission; N-acetyl ethanolamide; CB1 receptor; cannabinoid; hippocampus

Funding

  1. NIDA NIH HHS [DA11806, R37 DA007304, R01 DA007304, DA07097, DA07304] Funding Source: Medline

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N-(hydroxyphenyl)-arachidonamide (AM404) is an inhibitor of endocannabinoid transport. We examined the effects of AM404 on glutamatergic synaptic transmission using network-driven increases in intracellular Ca2+ concentration ([Ca2+] spikes) as an assay. At a concentration of I muM AM404 inhibited [Ca2+](i) spiking by 73 +/- 8%. The cannabinoid CB I receptor antagonist N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide hydrochloride (SR141716A), the vanilloid VR1 receptor antagonist capsazepine (CPZ), and treatment with pertussis toxin failed to block AM404-mediated inhibition. AM404 (3 muM) inhibited action-potential-evoked Ca2+ influx by 58 +/- 3% but failed to affect calcium influx evoked by depolarization with 30 mM K+ suggesting that the inhibition of electrically evoked [Ca2+](i) increases and that [Ca2+](i) spiking was due to inhibition of Na+ channels. Palmitoylethanolamide (PMEA), capsaicin (CAP) and (5Z,8Z,11Z,14Z)-N-(4-hydroxy-2-methylphenyl)-5,8,11,14-eicosatetraenamide (VDM11), compounds structurally similar to AM404, inhibited [Ca2+](i) spiking by 34 +/- 10%, 42 +/- 18% and 67 +/- 12%, respectively. Thus, AM404 and related compounds inhibit depolarization-induced Ca2+ influx independent of cannabinoid receptors, suggesting caution when using these agents as pharmacological probes to study synaptic transmission. (C) 2004 Elsevier B.V. All rights reserved.

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