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Synaptic versus extrasynaptic NMDA receptors: Role in PCP‐induced neurotoxicity and development of locomotor sensitization
Author(s) -
Anastasio Noelle,
Xia Yan,
Wang Cheng Z,
Johnson Kenneth M
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.716.3
Subject(s) - ifenprodil , nmda receptor , neurotoxicity , sensitization , antagonist , pharmacology , neuroscience , chemistry , glutamate receptor , receptor , psychology , biology , toxicity , biochemistry , organic chemistry
The relationship between PCP‐induced neurotoxicity in perinatal rats and the development of behavioral deficits is unclear as is the role of specific NMDAR subunits in both. This lab has reported that activation of synaptic NMDAR can prevent PCP‐induced death implying that NR1/NR2A, thought to be synaptic, and NR1/NR2B, thought to be extrasynaptic, are differentially involved in the behavioral and neurotoxic effects of PCP. Using cortical organotypic slices as a model, we found that the NR2A antagonist, NVPAAM007, is neurotoxic, while ifenprodil, NR2B antagonist, is not. Further, rat pups treated with either PCP or PEAQX (NR2A antagonist) showed marked elevation of caspase 3 activity in the cortex, while ifenprodil showed no effect. Rat pups were treated with saline or PCP on PN7, 9 and 11, challenged with PCP between PN28‐35 and locomotor activity measured. This regimen caused a sensitized locomotor response to PCP challenge. A similar response to PCP challenge was observed following treatment with ifenprodil on PN7, 9 and 11. These preliminary data suggest that sensitization to PCP involves changes in NR2B receptors and may not be the result of the neurotoxic effects of PCP. Future experiments with PEAQX will be performed in order to distinguish the role of NR2 subunits in aberrant behaviors and the link between neurotoxicity and locomotor sensitization. Supported by F31DA022824 & DA02073.