The selective dopamine D receptor agonist SKF81297 modulates NMDA receptor currents independently of D receptors.

Dopamine D receptor (DR) agonists are frequently used to study the role of DRs in neurotransmission and behaviour. They have been repeatedly shown to modulate glutamatergic NMDAR currents in the prefrontal cortex (PFC), giving rise to the idea that DR activation tunes glutamatergic networks by regulating NMDAR activity. We report that the widely used DR agonist SKF81297 potentiates NMDAR currents in a dose-dependent manner, independently of DR activation in mPFC slices, cortical neuron cultures and NMDAR-expressing recombinant HEK293 cells. SKF81297 potentiated NMDAR currents through both GluN2A and GluN2B subtypes in the absence of DR expression, while inhibiting NMDAR currents through GluN2C and GluN2D subtypes. In contrast, the DR ligands SKF38393, dopamine and SCH23390 inhibited GluN2A- and GluN2B-containing NMDAR currents. SKF81297 also inhibited GluN2A- and GluN2B-containing NMDAR currents at higher concentrations and when glutamate/glycine levels were high, exhibiting bidirectional modulation. To our knowledge, these findings are the first report of a DR-independent positive modulatory effect of a DR ligand on NMDA receptors. Importantly, our results further emphasize the possibility of off-target effects of many DR ligands, which has significant implications for interpreting the large body of research relying on these compounds to examine dopamine functions.