Abstract: The cannabinoid 1 receptor antagonist AM 251 is known to block the inhibitory effects of endocannabinoids and synthetic cannabinoid agonists on transmitter release through an action at presynaptic cannabinoid 1 receptors in brain. We examined the ability of AM 251 to inhibit sodium channel‐dependent functions and the binding of (3H)batrachotoxinin A 20‐α‐benzoate to sodium channels in mouse brain synaptic preparations. Depolarization of synaptoneurosomes by the sodium channel site 2‐specific neurotoxin veratridine, which is abolished by tetrodotoxin, was found to be inhibited in a concentration‐dependent fashion by AM 251 (IC50=8.9 μM). Veratridine‐dependent (tetrodotoxin suppressible) release, of L‐glutamic acid and GABA from synaptosomes was also reduced by AM 251 (IC50s=8.5 μM (L‐glutamic acid), 9.2 μM (GABA)). The binding of the radioligand (3H)batrachotoxinin A 20‐α‐benzoate to site 2 on sodium channels was displaced by AM 251 (IC50=11.2 μM). Scatchard analysis of binding showed that at its IC50, AM 251 increased (by 2.3 times) the KD of radioligand without altering Bmax, suggesting a competitive mechanism of inhibition by AM 251. Kinetic experiments indicated that AM 251 inhibits equilibrium binding by allosterically accelerating the dissociation of the (3H)‐batrachotoxinin A 20‐α‐benzoate:sodium channel complex. Our data suggest that micromolar concentrations of AM 251 are capable of reducing neuronal excitability and inhibiting release of excitatory and inhibitory transmitters through blockade of voltage‐sensitive sodium channels in brain.
Basic and Clinical Pharmacology & Toxicology – Wiley
Published: Feb 1, 2004
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