Journal Article

Effect of the TAAR1 Partial Agonist Ralmitaront on Presynaptic Dopamine Synthesis Capacity Measured Using 18FDOPA PET in Naïve and Cocaine-Treated Mice

Irvine, Elaine E, Gerlach, Irene, Halff, Els F, Tang, Sac-Pham, Veronese, Mattia, Rutigliano, Grazia, Howes, Oliver D, Hoener, Marius C, Kokkinou, Michelle, Withers, Dominic J, Holiga, Štefan, Bonsall, David R, Natesan, Sridhar, Wells, Lisa A

2024

Overview

Elevated dopamine synthesis capacity is part of the pathophysiology of schizophrenia thought to underlie psychosis. Drugs that reduce this phenomenon could thus be potential treatments for these disorders. In this study, we evaluated the ability of the trace amine-associated receptor 1 (TAAR1) partial agonist ralmitaront to reduce presynaptic dopamine synthesis capacity.PurposeElevated dopamine synthesis capacity is part of the pathophysiology of schizophrenia thought to underlie psychosis. Drugs that reduce this phenomenon could thus be potential treatments for these disorders. In this study, we evaluated the ability of the trace amine-associated receptor 1 (TAAR1) partial agonist ralmitaront to reduce presynaptic dopamine synthesis capacity.Ralmitaront (3 mg/kg, i.p.), a TAAR1 partial agonist, was evaluated using [18F]DOPA PET for its ability to modulate presynaptic dopamine synthesis capacity in naïve mice as well as mice in an induced hyperdopaminergic state following acute cocaine administration (20 mg/kg, i.p.).ProceduresRalmitaront (3 mg/kg, i.p.), a TAAR1 partial agonist, was evaluated using [18F]DOPA PET for its ability to modulate presynaptic dopamine synthesis capacity in naïve mice as well as mice in an induced hyperdopaminergic state following acute cocaine administration (20 mg/kg, i.p.).Cocaine treatment on its own did not induce elevated dopamine synthesis capacity when compared to the control group. Pretreatment with ralmitaront significantly reduced dopamine synthesis capacity when given either alone (44%) or in combination with the psychostimulant cocaine (50%) when compared to the control group.ResultsCocaine treatment on its own did not induce elevated dopamine synthesis capacity when compared to the control group. Pretreatment with ralmitaront significantly reduced dopamine synthesis capacity when given either alone (44%) or in combination with the psychostimulant cocaine (50%) when compared to the control group.The TAAR1 agonist ralmitaront reduces striatal dopamine synthesis capacity, indexed as KiMod, both in naïve animals and when given prior to acute cocaine. This indicates the potential of TAAR1 agonism to address disorders characterized by striatal hyperdopaminergia.ConclusionsThe TAAR1 agonist ralmitaront reduces striatal dopamine synthesis capacity, indexed as KiMod, both in naïve animals and when given prior to acute cocaine. This indicates the potential of TAAR1 agonism to address disorders characterized by striatal hyperdopaminergia.