The Trace Amine-Associated Receptor 1 (TAAR1)

A new perspective for schizophrenia: TAAR1 agonists reveal antipsychotic- and antidepressant-like activity, improve cognition and control body weight.

Schizophrenia is a chronic, severe and highly complex mental illness. Current treatments manage the positive symptoms, yet have minimal effects on the negative and cognitive symptoms, two prominent features of the disease with critical impact on the long-term morbidity. In addition, antipsychotic treatments trigger serious side effects that precipitate treatment discontinuation. Here, we show that activation of the trace amine-associated receptor 1 (TAAR1), a modulator of monoaminergic neurotransmission, represents a novel therapeutic option. In rodents, activation of TAAR1 by two novel and pharmacologically distinct compounds, the full agonist RO5256390 and the partial agonist RO5263397, blocks psychostimulant-induced hyperactivity and produces a brain activation pattern reminiscent of the antipsychotic drug olanzapine, suggesting antipsychotic-like properties. TAAR1 agonists do not induce catalepsy or weight gain; RO5263397 even reduced haloperidol-induced catalepsy and prevented olanzapine from increasing body weight and fat accumulation. Finally, TAAR1 activation promotes vigilance in rats and shows pro-cognitive and antidepressant-like properties in rodent and primate models. These data suggest that TAAR1 agonists may provide a novel and differentiated treatment of schizophrenia as compared with current medication standards: TAAR1 agonists may improve not only the positive symptoms but also the negative symptoms and cognitive deficits, without causing adverse effects such as motor impairments or weight gain.

TAAR1 Modulates Cortical Glutamate NMDA Receptor Function.

Trace Amine-Associated Receptor 1 (TAAR1) is a G protein-coupled receptor expressed in the mammalian brain and known to influence subcortical monoaminergic transmission. Monoamines, such as dopamine, play also an important role within the prefrontal cortex (PFC) circuitry, which is critically involved in high order cognitive processes. TAAR1 selective ligands have shown potential antipsychotic, antidepressant and pro-cognitive effects in experimental animal models; however, it remains unclear if TAAR1 can affect PFC-related processes and functions. In this study, we document distinct pattern of expression of TAAR1 in the PFC, as well as altered subunit composition and deficient functionality of the glutamate N-methyl-D-aspartate (NMDA) receptors in the pyramidal neurons of layer V of PFC in mice lacking TAAR1. The dysregulated cortical glutamate transmission in TAAR1-KO mice was associated with aberrant behaviors in several tests, indicating a perseverative and impulsive phenotype of mutants. Conversely, pharmacological activation of TAAR1 with selective agonists reduced premature impulsive responses observed in the fixed-interval conditioning schedule in normal mice. Our study indicates that TAAR1 plays an important role in the modulation of NMDA receptor-mediated glutamate transmission in the PFC and related functions. Furthermore, these data suggest that development of TAAR1-based drugs could provide a novel therapeutic approach for the treatment of disorders related to aberrant cortical functions.

“Recently, TAAR1 functions have been extensively characterized, with particular attention paid to its role in the modulation of the midbrain dopamine system and its possible implications in psychiatric diseases. TAAR1 knockout (TAAR1-KO) mice display a higher sensitivity to amphetamine and other psychostimulants , and seem to have a supersensitive dopaminergic system, making them an interesting model relevant for schizophrenia. Accordingly, both full and partial TAAR1 selective agonists are efficacious in experimental rodent models of psychosis, such as pharmacologic or genetic mouse models of hyperdopaminergia, further supporting the idea that TAAR1 could represent a novel target for psychiatric diseases. Although there is evidence suggesting a potential TAAR1 involvement in cognitive functions, no studies evaluated TAAR1 role in cortical regions so far. Recently, it has been shown that TAAR1 agonists were able to suppress hyperactivity in pharmacologic or genetic mouse models of glutamate NMDA receptor deficiency and improved cognition in rats treated with the glutamate NMDA receptor antagonist phencyclidine (PCP). Intriguingly also,TAAR1 agonists, tested in phMRI studies in mice, shared a similar pattern of brain activation with the antipsychotic olanzapine with the most prominent activation being observed in the medial PFC.”

TAAR1 activation modulates monoaminergic neurotransmission, preventing hyperdopaminergic and hypoglutamatergic activity.

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 anxiolytic- and antipsychotic-like properties for agonists such as RO5166017, opening treatment opportunities for psychiatric disorders

Trace Amine-Associated Receptor 1 Partial Agonism Reveals Novel Paradigm for Neuropsychiatric Therapeutics.

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.

