Trace amine associated receptor 1 and movement control

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Abstract

The recently discovered trace amine associated receptors (TAARs) represent attractive potential mediators of certain aspects of movement control. The TAAR that is best characterized, TAAR1, is particularly interesting because it can be activated by a variety of monoaminergic compounds including trace amines, amphetamines and dopamine metabolites. By using an experimental paradigm developed in our laboratory that involves a novel model of acute dopamine deficiency (DDD mice), and mice lacking TAAR1 (TAAR1 knockout mice), we explored the role of TAAR1 in movement control and actions of antiparkinsonian drugs. These investigations may eventually bring novel approaches to the pharmacology of Parkinson's disease.

Introduction

Currently, the mainstay of therapeutic management of Parkinson's disease (PD) is still the pharmacological alleviation of motor symptoms. Dopamine replacement therapy by administration of the dopamine precursor l-dopa or direct dopamine (DA) agonists has been used with great success for many years [1], [2]; however, this approach has certain limitations related to psychotic reactions, fluctuations in motor performance and dyskinesias that often develop following chronic l-dopa treatment. Despite these serious side-effects, l-dopa remains the most commonly used treatment in the management of PD particularly because it provides superior efficacy in comparison to direct DA agonists or other available pharmacological treatments. While the role of dopamine in the effects of l-dopa is undisputed, several researchers postulated that additional targets could be activated by l-dopa or its metabolic derivatives to provide additional benefits of l-dopa over direct DA agonists used in PD [1]. Furthermore, it has been suggested that some particular neurons can use l-dopa as a neurotransmitter [3].

Section snippets

Trace amines and their receptors

Trace amines (TAs) are biogenic amines such as tyramine, tryptamine, octopamine, and β-phenylethylamine (β-PEA) that are mostly known for their important roles in invertebrate physiological functions including movement control. TAs have also been found in the mammalian central nervous system (CNS) but at levels that are substantially lower in comparison to the classic monoaminergic neurotransmitters norepinephrine, serotonin and DA [4], [5], [6]. Numerous studies have indicated that TA

Unexpected effects of amphetamine derivatives in a novel mouse model of acute dopamine deficiency, DDD mice

Recently, a model of acute DA deficiency has been developed in our laboratory by using mice lacking the DAT (DAT knockout [KO] mice). In DAT-KO mice, the lack of re-uptake mechanism prevents recycling of the released DA into the presynaptic terminal, thereby resulting in a depletion of intraneuronal storage of DA [12], [13]. The remaining DA in these mice is exclusively dependent on its de novo synthesis. Acute blockade of DA synthesis in DAT-KO mice by α-methyl-p-tyrosine (the irreversible

TAAR1-KO mice

To date, all endogenous and small molecule ligands that act as TAAR1 agonists have actions in the CNS at secondary sites [8], [9], [17], [18], including the DAT and vesicular monoamine transporter 2. Thus, in the absence of selective TAAR1 ligands, a line of TAAR1-KO mice provides a straightforward approach to investigate the contribution of TAAR1 to pharmacologically regulated behaviors [16]. These mice could provide important information on the pathophysiological consequences of TAAR1

Double-KO mice lacking both the DAT and TAAR1 (double DAT/TAAR1-KO mice)

Many TAAR1 ligands, including β-PEA and amphetamines, demonstrate potent interaction with the DAT, thereby significantly complicating the elucidation of TAAR1-mediated actions. Mice lacking the DAT provide a unique opportunity to directly investigate DAT-independent actions of drugs [12], [20]. Furthermore, hyperdopaminergic DAT-KO mice represent a very sensitive model with which to investigate the actions of compounds on locomotor activity [12]. It should be noted that, in common with

Conclusions

Taken together, these data demonstrate that TAAR1 is significantly involved in motor control and probably exerts an “inhibitory” action on locomotion. With regard to the mechanism of TAAR1 involvement in movement control, we are following three hypothesis-driven lines of investigation. One hypothesis suggests that TAAR1 interacts directly with the DAT. Recent studies have demonstrated that monoamine transporters can modulate activation of TAAR1 and that TAAR1 and DAT can be co-expressed in a

Conflict of interest statement

The authors have declared no conflicts of interest.

Role of the funding source

This work was supported by the Michael J. Fox Foundation for Parkinson's Research. An unrestricted gift to Duke University from Lundbeck Research USA is greatly appreciated. The authors retained full editorial control and responsibilities throughout the preparation of the manuscript.

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    This article is based on a presentation given at the LIMPE Seminars 2007 “Experimental Models in Parkinson's Disease” held in September 2007 at the “Porto Conte Ricerche” Congress Center in Alghero, Sardinia, Italy.

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