title: Brain-specific overexpression of trace amine-associated receptor 1 alters monoaminergic neurotransmission and decreases sensitivity to amphetamine.
abstract: Trace amines (TAs) such as β-phenylethylamine, p-tyramine, or tryptamine are biogenic amines found in the brain at low concentrations that have been implicated in various neuropsychiatric disorders like schizophrenia, depression, or attention deficit hyperactivity disorder. TAs are ligands for the recently identified trace amine-associated receptor 1 (TAAR1), an important modulator of monoamine neurotransmission. Here, we sought to investigate the consequences of TAAR1 hypersignaling by generating a transgenic mouse line overexpressing Taar1 specifically in neurons. Taar1 transgenic mice did not show overt behavioral abnormalities under baseline conditions, despite augmented extracellular levels of dopamine and noradrenaline in the accumbens nucleus (Acb) and of serotonin in the medial prefrontal cortex. In vitro, this was correlated with an elevated spontaneous firing rate of monoaminergic neurons in the ventral tegmental area, dorsal raphe nucleus, and locus coeruleus as the result of ectopic TAAR1 expression. Furthermore, Taar1 transgenic mice were hyposensitive to the psychostimulant effects of amphetamine, as it produced only a weak locomotor activation and failed to alter catecholamine release in the Acb. Attenuating TAAR1 activity with the selective partial agonist RO5073012 restored the stimulating effects of amphetamine on locomotion. Overall, these data show that Taar1 brain overexpression causes hyposensitivity to amphetamine and alterations of monoaminergic neurotransmission. These observations confirm the modulatory role of TAAR1 on monoamine activity and suggest that in vivo the receptor is either constitutively active and/or tonically activated by ambient levels of endogenous agonist(s).
authors: Neuroscience Research, Pharmaceuticals Division, F. Hoffmann-La Roche Ltd., Basel, Switzerland.
authors: Florent G
authors: FG
authors: Revel
authors: Claas A
authors: CA
authors: Meyer
authors: Amyaouch
authors: A
authors: Bradaia
authors: Karine
authors: K
authors: Jeanneau
authors: Eleonora
authors: E
authors: Calcagno
authors: Cédric B
authors: CB
authors: André
authors: Markus
authors: M
authors: Haenggi
authors: Marie-Thérèse
authors: MT
authors: Miss
authors: Guido
authors: G
authors: Galley
authors: Roger D
authors: RD
authors: Norcross
authors: Roberto W
authors: RW
authors: Invernizzi
authors: Joseph G
authors: JG
authors: Wettstein
authors: Jean-Luc
authors: JL
authors: Moreau
authors: Marius C
authors: MC
authors: Hoener
mesh_terms: D000661:Amphetamine / Q000494:pharmacology*; D000814:Aniline Compounds / Q000494:pharmacology; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D015306:Biogenic Monoamines / Q000502:physiology*; D001923:Brain Chemistry / Q000502:physiology*; D000697:Central Nervous System Stimulants / Q000494:pharmacology*; D059290:Dopaminergic Neurons / Q000187:drug effects; D055724:Electrophysiological Phenomena; D007093:Imidazoles / Q000494:pharmacology; D066298:In Vitro Techniques; D051379:Mice; D008810:Mice, Inbred C57BL; D017551:Microdialysis; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D018408:Patch-Clamp Techniques; D010641:Phenotype; D043562:Receptors, G-Protein-Coupled / Q000096:biosynthesis* / Q000502:physiology*; D009435:Synaptic Transmission / Q000502:physiology*; D017557:Ventral Tegmental Area / Q000187:drug effects / Q000502:physiology; D005680:gamma-Aminobutyric Acid / Q000502:physiology; D000095383:Trace Amine-Associated Receptors
chemical_list: D000661:Amphetamine; D000814:Aniline Compounds; D015306:Biogenic Monoamines; D000697:Central Nervous System Stimulants; D007093:Imidazoles; D043562:Receptors, G-Protein-Coupled; D005680:gamma-Aminobutyric Acid; D000095383:Trace Amine-Associated Receptors; C576475:(4-chlorophenyl)-(1H-imidazol-4-ylmethyl)-isopropyl-amine