A “D-cell hypothesis” of schizophrenia has been proposed:

“In brains of patients with schizophrenia, the number of D-neurons is reduced in the striatum and nucleus accumbens, and this might cause the decrease of amounts of trace amines though the direct evidences have not yet been shown. The decrease of striatal D-neurons may be due to dysfunction of neural stem cells in the subventricular zone of lateral ventricle, as previously described. Enlargement of the lateral ventricle, a usual finding documented in brain imaging studies of schizophrenia, may also be due to dysfunction of neural stem cells of the subventricular zone.

The decrease of TAAR1 stimulation on VTA DA neurons increased the firing frequency of VTA DA neurons. This mechanism, which has recently been explored using animal models, may cause mesolimbic DA hyperactivity.

DA hyperactivity in the striatum might also inhibit forebrain neural stem cell proliferation, as Kippen et al. showed, and may lead additional decrease of D-neurons, which may induce additional hyperactivity of mesolimbic DA system. Actions of D2 blocking agents in pharmacotherapy of schizophrenia might partially be explained by the decrease of inhibition to forebrain neural stem cell proliferations. It might be consistent with the clinical experiences that D2 blocker is effective for treatment of schizophrenia.”

https://i1.wp.com/file.scirp.org/Html/17-3900091%5C35e36c0a-29b5-4827-a2ed-832e6ebbe9ba.jpg
Schema of “D-cell hypothesis” of schizophrenia: So-called D-cells, as trace amine-producing cells, might be a clue for elucidating pathogenesis of DA hyperactivity of schizophrenia.

Trace amine-associated receptors: ligands, neural circuits, and behaviors

“TAAR1 functions in the brain to regulate neuron excitability and neurotransmitter usage. TAAR1 agonists include putative trace amines (tyramine, octopamine, tryptamine, 2-phenylethylamine), psychoactive chemicals (amphetamines), thyronamines, and other amines. These chemicals exert various physiological effects, presumably through TAAR1-dependent and TAAR1-independent mechanisms; for example, thryonamine-induced hypothermia persists in TAAR1 knockout mice. Synthetic agonists and antagonists with improved specificity for TAAR1 acutely modulate aminergic neuron firing with effects eliminated in TAAR1 knockout mice. Furthermore, aminergic neurons fire at elevated rates in TAAR1 knockout mice, with TAAR1 inhibitory effects mediated through Gαs and inwardly rectifying potassium channels”

Interactions between TAAR1 and the dopamine D2 receptor have been studied. D2R antagonists enhanced the TAAR1-mediated increase in cAMP, possibly by disrupting TAAR1-D2R interaction [1]  A recent study revealed that postsynaptic D2 dopamine receptor supersensitivity develops in the striatum of mice lacking TAAR1 [2]

TAAR1 plays a role in the functional regulation of monoamine transporters and the neuronal regulatory mechanisms that modulate dopaminergic activity [3] Expanding on this, Leo et al. (2014) found a close interaction between TAAR1 and D2 autoreceptor regulation which seemed to mediate the inhibitory influence of TAAR1 on dopamine neurotransmission. Other mechanisms such as modulation of dopamine transporter (DAT), or activation of inwardly rectifying K(+) channels were not observed in their study [4]

There may be a role for trace amine systems in clozapine-mediated effects [5]

TAAR1 has been implicated in the behavioral and reinforcement-related effects of psychostimulants [6, 7, 8] and ethanol [9]. Modulation of TAAR1 is a promising target in the search for new therapeutics for the treatment of addiction.

TAAR1-targeted drugs may also alter immune function [10]

While there are several endogenous TAAR1 ligands, 3-iodothyronamine is hypothesised to derive from thyroid hormone metabolism:

“3-iodothyronamine (T1AM) should be considered as a component of thyroid hormone signaling and might play a significant physiological and/or pathophysiological role. T1AM is a novel chemical messenger, that interacts with a specific G protein-coupled receptor, TAAR1, and possibly with other molecular targets. At tissue concentrations close to the physiological range it produces significant metabolic and neurological effects. From the metabolic side, it stimulates lipid catabolism and induces in general anti-insulin responses; from the neurological side, it has been reported to favor learning and memory, modulate sleep and feeding, and decrease the pain threshold.” [11]

Advertisements

Leave a Reply

Fill in your details below or click an icon to log in:

WordPress.com Logo

You are commenting using your WordPress.com account. Log Out / Change )

Twitter picture

You are commenting using your Twitter account. Log Out / Change )

Facebook photo

You are commenting using your Facebook account. Log Out / Change )

Google+ photo

You are commenting using your Google+ account. Log Out / Change )

Connecting to %s