The selective dopamine D₁ receptor agonist SKF81297 modulates NMDA receptor currents independently of D₁ receptors

Dopamine D₁ receptor (D₁R) agonists are frequently used to study the role of D₁Rs 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 D₁R activation tunes glutamatergic networks by regulating NMDAR activity. We report that the widely used D₁R agonist SKF81297 potentiates NMDAR currents in a dose-dependent manner, independently of D₁R 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 D₁R expression, while inhibiting NMDAR currents through GluN2C and GluN2D subtypes. In contrast, the D₁R 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 D₁R-independent positive modulatory effect of a D₁R ligand on NMDA receptors. Importantly, our results further emphasize the possibility of off-target effects of many D₁R ligands, which has significant implications for interpreting the large body of research relying on these compounds to examine dopamine functions.