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Dopamine D1 receptor activation blocks phencyclidine ‐ induced neurotoxicity by enhancing synaptic strength
Author(s) -
Johnson Kenneth M.,
Lei Gang
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.716.1
Subject(s) - neuroprotection , neurotoxicity , nmda receptor , microbiology and biotechnology , biology , dopamine , small interfering rna , agonist , chemistry , pharmacology , receptor , neuroscience , biochemistry , toxicity , transfection , organic chemistry , gene
PCP‐induced neurotoxicity has been used to model both cellular and behavioral aspects of schizophrenia. This study investigates the mechanism underlying the protective effects of dihydrexidine (DHX), a D1R agonist in cultured cortical neurons. DHX (10 uM) significantly blocks the toxic effects of 1 uM PCP as measured by apoptosis and MTT assays. DHX protection against PCP is PKA dependent, as selective inhibitors of PKA block neuroprotection. However, inhibition of either PKC with bisindolyl‐maleimide I or CaMKII with KN93 had no effect. DHX also significantly increased NR1 phosphorylation at serine 897, which is known to increase NMDAR function. Treatment of neurons with DHX increased the density of NR1 on the cell surface, an effect prevented by lavendustin A, a tyrosine kinase inhibitor or PP2, a SRC kinase family inhibitor, but not by PKI 14–22 , implying that NMDAR trafficking initiated by D1 receptor activation may be regulated by the tyrosine kinase pathway. Both LvA and PP2 partially blocked the protection by DHX. Moreover, NR2B subunits associated with PSD95 were robustly increased by DHX, suggesting that activation of D1 receptors increases NMDAR synaptic insertion. Thus, we suggest that dopamine D1 activation enhances synaptic strength via increasing NMDAR phosphorylation and trafficking, thereby providing neuroprotection against toxicity caused by blocking NMDAR activity. Supported by DA‐02073.