Activation of the trace amine-associated receptor 1 prevents relapse to cocaine seeking.
The trace amine-associated receptor 1 (TAAR1) has emerged as a promising target for medication development in addiction because of its ability to regulate dopamine (DA) transmission. We tested in rats the efficacy of RO5203648 and RO5256390, partial and full TAAR1 agonists, respectively, in models of cocaine relapse. Using a model of context-induced relapse, both RO5203648 and RO5256390 dose-dependently suppressed cocaine seeking after a 2-week period of withdrawal from chronic cocaine self-administration. In a model of extinction-reinstatement, RO5203648 completely inhibited cocaine-primed reinstatement of cocaine seeking. At doses that effectively suppressed cocaine seeking neither RO5203648 nor RO5256390 altered responding maintained by a natural reward. Moreover, fast scan cyclic voltammetry data showed that RO5203648 prevented cocaine-induced DA overflow in the nucleus accumbens without altering DA half-life, suggesting that the partial TAAR1 agonist attenuated cocaine-stimulated DA overflow by mechanisms other than direct interference with DA uptake. Collectively, these data provide strong evidence in support of TAAR1 as a neuropharmacological target for the treatment of cocaine addiction.
Behavioural Neuroscience, Department of Psychology, University of Canterbury, Christchurch, New Zealand.
Yui
Y
Pei
Behavioural Neuroscience, Department of Psychology, University of Canterbury, Christchurch, New Zealand.
Jungah
J
Lee
Department of Neuroscience and Brain Technologies, Italian Institute of Technology, Genoa, Italy.
Damiana
D
Leo
1] Department of Neuroscience and Brain Technologies, Italian Institute of Technology, Genoa, Italy [2] Skolkovo Institute of Science and Technology, Skolkovo, Russia [3] Faculty of Biology and Soil Science, St Petersburg State University, St Petersburg, Russia.
Raul R
RR
Gainetdinov
Neuroscience Research, Pharmaceuticals Division, F Hoffmann-La Roche, Basel, Switzerland.
Marius C
MC
Hoener
Behavioural Neuroscience, Department of Psychology, University of Canterbury, Christchurch, New Zealand.
Juan J
JJ
Canales
D000818:Animals; D002491:Central Nervous System Agents / Q000494:pharmacology*; D002908:Chronic Disease; D003042:Cocaine / Q000008:administration & dosage; D019970:Cocaine-Related Disorders / Q000188:drug therapy* / Q000503:physiopathology; D004298:Dopamine / Q000378:metabolism; D018765:Dopamine Uptake Inhibitors / Q000008:administration & dosage; D004305:Dose-Response Relationship, Drug; D058999:Drug-Seeking Behavior / Q000187:drug effects* / Q000502:physiology; D005108:Extinction, Psychological / Q000187:drug effects / Q000502:physiology; D008297:Male; D009714:Nucleus Accumbens / Q000187:drug effects / Q000503:physiopathology; D010080:Oxazoles / Q000494:pharmacology*; D011897:Random Allocation; D051381:Rats; D020318:Rats, Long-Evans; D043562:Receptors, G-Protein-Coupled / Q000819:agonists* / Q000378:metabolism; D012646:Self Administration; D000095383:Trace Amine-Associated Receptors
D002491:Central Nervous System Agents; D003042:Cocaine; D004298:Dopamine; 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