The emerging role of trace amine-associated receptor 1 in the functional regulation of monoamine transporters and dopaminergic activity

Abstract

It is now recognized that trace amine associated-receptor 1 (TAAR1) plays a functional role in the regulation of brain monoamines and the mediation of action of amphetamine-like psychostimulants. Accordingly, research on TAAR1 opens the door to a new avenue of approach for medications development to treat drug addiction as well as the spectrum of neuropsychiatric disorders hallmarked by aberrant regulation of brain monoamines. This overview focuses on recent studies which reveal a role for TAAR1 in the functional regulation of monoamine transporters and the neuronal regulatory mechanisms that modulate dopaminergic activity.

Figure 1. A hypothetical model that summarizes TAAR1 agonist effects at the dopamine neuronal terminal incorporating in vitro, ex vivo and in vivo data

Left: Depiction of a dopaminergic synaptic terminal that expresses TAAR1. TAAR1 activation triggers cellular signaling events including activation of PKA and PKC that lead to phosphorylation-dependent dopamine efflux via the dopamine transporter and dopamine transporter internalization. In addition, TAAR1 agonists (such as amphetamine, methamphetamine or trace amine) compete with dopamine for reuptake (competitive inhibition). These processes raise extracellular dopamine levels. Bradaia et al (2009) has reported that the TAAR1 antagonist, EPPTB, increases the firing frequency of dopamine neurons, suggesting that TAAR1 either exhibits constitutive activity or is tonically activated by ambient levels of endogenous agonist. These investigators also showed a reduction in firing frequency of dopamine neurons in response to the TAAR1 agonist tyramine. In mouse substantia nigra, Xie et al (2007) observed frequent TAAR1-expressing neurons in the midst of DAT-positive neurons and processes that did not coexpress DAT but that were in approximation to DAT neurons (a previously unpublished image illustrating this proximity is shown in Figure 2). Accordingly, the model presented predicts that TAAR1 agonists decrease the firing frequency of dopamine neurons by activating TAAR1 in adjacent inhibitory neurons, while also increasing extracellular levels of dopamine via both competitive inhibition of reuptake of dopamine as well as by non-competitive, TAAR1-mediated uptake inhibition and promotion of efflux. It is notable that the increased levels of extracellular dopamine may not be highly localized to the dopaminergic synapse, in that the location of dopamine transporters spans the neuron throughout its entire somatodendritic and axonal domains and at terminals resides outside of synaptic active zones, whereas dopamine is released from the somata of substantia nigra neurons by exocytosis in response to neuronal electrical activity (Ciliax et al. 1999; Jaffe et al. 1998). Also, these non-competitive effects are PKA- and PKC-dependent and are attenuated by D2 receptor activation. Right: Depiction of a dopaminergic terminal in a TAAR1 knockout mouse. In the absence of TAAR1, agonists such as amphetamine and methamphetamine do not trigger phosphorylation-dependent dopamine efflux via the dopamine transporter nor dopamine transporter internalization, yet the competitive inhibition of dopamine reuptake (which is TAAR1-independent) by amphetamine still occurs. In the absence of TAAR1, TAAR1 knockout mice show a greater locomotor response to amphetamine and release more dopamine (and norepinephrine) in response to amphetamine than do WT mice. As TAAR1 activation decreases the firing frequency of dopamine neurons, TAAR1 knockout mice may have a higher firing frequency which is not decreased in response to amphetamine. The collective effects of these processes may result in the higher synaptic dopamine levels induced by amphetamine in TAAR1 knockout mice, and also explain the enhanced behavioral response to amphetamine.

Figure 2. A Confocal image showing TAAR1-positive non-dopaminergic neurons adjacent to DAT-positive dopaminergic neurons in substantia nigra of an adult rhesus monkey

In the double-label immunofluorescent image (right), neurons are present that express either TAAR1 (green) or DAT (red), but not both. TAAR1 staining is observed in two neurons (N) with apparent intracellular localization, as well as in an epithelial cell (E) where it appears to be localized to the extracellular plasma membrane. Note the proximity of TAAR1-positive neurons to two dopamine neurons (D). Nuclei (blue); red blood cells in endothelial cell (purple). Smaller images of individual channels, including TAAR1 (green), DAT (red), and differential interference contract (DIC), are shown on the left side of the larger composite panel. Micrometer bar = 20 microns. Methods can be found in Xie et al., 2007.