Interaction between the trace amine-associated receptor 1 and the dopamine D2 receptor controls cocaine’s neurochemical actions

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.