Dopamine D(1) and D(3) receptors oppositely regulate NMDA- and cocaine-induced MAPK signaling via NMDA receptor phosphorylation.
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.
Jiao
Hongyuan
H
Department of Anesthesia and Critical Care, University of Chicago, Chicago, Illinois, USA.
Zhang
Lu
L
Gao
Fenge
F
Lou
Danwen
D
Zhang
Jianhua
J
Xu
Ming
M
D000818:Animals; D015153:Blotting, Western; D001923:Brain Chemistry / Q000187:drug effects; D002421:Caudate Nucleus / Q000187:drug effects / Q000378:metabolism; D003042:Cocaine / Q000494:pharmacology*; D003627:Data Interpretation, Statistical; D016291:Dizocilpine Maleate / Q000494:pharmacology; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology*; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D018698:Glutamic Acid / Q000494:pharmacology; D048031:JNK Mitogen-Activated Protein Kinases / Q000502:physiology; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology*; D016202:N-Methylaspartate / Q000494:pharmacology*; D010766:Phosphorylation; D011699:Putamen / Q000187:drug effects / Q000378:metabolism; D017447:Receptors, Dopamine D1 / Q000187:drug effects / Q000502:physiology*; D050637:Receptors, Dopamine D3 / Q000187:drug effects / Q000502:physiology*; D016194:Receptors, N-Methyl-D-Aspartate / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects*; D048051:p38 Mitogen-Activated Protein Kinases / Q000502:physiology
D018765:Dopamine Uptake Inhibitors; D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; D017447:Receptors, Dopamine D1; D050637:Receptors, Dopamine D3; D016194:Receptors, N-Methyl-D-Aspartate; D018698:Glutamic Acid; D016202:N-Methylaspartate; D016291:Dizocilpine Maleate; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D003042:Cocaine