title: Selective activation of the trace amine-associated receptor 1 decreases cocaine's reinforcing efficacy and prevents cocaine-induced changes in brain reward thresholds.
abstract: The newly discovered trace amine-associated receptor 1 (TAAR1) has emerged as a promising target for medication development in stimulant addiction due to its ability to regulate dopamine (DA) function and modulate stimulants' effects. Recent findings indicate that TAAR1 activation blocks some of the abuse-related physiological and behavioral effects of cocaine. However, findings from existing self-administration studies are inconclusive due to the very limited range of cocaine unit doses tested. Here, in order to shed light on the influence of TAAR1 on cocaine's reward and reinforcement, we studied the effects of partial and full activation of TAAR1on (1) the dose-response curve for cocaine self-administration and (2) cocaine-induced changes in intracranial self-stimulation (ICSS). In the first experiment, we examined the effects of the selective full and partial TAAR1 agonists, RO5256390 and RO5203648, on self-administration of five unit-injection doses of cocaine (0.03, 0.1, 0.2, 0.45, and 1mg/kg/infusion). Both agonists induced dose-dependent downward shifts in the cocaine dose-response curve, indicating that both partial and full TAAR1 activation decrease cocaine, reinforcing efficacy. In the second experiment, RO5256390 and the partial agonist, RO5263397, dose-dependently prevented cocaine-induced lowering of ICSS thresholds. Taken together, these data demonstrated that TAAR1 stimulation effectively suppresses the rewarding and reinforcing effects of cocaine in self-administration and ICSS models, supporting the candidacy of TAAR1 as a drug discovery target for cocaine addiction.
authors.affiliation: School of Psychology, University of Leicester, Leicester, United Kingdom; Department of Psychology, University of Canterbury, Christchurch, New Zealand.
authors.forename: Yue
authors.initials: Y
authors.lastname: Pei
authors.affiliation: Neuroscience, Ophthalmology and Rare Diseases Discovery & Translational Area, pRED, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Basel, Switzerland.
authors.forename: Patrick
authors.initials: P
authors.lastname: Mortas
authors.affiliation: Neuroscience, Ophthalmology and Rare Diseases Discovery & Translational Area, pRED, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Basel, Switzerland.
authors.forename: Marius C
authors.initials: MC
authors.lastname: Hoener
authors.affiliation: School of Psychology, University of Leicester, Leicester, United Kingdom. Electronic address: jjc30@leicester.ac.uk.
authors.forename: Juan J
authors.initials: JJ
authors.lastname: Canales
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001921:Brain / Q000187:drug effects*; D003042:Cocaine / Q000494:pharmacology*; D003216:Conditioning, Operant / Q000187:drug effects; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D008297:Male; D010080:Oxazoles / Q000008:administration & dosage; D051381:Rats; D020318:Rats, Long-Evans; D043562:Receptors, G-Protein-Coupled / Q000819:agonists / Q000378:metabolism*; D012201:Reward; D012646:Self Administration; D017557:Ventral Tegmental Area / Q000187:drug effects / Q000378:metabolism; D000095383:Trace Amine-Associated Receptors
chemical_list: D003042:Cocaine; D018765:Dopamine Uptake Inhibitors; D010080:Oxazoles; D043562:Receptors, G-Protein-Coupled; D000095383:Trace Amine-Associated Receptors; C580579:4-(3,4-dichlorophenyl)-4,5-dihydrooxazol-2-ylamine; C000596180:4-(3-fluoro-2-methylphenyl)-4,5-dihydrooxazol-2-ylamine
keywords: Cocaine; Intracranial self-stimulation; Reward; Self-administration; Trace amine-associated receptor 1