“TAARgeting Addiction”—The Alamo Bears Witness to Another Revolution

Highlights

• Recent progress on trace amine-associated receptor 1 (TAAR1) was described.

• Historical perspective of TAAR1 and its interaction with dopaminergic system was reviewed.

• Both in vitro and in vivo evidence support the critical role of TAAR1 in drug addiction.

Abstract

Background

In keeping with the free-thinking tradition San Antonians are known for, the Scientific Program Committee of the Behavior, Biology and Chemistry: Translational Research in Addiction Conference chose trace amine-associated receptor 1 (TAAR1) as the focus of the plenary symposium for its 7th annual meeting held at the University of Texas Health Science Center at San Antonio on March 14 and 15, 2015. The timing of the meeting's plenary session on TAAR1 coincided with the Ides of March, an apt concurrence given the long association of this date with the overthrow of the status quo. And whether aware of the coincidence or not, those in attendance witnessed the plunging of the metaphorical dagger into the heart of the dopamine (DA) transporter (DAT)-centric view of psychostimulant action.

Methods

The symposium's four plenary presentations focused on the molecular and cellular biology, genetics, medicinal chemistry and behavioral pharmacology of the TAAR1 system and the experimental use of newly developed selective TAAR1 ligands.

Results

The consensus was that TAAR1 is a DA and methamphetamine receptor, interacts with DAT and DA D2 receptors, and is essential in modulating addiction-related effects of psychostimulants.

Conclusions

Collectively the findings presented during the symposium constitute a significant challenge to the current view that psychostimulants such as methamphetamine and amphetamine solely target DAT to interfere with normal DA signaling and provide a novel conceptual framework from which a more complete understanding of the molecular mechanisms underlying the actions of DA and METH is likely to emerge.

Introduction

One feature that many drugs of abuse have in common is their ability to elevate extracellular dopamine (DA) levels in the brain, an effect that has been correlated with reward-related behaviors (Wise, 1980, Di Chiara and Imperato, 1988). For almost 50 years, researchers interested in trying to understand the physiological and behavioral mechanisms underlying the actions of the psychostimulants such as cocaine, amphetamine (AMPH) and methamphetamine (METH) attempted to identify their primary molecular targets of action. With the publication by Giros et al. (1996) showing that genetically engineered mice lacking (knockout, KO) the DA transporter (DAT) from conception were indifferent to cocaine and AMPH in terms of spontaneous locomotor activity and the release and uptake of DA, the DAT was cast as the site of action for both types of stimulants; a view that quickly came to be considered as established fact.

Regrettably, despite numerous challenges, including the increasingly recognized role of vesicular monoamine transporter 2 (Fleckenstein et al., 2007), the predominance of the DAT-centric view of psychostimulant action has hindered attempts to consider, let alone identify and characterize, additional molecular targets of action. The first serious challenges to the DAT-centric dogma of psychostimulant action came in 1998 when Rocha et al. (1998) and Sora et al. (1998) reported that two lines of genetically engineered mice lacking DAT from conception (i.e., a developmental knockout) were still responsive to cocaine. These reports were soon followed by the publication by Carboni et al. (2001) showing that in the DAT KO mice generated by Giros et al. (1996), cocaine and AMPH could still cause significant increases in extracellular DA levels in the nucleus accumbens. That same year Spielewoy et al. (2001), using descendants from the same line of DAT KO mice, reported daily exposure to AMPH resulted in a hypolocomotion phenotype compared to their WT littermates.

In an attempt to resolve the issue, Budygin et al. (2004) and Sotnikova et al. (2004) used descendants from the Giros lineage of DAT KO mice in a series of physiological and behavioral studies. In experiments designed to determine whether or not the reward valence of AMPH differed between WT and DAT KO mice, Budygin et al. (2004) found the absence of DAT did not eliminate AMPH-induced rewarding effect as measured by place conditioning. Furthermore, AMPH retained its ability to increase extracellular DA in the nucleus accumbens of DAT KO mice whereas exposure to the noncatecholic biogenic amine β-phenylethylamine (PEA), sometimes referred to as the endogenous AMPH (Sabelli et al., 1975, Wolf and Mosnaim, 1983), resulted in the inhibition of novelty-induced locomotion typically displayed by these KO mice, consistent with the idea that sites of action in addition to the DAT, such as a trace amine-sensitive receptor (Boulton et al., 1972, Berry, 2007), could be responsible (Sotnikova et al., 2004).

