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.