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

Brooke G. Kelley, Stanley A. Thayer

Research output: Contribution to journalArticlepeer-review

35 Scopus citations

Abstract

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 1 μM AM404 inhibited [Ca2+]i spiking by 73±8%. The cannabinoid CB1 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 μM) 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 [Ca 2+]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.

Original languageEnglish (US)
Pages (from-to)33-39
Number of pages7
JournalEuropean Journal of Pharmacology
Volume496
Issue number1
DOIs
StatePublished - Aug 2 2004

Bibliographical note

Funding Information:
This work was supported by grants DA07304 and DA11806 from the National Institute on Drug Abuse (NIDA) and by grant IBN0110409 from the National Science Foundation. B.K. was supported by NIDA training grant DA07097. We thank Wenna Lin for excellent technical assistance.

Keywords

  • AM404
  • CB receptor
  • Cannabinoid
  • Excitatory synaptic transmission
  • Hippocampus
  • N-acetyl ethanolamide

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