title: N-arachidonoyl-dopamine tunes synaptic transmission onto dopaminergic neurons by activating both cannabinoid and vanilloid receptors.
abstract: In the present study, we used electrophysiological, biochemical, and confocal microscopy techniques, to investigate the functional role of transient receptor potential vanilloid type 1 (TRPV1) and cannabinoid type 1 receptors (CB1-R) in the substantia nigra pars compacta (SNpc) and their stimulation by the endocannabinoid N-arachidonoyl-dopamine (NADA). Liquid chromatography-mass spectrometry analyses revealed that a NADA-like compound is produced in substantia nigra slices, in conditions of hyperactivity. Moreover, the functional role of both TRPV1 and CB1-R in modulating synaptic transmission in this area was suggested by confocal microscopy data, showing TRPV1 and CB1-R immunoreactivity in punctate structures, probably representing synaptic contacts on cell bodies of the SNpc. In patch-clamp recordings from dopamine (DA) neurons of the SNpc, we found that NADA increases or reduces glutamatergic transmission onto DA neurons by activating TRPV1 and CB1 receptors, respectively, whereas it decreases GABAergic transmission via CB1 stimulation. Facilitation of glutamate release through TRPV1 was blocked in the presence of a selective blocker of the putative endocannabinoid membrane transporter (EMT), indicating that NADA needs to be taken up by cells to interact with this receptor. In line with these data, biochemical results demonstrated that NADA selectively acted at CB1-R when its re-uptake was blocked. Altogether these data demonstrate a significant role exerted by the endocannabinoid/endovanilloid NADA in the regulation of synaptic transmission to DA neurons of the SNpc. Moreover, they highlight a key function of the EMT transporter in promoting the stimulation of TRPV1 or CB1-R, thus favoring facilitation or inhibition of glutamate synaptic release.
authors.affiliation: Experimental Neurology, IRCCS Fondazione Santa Lucia, Rome, Italy. s.marinelli@ebri.it
authors.forename: Silvia
authors.initials: S
authors.lastname: Marinelli
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Di Marzo
authors.forename: Fulvio
authors.initials: F
authors.lastname: Florenzano
authors.forename: Filomena
authors.initials: F
authors.lastname: Fezza
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Viscomi
authors.forename: Mario
authors.initials: M
authors.lastname: van der Stelt
authors.forename: Giorgio
authors.initials: G
authors.lastname: Bernardi
authors.forename: Marco
authors.initials: M
authors.lastname: Molinari
authors.forename: Mauro
authors.initials: M
authors.lastname: Maccarrone
authors.forename: Nicola B
authors.initials: NB
authors.lastname: Mercuri
mesh_terms: D000818:Animals; D001095:Arachidonic Acids / Q000378:metabolism* / Q000494:pharmacology; D004298:Dopamine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D005455:Fluorescent Antibody Technique; D018698:Glutamic Acid / Q000378:metabolism; D008297:Male; D018613:Microscopy, Confocal; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D009924:Organ Culture Techniques; D027701:Organic Cation Transport Proteins / Q000187:drug effects / Q000378:metabolism; D018408:Patch-Clamp Techniques; D017729:Presynaptic Terminals / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D043884:Receptor, Cannabinoid, CB1 / Q000187:drug effects / Q000378:metabolism; D043882:Receptors, Cannabinoid / Q000187:drug effects / Q000378:metabolism*; D013378:Substantia Nigra / Q000187:drug effects / Q000378:metabolism*; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology*; D050916:TRPV Cation Channels / Q000187:drug effects / Q000378:metabolism*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism; D000099254:Organic Cation Transporter 3
chemical_list: D001095:Arachidonic Acids; D004298:Dopamine; D018698:Glutamic Acid; D027701:Organic Cation Transport Proteins; D043884:Receptor, Cannabinoid, CB1; D043882:Receptors, Cannabinoid; D050916:TRPV Cation Channels; D005680:gamma-Aminobutyric Acid; D000099254:Organic Cation Transporter 3; C493922:Trpv1 protein, rat; C474941:arachidonyl dopamine