title: The trace amine-associated receptor 1 modulates methamphetamine's neurochemical and behavioral effects.
abstract: The newly discovered trace amine-associated receptor 1 (TAAR1) has the ability to regulate both dopamine function and psychostimulant action. Here, we tested in rats the ability of RO5203648, a selective TAAR1 partial agonist, to modulate the physiological and behavioral effects of methamphetamine (METH). In experiment 1, RO5203468 dose- and time-dependently altered METH-induced locomotor activity, manifested as an early attenuation followed by a late potentiation of METH's stimulating effects. In experiment 2, rats received a 14-day treatment regimen during which RO5203648 was co-administered with METH. RO5203648 dose-dependently attenuated METH-stimulated hyperactivity, with the effects becoming more apparent as the treatments progressed. After chronic exposure and 3-day withdrawal, rats were tested for locomotor sensitization. RO5203648 administration during the sensitizing phase prevented the development of METH sensitization. However, RO5203648, at the high dose, cross-sensitized with METH. In experiment 3, RO5203648 dose-dependently blocked METH self-administration without affecting operant responding maintained by sucrose, and exhibited lack of reinforcing efficacy when tested as a METH's substitute. Neurochemical data showed that RO5203648 did not affect METH-mediated DA efflux and uptake inhibition in striatal synaptosomes. In vivo, however, RO5203648 was able to transiently inhibit METH-induced accumulation of extracellular DA levels in the nucleus accumbens. Taken together, these data highlight the significant potential of TAAR1 to modulate METH's neurochemical and behavioral effects.
authors.affiliation: Department of Psychology, University of Canterbury Christchurch, New Zealand.
authors.forename: Rachel
authors.initials: R
authors.lastname: Cotter
authors.affiliation: Department of Psychology, University of Canterbury Christchurch, New Zealand ; Behavioural Neuroscience, School of Psychology, University of Leicester Leicester, UK.
authors.forename: Yue
authors.initials: Y
authors.lastname: Pei
authors.affiliation: Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia Genoa, Italy.
authors.forename: Liudmila
authors.initials: L
authors.lastname: Mus
authors.affiliation: Neuroscience Research, Pharmaceuticals Division, F. Hoffmann-La Roche Ltd. Basel, Switzerland.
authors.forename: Anja
authors.initials: A
authors.lastname: Harmeier
authors.affiliation: Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia Genoa, Italy ; Skolkovo Institute of Science and Technology Skolkovo, Moscow, Russia ; Faculty of Biology, St. Petersburg State University St. Petersburg, Russia.
authors.forename: Raul R
authors.initials: RR
authors.lastname: Gainetdinov
authors.affiliation: Neuroscience Research, Pharmaceuticals Division, F. Hoffmann-La Roche Ltd. Basel, Switzerland.
authors.forename: Marius C
authors.initials: MC
authors.lastname: Hoener
authors.affiliation: Behavioural Neuroscience, School of Psychology, University of Leicester Leicester, UK.
authors.forename: Juan J
authors.initials: JJ
authors.lastname: Canales
keywords: methamphetamine; microdialysis; self-administration; sensitization; synaptosomes; trace amine-associated receptor