title: The selective antagonist EPPTB reveals TAAR1-mediated regulatory mechanisms in dopaminergic neurons of the mesolimbic system.
abstract: Trace amine-associated receptor 1 (TAAR1) is a G protein-coupled receptor (GPCR) that is nonselectively activated by endogenous metabolites of amino acids. TAAR1 is considered a promising drug target for the treatment of psychiatric and neurodegenerative disorders. However, no selective ligand to identify TAAR1-specific signaling mechanisms is available yet. Here we report a selective TAAR1 antagonist, EPPTB, and characterize its physiological effects at dopamine (DA) neurons of the ventral tegmental area (VTA). We show that EPPTB prevents the reduction of the firing frequency of DA neurons induced by p-tyramine (p-tyr), a nonselective TAAR1 agonist. When applied alone, EPPTB increases the firing frequency of DA neurons, suggesting that TAAR1 either exhibits constitutive activity or is tonically activated by ambient levels of endogenous agonist(s). We further show that EPPTB blocks the TAAR1-mediated activation of an inwardly rectifying K(+) current. When applied alone, EPPTB induces an apparent inward current, suggesting the closure of tonically activated K(+) channels. Importantly, these EPPTB effects were absent in Taar1 knockout mice, ruling out off-target effects. We additionally found that both the acute application of EPPTB and the constitutive genetic lack of TAAR1 increase the potency of DA at D2 receptors in DA neurons. In summary, our data support that TAAR1 tonically activates inwardly rectifying K(+) channels, which reduces the basal firing frequency of DA neurons in the VTA. We hypothesize that the EPPTB-induced increase in the potency of DA at D2 receptors is part of a homeostatic feedback mechanism compensating for the lack of inhibitory TAAR1 tone.
authors.affiliation: Department of Biomedicine, Institute of Physiology, Pharmazentrum, University of Basel, CH-4056 Basel, Switzerland.
authors.forename: Amyaouch
authors.initials: A
authors.lastname: Bradaia
authors.forename: Gerhard
authors.initials: G
authors.lastname: Trube
authors.forename: Henri
authors.initials: H
authors.lastname: Stalder
authors.forename: Roger D
authors.initials: RD
authors.lastname: Norcross
authors.forename: Laurence
authors.initials: L
authors.lastname: Ozmen
authors.forename: Joseph G
authors.initials: JG
authors.lastname: Wettstein
authors.forename: Audrée
authors.initials: A
authors.lastname: Pinard
authors.forename: Danièle
authors.initials: D
authors.lastname: Buchy
authors.forename: Martin
authors.initials: M
authors.lastname: Gassmann
authors.forename: Marius C
authors.initials: MC
authors.lastname: Hoener
authors.forename: Bernhard
authors.initials: B
authors.lastname: Bettler
mesh_terms: D000200:Action Potentials / Q000502:physiology; D000818:Animals; D001549:Benzamides / Q000737:chemistry* / Q000378:metabolism*; D004298:Dopamine / Q000378:metabolism*; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels / Q000378:metabolism; D006801:Humans; D008032:Limbic System / Q000166:cytology / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D015394:Molecular Structure; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D009865:Oocytes / Q000166:cytology / Q000502:physiology; D018408:Patch-Clamp Techniques; D011759:Pyrrolidines / Q000737:chemistry* / Q000378:metabolism*; D051381:Rats; D017448:Receptors, Dopamine D2 / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors / Q000378:metabolism; D017557:Ventral Tegmental Area / Q000166:cytology / Q000378:metabolism; D014982:Xenopus laevis; D000095383:Trace Amine-Associated Receptors
chemical_list: D001549:Benzamides; D004298:Dopamine; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; D011759:Pyrrolidines; D017448:Receptors, Dopamine D2; D043562:Receptors, G-Protein-Coupled; D000095383:Trace Amine-Associated Receptors; C546333:N-(3-ethoxyphenyl)-4-pyrrolidin-1-yl-3-trifluoromethylbenzamide