Anandamide and NADA bi‐directionally modulate presynaptic Ca2+ levels and transmitter release in the hippocampus

• Published in: British journal of pharmacology Vol. 151; no. 4; pp. 551 - 563
• Main Authors: Köfalvi, A, Pereira, M F, Rebola, N, Rodrigues, R J, Oliveira, C R, Cunha, R A
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01-06-2007; Nature Publishing; Nature Publishing Group
• Subjects: anandamide; Animals; Arachidonic Acids - pharmacology; Biological and medical sciences; calcium; Calcium - metabolism; Dopamine - analogs & derivatives; Dopamine - pharmacology; Endocannabinoids; Fluorometry; GABA; gamma-Aminobutyric Acid - secretion; glutamate; Glutamic Acid - secretion; hippocampus; Hippocampus - drug effects; Hippocampus - metabolism; Male; Medical sciences; nerve terminals; N‐arachidonoyl dopamine; Pharmacology. Drug treatments; Polyunsaturated Alkamides - pharmacology; Rats; Rats, Wistar; Receptor, Cannabinoid, CB1 - physiology; Receptor, Cannabinoid, CB2 - physiology; Receptors, Dopamine - physiology; Research Papers; TRPV Cation Channels - physiology; N-arachidonoyl dopamine; Dopamine; Calcium; Arachidonic acid derivatives; Central nervous system; nerve terminals; Endogenous substance; Cannabinoid; Catecholamine; Glutamate; Inorganic element; Encephalon; Anandamide; Nerve ending; Excitatory aminoacid; Neurotransmitter; GABA; Hippocampus; Release
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1038/sj.bjp.0707252

Background and purpose:
Inhibitory CB1 cannabinoid receptors and excitatory TRPV1 vanilloid receptors are abundant in the hippocampus. We tested if two known hybrid endocannabinoid/endovanilloid substances, N‐arachidonoyl‐dopamine (NADA) and anandamide (AEA), presynapticaly increased or decreased intracellular calcium level ([Ca2+]i) and GABA and glutamate release in the hippocampus.
Experimental approach:
Resting and K+‐evoked levels of [Ca2+]i and the release of [3H]GABA and [3H]glutamate were measured in rat hippocampal nerve terminals.
Key results:
NADA and AEA per se triggered a rise of [Ca2+]i and the release of both transmitters in a concentration‐ and external Ca2+‐dependent fashion, but independently of TRPV1, CB1, CB2, or dopamine receptors, arachidonate‐regulated Ca2+‐currents, intracellular Ca2+ stores, and fatty acid metabolism. AEA was recently reported to block TASK‐3 potassium channels thereby depolarizing membranes. Common inhibitors of TASK‐3, Zn2+, Ruthenium Red, and low pH mimicked the excitatory effects of AEA and NADA, suggesting that their effects on [Ca2+]i and transmitter levels may be attributable to membrane depolarization upon TASK‐3 blockade. The K+‐evoked Ca2+ entry and Ca2+‐dependent transmitter release were inhibited by nanomolar concentrations of the CB1 receptor agonist WIN55212‐2; this action was sensitive to the selective CB1 receptor antagonist AM251. However, in the low micromolar range, WIN55212‐2, NADA and AEA inhibited the K+‐evoked Ca2+ entry and transmitter release independently of CB1 receptors, possibly through direct Ca2+ channel blockade.
Conclusions and implications:
We report here for hybrid endocannabinoid/endovanilloid ligands novel dual functions which were qualitatively similar to activation of CB1 or TRPV1 receptors, but were mediated through interactions with different targets.
British Journal of Pharmacology (2007) 151, 551–563; doi:10.1038/sj.bjp.0707252