[Show abstract][Hide abstract] 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 behavioural 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 behavioural effects.
[Show abstract][Hide abstract] ABSTRACT: Dysregulation of monoaminergic neurotransmission is a hallmark of major neuropsychiatric disorders. The trace amine-associated receptor 1 (TAAR1) is a Galphas protein-coupled receptor activated by trace amines like p-tyramine and beta-phenylethylamine, endogenous compounds with structural similarity to biogenic amines. Through a medicinal chemistry program the first potent and selective TAAR1 ligands were identified and further optimized for their physicochemical and pharmacokinetic properties in rat, Cynomolgus monkey and human. By manipulating TAAR1 activity using these optimized ligands and Taar1 knock-out as well as Taar1 overexpressing animals, we showed that TAAR1 modulated dopaminergic, serotonergic and glutamatergic neurotransmission. In rodents, activation of TAAR1 by these compounds blocked psychostimulant-induced hyperactivity and reversed cocaine-induced facilitation of intra-cranial self-stimulation of the ventral tegmental area. Importantly, TAAR1 agonists did not induce the typical side-effects produced by current antipsychotic drugs such as catalepsy or weight gain in rats. TAAR1 agonism even reduced haloperidol-induced catalepsy and, remarkably, prevented olanzapine from increasing body weight and fat accumulation and controlled glucose levels. Moreover, TAAR1 agonists produced pro-cognitive effects in rodents and non-human primates, and were active in models indicative for negative symptoms and showed anti-addictive properties in rats. These data suggest that TAAR1 agonists represent a novel and differentiated option versus existing therapies for treating schizophrenia with better efficacy and, given the beneficial metabolic and anti-diabetic effects, may provide an additional benefit by not increasing metabolic syndrome like current antipsychotic drugs. Proof-of-concept studies in humans are now awaited to determine whether these findings translate into therapeutic advances.
European Neuropsychopharmacology 10/2014; 24:S115. · 5.40 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: BACKGROUND: Trace amines, compounds structurally related to classical biogenic amines, represent endogenous ligands of the trace amine-associated receptor 1 (TAAR1). Because trace amines also influence the activity of other targets, selective ligands are needed for the elucidation of TAAR1 function. Here we report on the identification and characterization of the first selective and potent TAAR1 partial agonist. METHODS: The TAAR1 partial agonist RO5203648 was evaluated for its binding affinity and functional activity at rodent and primate TAAR1 receptors stably expressed in HEK293 cells, for its physicochemical and pharmacokinetic properties, for its effects on the firing frequency of monoaminergic neurons ex vivo, and for its properties in vivo with genetic and pharmacological models of central nervous system disorders. RESULTS: RO5203648 showed high affinity and potency at TAAR1, high selectivity versus other targets, and favorable pharmacokinetic properties. In mouse brain slices, RO5203648 increased the firing frequency of dopaminergic and serotonergic neurons in the ventral tegmental area and the dorsal raphe nucleus, respectively. In various behavioral paradigms in rodents and monkeys, RO5203648 demonstrated clear antipsychotic- and antidepressant-like activities as well as potential anxiolytic-like properties. Furthermore, it attenuated drug-taking behavior and was highly effective in promoting attention, cognitive performance, and wakefulness. CONCLUSIONS: With the first potent and selective TAAR1 partial agonist, RO5203648, we show that TAAR1 is implicated in a broad range of relevant physiological, behavioral, and cognitive neuropsychiatric dimensions. Collectively, these data uncover important neuromodulatory roles for TAAR1 and suggest that agonists at this receptor might have therapeutic potential in one or more neuropsychiatric domains.