title: Activation of dopamine D1 receptors blocks phencyclidine-induced neurotoxicity by enhancing N-methyl-D-aspartate receptor-mediated synaptic strength.
abstract: Early postnatal blockade of NMDA receptors by phencyclidine (PCP) causes cortical apoptosis in animals. This is associated with the development of schizophrenia-like behaviors in rats later in life. Recent studies show that the mechanism involves a loss of neurotrophic support from the phosphoinositol-3 kinase/Akt pathway, which is normally maintained by synaptic NMDA receptor activation. Here we report that activation of dopamine D1 receptors (D1R) with dihydrexidine (DHX) prevents PCP-induced neurotoxicity in cortical neurons by enhancing the efficacy of NMDAergic synapses. DHX increases serine phosphorylation of the NR1 subunit through protein kinase A activation and tyrosine phosphorylation of the NR2B subunit via Src kinase. DHX enhances recruitment of NR1 and NR2B, but not NR2A, into synapses. DHX also facilitated the synaptic response in cortical slices and this was blocked by an NR2B antagonist. DHX pre-treatment of rat pups prior to PCP on postnatal days 7, 9 and 11 inhibited PCP-induced caspase-3 activation on PN11 and deficits in pre-pulse inhibition of acoustic startle measured on PN 26-28. In summary, these data demonstrate that PCP-induced deficits in NMDA receptor function, neurotoxicity and subsequent behavioral deficits may be prevented by D1R activation in the cortex and further, it is suggested that D1R activation may be beneficial in treating schizophrenia.
authors.affiliation: Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, Texas 77555-1031, USA.
authors.forename: Gang
authors.initials: G
authors.lastname: Lei
authors.forename: Noelle C
authors.initials: NC
authors.lastname: Anastasio
authors.forename: Yu
authors.initials: Y
authors.lastname: Fu
authors.forename: Volker
authors.initials: V
authors.lastname: Neugebauer
authors.forename: Kenneth M
authors.initials: KM
authors.lastname: Johnson
mesh_terms: D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D017868:Cyclic AMP-Dependent Protein Kinases / Q000502:physiology; D018491:Dopamine Agonists / Q000494:pharmacology*; D004594:Electrophysiology; D004797:Enzyme-Linked Immunosorbent Assay; D018691:Excitatory Amino Acid Antagonists / Q000633:toxicity*; D005260:Female; D047468:Immunoprecipitation; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D018696:Neuroprotective Agents; D020258:Neurotoxicity Syndromes / Q000517:prevention & control*; D018408:Patch-Clamp Techniques; D010617:Phenanthridines / Q000494:pharmacology*; D010622:Phencyclidine / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D010766:Phosphorylation; D051381:Rats; D017207:Rats, Sprague-Dawley; D017447:Receptors, Dopamine D1 / Q000819:agonists*; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects*; D013216:Reflex, Startle / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D013569:Synapses / Q000187:drug effects*; D014443:Tyrosine / Q000378:metabolism
chemical_list: D018491:Dopamine Agonists; D018691:Excitatory Amino Acid Antagonists; D008565:Membrane Proteins; D018696:Neuroprotective Agents; D010617:Phenanthridines; D017447:Receptors, Dopamine D1; D016194:Receptors, N-Methyl-D-Aspartate; C061532:dihydrexidine; D014443:Tyrosine; D017868:Cyclic AMP-Dependent Protein Kinases; D010622:Phencyclidine