Interaction between the trace amine-associated receptor 1 and the dopamine D2 receptor controls cocaine’s neurochemical actions
Asif-Malik, A and Hoener, MC and Canales, J, Interaction between the trace amine-associated receptor 1 and the dopamine D2 receptor controls cocaine's neurochemical actions, Scientific Reports, 7, (1) Article 13901. ISSN 2045-2322 (2017) [Refereed Article]
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 efects have not yet been elucidated.
Here, we used fast-scan cyclic voltammetry to measure DA dynamics and explore such mechanisms.
We show, frst, 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 efects whereas subefective
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
efects 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 efects of TAAR1 activation on cocaine-induced changes in DA transmission. Collectively, the
present observations reveal that the ability of TAAR1 to regulate cocaine efects 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.