Interaction Between the Trace Amine-Associated Receptor 1 and the Dopamine D2 Receptor Controls Cocaine\u2019s Neurochemical Actions

Aman Asif-Malik,Marius C Hoener,Juan J Canales

doi:10.1038/s41598-017-14472-z

Abstract

Recent evidence suggests that the trace amine-associated receptor 1 (TAAR1) plays a pivotal role in the regulation of dopamine (DA) transmission and cocaine’s actions. However, the underlying mechanisms through which TAAR1 activation mediates these effects have not yet been elucidated. Here, we used fast-scan cyclic voltammetry to measure DA dynamics and explore such mechanisms. We show, first, that the full TAAR1 agonist, RO5256390, dose-dependently blocked cocaine-induced inhibition of DA clearance in slices of the nucleus accumbens. Second, subthreshold inhibition of PKA or PKC phosphorylation did not prevent TAAR1 suppression of cocaine effects whereas subeffective doses of the DA D2 receptor antagonist, L-741,626, rescued cocaine’s ability to produce changes in DA uptake in the presence of full TAAR1 activation, thus indicating that TAAR1 modulation of cocaine effects requires simultaneous DA D2 receptor activation. Predictably, inhibition of glycogen synthase kinase-3 (GSK-3), which results from activation of D2/TAAR1 heterodimers, fully reproduced the inhibitory effects of TAAR1 activation on cocaine-induced changes in DA transmission. Collectively, the present observations reveal that the ability of TAAR1 to regulate cocaine effects is linked to cooperative interactions with D2 autoreceptors and associated downstream molecular targets converging on GSK-3 and suggest a new mechanism to disrupt cocaine neurochemical actions.

Highlights

The trace amine-associated receptor 1 (TAAR1) is a G protein-coupled receptor that is responsive to trace amines (TAs), the major catecholamines and synthetic compounds structurally related to TAs, including amphetamine and its numerous analogues, triggering accumulation of cAMP via adenylyl cyclase activation[1,2]
This study set out to examine the ability of TAAR1 to regulate the neurochemical effects of cocaine, measuring DA release and uptake dynamics in the nucleus accumbens (NAc) in real time
That TAAR1 activation completely prevented the effects of cocaine on DA uptake, which we showed to require co-activation of DA D2 autoreceptors, but not the recruitment of its associated PKA and PKC signalling cascades

Summary

Introduction

The trace amine-associated receptor 1 (TAAR1) is a G protein-coupled receptor that is responsive to trace amines (TAs), the major catecholamines and synthetic compounds structurally related to TAs, including amphetamine and its numerous analogues, triggering accumulation of cAMP via adenylyl cyclase activation[1,2]. TAAR1 stimulation triggers accumulation of cAMP via Gαs-adenylyl cyclase activation which can, in turn, promote PKA and PKC phosphorylation[1,2,3,16], and activates a G protein-independent, β-arrestin2-dependent pathway involving protein kinase B (AKT)/glycogen synthase kinase-3 (GSK-3)[17], which is modulated by DA D2 receptors[18] Such widespread molecular interactions complicate the identification of the mechanisms responsible for TAAR1’s capacity to regulate cocaine’s neurochemical actions, here we used in vitro fast-scan cyclic voltammetry to monitor changes in electrically evoked DA transmission produced by cocaine and aimed to characterize the underlying substrates linked to TAAR1’s ability to regulate the neurochemical actions of cocaine

Methods

Results

Conclusion