Trace Amine-Associated Receptor 1 Modulates Dopaminergic Activity

Abstract

The recent identification of the trace amine-associated receptor (TAAR)1 provides an opportunity to dissociate the effects of trace amines on the dopamine transporter from receptor-mediated effects. To separate both effects on a physiological level, a Taar1 knockout mouse line was generated. Taar1 knockout mice display increased sensitivity to amphetamine as revealed by enhanced amphetamine-triggered increases in locomotor activity and augmented striatal release of dopamine compared with wild-type animals. Under baseline conditions, locomotion and extracellular striatal dopamine levels were similar between Taar1 knockout and wild-type mice. Electrophysiological recordings revealed an elevated spontaneous firing rate of dopaminergic neurons in the ventral tegmental area of Taar1 knockout mice. The endogenous TAAR1 agonist p-tyramine specifically decreased the spike frequency of these neurons in wild-type but not in Taar1 knockout mice, consistent with the prominent expression of Taar1 in the ventral tegmental area. Taken together, the data reveal TAAR1 as regulator of dopaminergic neurotransmission.

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

“…Taar1 − / − mice also display greater locomotor stimulation to amphetamine and MA (Achat-Mendes et al, 2012;Lindemann et al, 2008;Wolinsky et al, 2007), consistent with the idea that TAAR1 function is important for counteracting some MA effects. However, the role of TAAR1 function in sensitivity to aversive effects of MA has not been examined.…”

“…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). Similarly, MAHDR mice, which carry the non-functional version of the TAAR1, also exhibit lower resting DA tone in the NAcc and medial prefrontal cortex (mPFC), and higher MA-induced DA release in the mPFC, but not in the NAcc (Lominac et al, 2014).…”

“…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).…”

The selective antagonist EPPTB reveals TAAR1-mediated regulatory mechanisms in dopaminergic neurons of the mesolimbic system

“…However, because TAs not only activate TAAR1 but also influence the activity of TAAR4, DA transporters, adrenergic, as well as serotonin receptors it was difficult to assign specific physiological functions to TAAR1 (1, 6). With the availability of Taar1 knockout mice (7,8) it became clear that TAAR1 can inhibit DA neurons in the VTA via a receptor-mediated pathway. The genetic absence of TAAR1 clearly increased the spontaneous firing rate of DA neurons but the underlying signaling mechanism remained unclear (7).…”

“…With the availability of Taar1 knockout mice (7,8) it became clear that TAAR1 can inhibit DA neurons in the VTA via a receptor-mediated pathway. The genetic absence of TAAR1 clearly increased the spontaneous firing rate of DA neurons but the underlying signaling mechanism remained unclear (7). Taar1 knockout mice also display behavioral and neurochemical signs of DA supersensitivity, a feature thought to relate to positive symptoms of schizophrenia (8).…”