Dopamine D1 and D3 receptors oppositely regulate NMDA‐ and cocaine‐induced MAPK signaling via NMDA receptor phosphorylation

Abstract Development of drug addiction involves complex molecular changes in the CNS. The mitogen‐activated protein kinase (MAPK) signaling pathway plays a key role in mediating neuronal activation induced by dopamine, glutamate, and drugs of abuse. We previously showed that dopamine D 1 and D 3 receptors play different roles in regulating cocaine‐induced MAPK activation. Although there are functional and physical interactions between dopamine and glutamate receptors, little is known regarding the involvement of D 1 and D 3 receptors in modulating glutamate‐induced MAPK activation and underlying mechanisms. In this study, we show that D 1 and D 3 receptors play opposite roles in regulating N ‐methyl‐ d ‐aspartate (NMDA) ‐induced activation of extracellular signal‐regulated kinase (ERK) in the caudate putamen (CPu). D 3 receptors also inhibit NMDA‐induced activation of the c‐Jun N‐terminal kinase and p38 kinase in the CPu. NMDA‐induced activation of the NMDA‐receptor R1 subunit (NR1), Ca 2+ /calmodulin‐dependent protein kinase II and the cAMP‐response element binding protein (CREB), and cocaine‐induced CREB activation in the CPu are also oppositely regulated by dopamine D 1 and D 3 receptors. Finally, the blockade of NMDA‐receptor reduces cocaine‐induced ERK activation, and inhibits phosphorylation of NR1, Ca 2+ /calmodulin‐dependent protein kinase II, and CREB, while inhibiting ERK activation attenuates cocaine‐induced CREB phosphorylation in the CPu. These results suggest that dopamine D 1 and D 3 receptors oppositely regulate NMDA‐ and cocaine‐induced MAPK signaling via phosphorylation of NR1.