In 2001, two groups (Borowsky et al., 2001, Bunzow et al., 2001) reported the discovery of a G-protein coupled receptor (GPCR) activated by noncatecholic biogenic amines including the so-called trace amines PEA, p-tyramine and DA. In addition the DA metabolite 3-methoxytyramine (3-MT) and the synthetic psychostimulants METH, AMPH and Ecstasy – but interestingly not cocaine – were also reported to be agonists of this new biogenic amine receptor (Bunzow et al., 2001). The significance of the reports by Borowsky et al. (2001) and Bunzow et al. (2001) was acknowledged immediately in commentaries accompanying both articles at the time of their publication (Premont et al., 2001, Kim and Zastrow, 2001, respectively). Unfortunately, the initial excitement and enthusiasm expressed by many over the discovery of a GPCR directly activated by METH/AMPH but not cocaine was not shared by those individuals tasked with making recommendations to domestic funding agencies, both public and private. As a consequence, in the United States and Canada, the number of laboratories conducting research in the field has remained small.

Fortunately, in Europe this area of research has received sustained and even increasing support over the last decade. In particular, F. Hoffmann-La Roche (Basel, Switzerland) established a drug development program targeting TAAR1 soon after the receptor's discovery. Their program led to the establishment of several non-primate and nonhuman primate animal models for the study of TAAR1-mediated signaling in addition to a collection of receptor-selective compounds including full agonists, partial agonists and an antagonist/inverse agonist as well as polyclonal and monoclonal antibodies against human, mouse, rat and nonhuman primate species of TAAR1 (Bradaia et al., 2009, Revel et al., 2011, Revel et al., 2012a). The availability of these and additional TAAR1-selective reagents (e.g., see www.genecards.org/cgi-bin/carddisp.pl?gene=TAAR1 and www.antibodypedia.com/gene/19712/TAAR1) continues to transform this emerging area of research not only by revealing the consequences of manipulating TAAR1-mediated signaling in cells, tissues and behavior but also by attracting investigators from diverse backgrounds and disciplines to the field.

Perhaps the most consistent in vitro observation reported across laboratories conducting TAAR1 research is that the receptor can be directly activated by nanomolar concentrations of DA and METH to stimulate the production of cAMP, in a pertussis toxin-insensitive manner, in heterologous cell-based expression systems. That TAAR1-mediated signaling is directly stimulated by METH/AMPH but not cocaine implies that its activity could contribute to the rewarding/appetitive/interoceptive effects of METH/AMPH that distinguish these drugs from cocaine. As such TAAR1 represents an unconventional yet attractive target against which novel therapeutics designed to treat psychosis, restore the functioning of DA neurons in Parkinson's disease patients and reduce relapse to the abuse of psychostimulants, and perhaps other drugs such alcohol, nicotine, opiates and cannabis as well, could be developed (Borowsky et al., 2001, Bunzow et al., 2001, Miller et al., 2005, Grandy, 2007, Snead et al., 2007, Wolinsky et al., 2007, Berry, 2007, Lindemann et al., 2008, Ledonne et al., 2010, Revel et al., 2011, Leo et al., 2014, Thorn et al., 2014a, Thorn et al., 2014b; Cotter et al., 2015, Miller, 2012).

Since the two first reports 14 years ago (Borowsky et al., 2001, Bunzow et al., 2001), evidence has accumulated that indicates TAAR1-mediated signaling modulates DA levels spatiotemporally in the central nervous system and periphery through a variety of mechanisms involving many different cell types in many anatomical locations (Miller, 2011). It was the intent of this symposium to stimulate interest in and discussion about this emerging area by bringing together leaders in the field to share their latest research findings in the context of psychostimulant abuse with a diverse audience composed of students, postdoctoral fellows, clinicians and basic scientists. It was in this setting that the role of TAAR1-mediated signaling as a function of psychostimulant (cocaine and AMPH/METH) exposure was explored. [Footnote: Four speakers presented at the symposium. Besides the three authors of this review, Dr. Giuseppe Cecere, a medicinal chemist from F. Hoffmann-La Roche, also gave a talk regarding the medicinal discovery and development of selective TAAR1 ligands. However, he did not contribute to the preparation of this review due to time conflict.]