title: Taar1-mediated modulation of presynaptic dopaminergic neurotransmission: role of D2 dopamine autoreceptors.
abstract: Trace Amine-Associated Receptor 1 (TAAR1) is a G protein-coupled receptor (GPCR) expressed in several mammalian brain areas and activated by "trace amines" (TAs). TAs role is unknown; however, discovery of their receptors provided an opportunity to investigate their functions. In vivo evidence has indicated an inhibitory influence of TAAR1 on dopamine (DA) neurotransmission, presumably via modulation of dopamine transporter (DAT) or interaction with the D2 DA receptor and/or activation of inwardly rectifying K(+) channels. To elucidate the mechanisms of TAAR1-dependent modulation, we used TAAR1 knockout mice (TAAR1-KO), a TAAR1 agonist (RO5166017) and a TAAR1 antagonist (EPPTB) in a set of neurochemical experiments. Analysis of the tissue content of TAAR1-KO revealed increased level of the DA metabolite homovanillic acid (HVA), and in vivo microdialysis showed increased extracellular DA in the nucleus accumbens (NAcc) of TAAR1-KO. In fast scan cyclic voltammetry (FSCV) experiments, the evoked DA release was higher in the TAAR1-KO NAcc. Furthermore, the agonist RO5166017 induced a decrease in the DA release in wild-type that could be prevented by the application of the TAAR1 antagonist EPPTB. No alterations in DA clearance, which are mediated by the DAT, were observed. To evaluate the interaction between TAAR1 and D2 autoreceptors, we tested the autoreceptor-mediated dynamics. Only in wild type mice, the TAAR1 agonist was able to potentiate quinpirole-induced inhibitory effect on DA release. Furthermore, the short-term plasticity of DA release following paired pulses was decreased in TAAR1-KO, indicating less autoinhibition of D2 autoreceptors. These observations suggest a close interaction between TAAR1 and the D2 autoreceptor regulation.
authors.affiliation: Department of Neuroscience and Brain Technology, Istituto Italiano di Tecnologia, 16163, Genova, Italy. Electronic address: damiana.leo@iit.it.
authors.forename: D
authors.initials: D
authors.lastname: Leo
authors.affiliation: Department of Neuroscience and Brain Technology, Istituto Italiano di Tecnologia, 16163, Genova, Italy. Electronic address: liudmila.mus@iit.it.
authors.forename: L
authors.initials: L
authors.lastname: Mus
authors.affiliation: Department of Neuroscience and Brain Technology, Istituto Italiano di Tecnologia, 16163, Genova, Italy. Electronic address: stefano.espinoza@iit.it.
authors.forename: S
authors.initials: S
authors.lastname: Espinoza
authors.affiliation: Neuroscience Research, Pharmaceuticals Division, F. Hoffmann-La Roche Ltd., CH-4070 Basel, Switzerland. Electronic address: marius.hoener@roche.com.
authors.forename: M C
authors.initials: MC
authors.lastname: Hoener
authors.affiliation: Department of Neuroscience and Brain Technology, Istituto Italiano di Tecnologia, 16163, Genova, Italy. Electronic address: tatiana.sotnikova@iit.it.
authors.forename: T D
authors.initials: TD
authors.lastname: Sotnikova
authors.affiliation: Department of Neuroscience and Brain Technology, Istituto Italiano di Tecnologia, 16163, Genova, Italy; Skolkovo Institute of Science and Technology, Skolkovo, 143025, Moscow Region, Russia; Faculty of Biology and Soil Science, St. Petersburg State University, 199034, St. Petersburg, Russia. Electronic address: raul.gainetdinov@iit.it.
authors.forename: R R
authors.initials: RR
authors.lastname: Gainetdinov
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D015306:Biogenic Monoamines / Q000378:metabolism; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D004298:Dopamine / Q000378:metabolism; D015259:Dopamine Agents / Q000494:pharmacology; D059290:Dopaminergic Neurons / Q000187:drug effects / Q000502:physiology*; D055664:Electrochemical Techniques; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010080:Oxazoles / Q000494:pharmacology; D010627:Phenethylamines / Q000494:pharmacology; D017729:Presynaptic Terminals / Q000378:metabolism*; D011759:Pyrrolidines / Q000494:pharmacology; D017448:Receptors, Dopamine D2 / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology*; D000095383:Trace Amine-Associated Receptors
chemical_list: D001549:Benzamides; D015306:Biogenic Monoamines; D004298:Dopamine; D015259:Dopamine Agents; D010080:Oxazoles; D010627:Phenethylamines; 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; C583451:RO5166017
keywords: Dopamine (DA); Dopamine receptor 2 (D2R); Fast scan cyclic voltammetry (FSCV); Neuropsychiatric disorders; Schizophrenia; Trace amine-associate receptor 1 (TAAR1)