title: TAAR1 activation modulates monoaminergic neurotransmission, preventing hyperdopaminergic and hypoglutamatergic activity.
abstract: The trace amine-associated receptor 1 (TAAR1), activated by endogenous metabolites of amino acids like the trace amines p-tyramine and β-phenylethylamine, has proven to be an important modulator of the dopaminergic system and is considered a promising target for the treatment of neuropsychiatric disorders. To decipher the brain functions of TAAR1, a selective TAAR1 agonist, RO5166017, was engineered. RO5166017 showed high affinity and potent functional activity at mouse, rat, cynomolgus monkey, and human TAAR1 stably expressed in HEK293 cells as well as high selectivity vs. other targets. In mouse brain slices, RO5166017 inhibited the firing frequency of dopaminergic and serotonergic neurons in regions where Taar1 is expressed (i.e., the ventral tegmental area and dorsal raphe nucleus, respectively). In contrast, RO5166017 did not change the firing frequency of noradrenergic neurons in the locus coeruleus, an area devoid of Taar1 expression. Furthermore, modulation of TAAR1 activity altered the desensitization rate and agonist potency at 5-HT(1A) receptors in the dorsal raphe, suggesting that TAAR1 modulates not only dopaminergic but also serotonergic neurotransmission. In WT but not Taar1(-/-) mice, RO5166017 prevented stress-induced hyperthermia and blocked dopamine-dependent hyperlocomotion in cocaine-treated and dopamine transporter knockout mice as well as hyperactivity induced by an NMDA antagonist. These results tie TAAR1 to the control of monoamine-driven behaviors and suggest anxiolytic- and antipsychotic-like properties for agonists such as RO5166017, opening treatment opportunities for psychiatric disorders.
authors.affiliation: Neuroscience Research, Pharmaceuticals Division, F. Hoffmann-La Roche Ltd., CH-4070 Basel, Switzerland.
authors.forename: Florent G
authors.initials: FG
authors.lastname: Revel
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Moreau
authors.forename: Raul R
authors.initials: RR
authors.lastname: Gainetdinov
authors.forename: Amyaouch
authors.initials: A
authors.lastname: Bradaia
authors.forename: Tatyana D
authors.initials: TD
authors.lastname: Sotnikova
authors.forename: Roland
authors.initials: R
authors.lastname: Mory
authors.forename: Sean
authors.initials: S
authors.lastname: Durkin
authors.forename: Katrin Groebke
authors.initials: KG
authors.lastname: Zbinden
authors.forename: Roger
authors.initials: R
authors.lastname: Norcross
authors.forename: Claas A
authors.initials: CA
authors.lastname: Meyer
authors.forename: Veit
authors.initials: V
authors.lastname: Metzler
authors.forename: Sylvie
authors.initials: S
authors.lastname: Chaboz
authors.forename: Laurence
authors.initials: L
authors.lastname: Ozmen
authors.forename: Gerhard
authors.initials: G
authors.lastname: Trube
authors.forename: Bruno
authors.initials: B
authors.lastname: Pouzet
authors.forename: Bernhard
authors.initials: B
authors.lastname: Bettler
authors.forename: Marc G
authors.initials: MG
authors.lastname: Caron
authors.forename: Joseph G
authors.initials: JG
authors.lastname: Wettstein
authors.forename: Marius C
authors.initials: MC
authors.lastname: Hoener
mesh_terms: D000818:Animals; D052117:Benzodioxoles / Q000494:pharmacology; D015306:Biogenic Monoamines / Q000378:metabolism*; D004298:Dopamine / Q000378:metabolism; D005973:Glutamine / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D001523:Mental Disorders; D051379:Mice; D010666:Phenylpropionates / Q000494:pharmacology; D043562:Receptors, G-Protein-Coupled / Q000819:agonists / Q000172:deficiency / Q000378:metabolism*; D009435:Synaptic Transmission / Q000502:physiology*; D000095383:Trace Amine-Associated Receptors
chemical_list: D052117:Benzodioxoles; D015306:Biogenic Monoamines; D004298:Dopamine; D005973:Glutamine; D010666:Phenylpropionates; D043562:Receptors, G-Protein-Coupled; D000095383:Trace Amine-Associated Receptors; C551588:4-(3-(6-(3-benzo(1,3)dioxol-5-yl-5-thiophen-3-ylphenoxy)hexyl)-2-(2-carboxyethyl)phenoxy)butyric acid