title: Anandamide and NADA bi-directionally modulate presynaptic Ca2+ levels and transmitter release in the hippocampus.
abstract: OBJECTIVE
  Inhibitory CB(1) cannabinoid receptors and excitatory TRPV(1) 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 ([Ca(2+)](i)) and GABA and glutamate release in the hippocampus.
  
  
  METHODS
  Resting and K(+)-evoked levels of [Ca(2+)](i) and the release of [(3)H]GABA and [(3)H]glutamate were measured in rat hippocampal nerve terminals.
  
  
  RESULTS
  NADA and AEA per se triggered a rise of [Ca(2+)](i) and the release of both transmitters in a concentration- and external Ca(2+)-dependent fashion, but independently of TRPV(1), CB(1), CB(2), or dopamine receptors, arachidonate-regulated Ca(2+)-currents, intracellular Ca(2+) stores, and fatty acid metabolism. AEA was recently reported to block TASK-3 potassium channels thereby depolarizing membranes. Common inhibitors of TASK-3, Zn(2+), Ruthenium Red, and low pH mimicked the excitatory effects of AEA and NADA, suggesting that their effects on [Ca(2+)](i) and transmitter levels may be attributable to membrane depolarization upon TASK-3 blockade. The K(+)-evoked Ca(2+) entry and Ca(2+)-dependent transmitter release were inhibited by nanomolar concentrations of the CB(1) receptor agonist WIN55212-2; this action was sensitive to the selective CB(1) receptor antagonist AM251. However, in the low micromolar range, WIN55212-2, NADA and AEA inhibited the K(+)-evoked Ca(2+) entry and transmitter release independently of CB(1) receptors, possibly through direct Ca(2+) channel blockade.
  
  
  CONCLUSIONS
  We report here for hybrid endocannabinoid/endovanilloid ligands novel dual functions which were qualitatively similar to activation of CB(1) or TRPV(1) receptors, but were mediated through interactions with different targets.
authors: Center for Neurosciences of Coimbra, University of Coimbra, Coimbra, Portugal. akofalvi@yahoo.com
authors: A
authors: A
authors: Köfalvi
authors: M F
authors: MF
authors: Pereira
authors: N
authors: N
authors: Rebola
authors: R J
authors: RJ
authors: Rodrigues
authors: C R
authors: CR
authors: Oliveira
authors: R A
authors: RA
authors: Cunha
mesh_terms: D000818:Animals; D001095:Arachidonic Acids / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism*; D004298:Dopamine / Q000031:analogs & derivatives* / Q000494:pharmacology; D063388:Endocannabinoids; D005470:Fluorometry; D018698:Glutamic Acid / Q000378:metabolism*; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D053284:Polyunsaturated Alkamides / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D043884:Receptor, Cannabinoid, CB1 / Q000502:physiology; D043885:Receptor, Cannabinoid, CB2 / Q000502:physiology; D011954:Receptors, Dopamine / Q000502:physiology; D050916:TRPV Cation Channels / Q000502:physiology; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
chemical_list: D001095:Arachidonic Acids; D063388:Endocannabinoids; D053284:Polyunsaturated Alkamides; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2; D011954:Receptors, Dopamine; D050916:TRPV Cation Channels; C493922:Trpv1 protein, rat; C474941:arachidonyl dopamine; D018698:Glutamic Acid; D005680:gamma-Aminobutyric Acid; D002118:Calcium; C078814:anandamide; D004298:Dopamine