TAAR1 activation modulates monoaminergic neurotransmission, preventing hyperdopaminergic and hypoglutamatergic activity

Abstract

The trace amine-associated receptor 1 (TAAR1), activated by endogenous metabolites of amino acids like the trace amines p-tyramine and β-phenylethylamine, has proven to be an important modulator of the dopaminergic system and is considered a promising target for the treatment of neuropsychiatric disorders. To decipher the brain functions of TAAR1, a selective TAAR1 agonist, RO5166017, was engineered. RO5166017 showed high affinity and potent functional activity at mouse, rat, cynomolgus monkey, and human TAAR1 stably expressed in HEK293 cells as well as high selectivity vs. other targets. In mouse brain slices, RO5166017 inhibited the firing frequency of dopaminergic and serotonergic neurons in regions where Taar1 is expressed (i.e., the ventral tegmental area and dorsal raphe nucleus, respectively). In contrast, RO5166017 did not change the firing frequency of noradrenergic neurons in the locus coeruleus, an area devoid of Taar1 expression. Furthermore, modulation of TAAR1 activity altered the desensitization rate and agonist potency at 5-HT 1A receptors in the dorsal raphe, suggesting that TAAR1 modulates not only dopaminergic but also serotonergic neurotransmission. In WT but not Taar1 −/− mice, RO5166017 prevented stress-induced hyperthermia and blocked dopamine-dependent hyperlocomotion in cocaine-treated and dopamine transporter knockout mice as well as hyperactivity induced by an NMDA antagonist. These results tie TAAR1 to the control of monoamine-driven behaviors and suggest anxiolyticand antipsychotic-like properties for agonists such as RO5166017, opening treatment opportunities for psychiatric disorders.drug discovery | serotonin | depression | schizophrenia | anxiety

Trace Amine-Associated Receptor 1 Regulation of Methamphetamine Intake and Related Traits

“…These genes are not located on mouse chromosome 10, and are therefore not candidates for the QTG in that region (Belknap et al, 2013). However, Taar1 is within the QTL interval, and it modulates monoamine levels by altering transporter function in mice and primates (Miller, 2011(Miller, ,2012Revel et al, 2011;Miller, 2008,2009). Furthermore, Taar1 − / − mice exhibit lower basal levels and greater amphetamine-induced release of DA in the striatum, compared with +/+ mice (Lindemann et al, 2008;Wolinsky et al, 2007).…”

“…For example, pretreatment with the TAAR1 agonist, RO5263397, reduces operant selfadministration of MA in rats (Jing et al, 2015). Trace amines, such as p-tyramine, β-phenylethylamine, octopamine, and tryptamine, interact with this G protein-coupled receptor (Borowsky et al, 2001;Bunzow et al, 2001;Lindemann et al, 2005;Wolinsky et al, 2007), and TAAR1 modulates monoamine activity, in part, through regulation of neurotransmitter availability and disposition (Revel et al, 2011;Xie and Miller, 2008). TAAR1 agonists reduce endogenous firing of dopaminergic (DA), noradrenergic (NE), and serotonergic (5-HT) neurons, and Taar1 knockout (− / − ) mice exhibit greater amphetamine-induced release of these neurotransmitters in the striatum, compared with wild-type (+/+) littermates (Lindemann et al, 2008;Wolinsky et al, 2007).…”

A Decade of Pharma Discovery Delivers New Tools Targeting Trace Amine-Associated Receptor 1

“…They have also reported the development of two lines of genetically engineered mice, one lacking TAAR1 and the other overexpressing TAAR1 in neurons (this issue of NPP). Their studies involving TAAR1 knockout mice reveal an elevated spontaneous firing frequency of midbrain dopamine neurons and a hypersensitivity to amphetamine (Revel et al, 2011). At face value, these data suggest TAAR1-mediated signaling normally exerts an inhibitory tone on dopamine neuron activity.…”

“…However, reaching a consensus as to how TAAR1-mediated signaling at the cellular level influences physiology and ultimately the behavior of wild-type animals has proven more challenging (Ledonne et al, 2011;MJ Beckstead, personal communication). Similarly, some report TAAR1 expression in dopamine-and serotoninproducing brain areas (Revel et al, 2012a;Revel et al, 2011;Xie et al, 2007), whereas others have had difficulty replicating these observations (Ledonne et al, 2011;Liberles and Buck, 2006). To fully understand the role(s) of TAAR1-mediated signaling in health and disease, these disparate experimental findings must be reconciled.…”

“…In the course of their TAAR1 medication development effort, Hoffmann-La Roche has publically disclosed the first and so far only TAAR1-selective antagonist, EPPTB; the first TAAR1-selective agonist (RO5166017; Revel et al, 2011); and the partial agonists RO5203648 (Revel et al, 2011) and RO5073012 (Revel et al, 2012a). They have also reported the development of two lines of genetically engineered mice, one lacking TAAR1 and the other overexpressing TAAR1 in neurons (this issue of NPP).…”