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Altered NMDA sensitivity and learning following chronic developmental NMDA antagonism
W J Brooks1, A C Weeks, J C Leboutillier
1Department of Psychology, University of Toronto, Scarborough, Ontario, Canada.
Physiology & Behavior
|October 23, 1997
Summary
Developmental exposure to phencyclidine (PCP), an N-methyl-D-aspartate (NMDA) antagonist, increases seizure sensitivity and impairs learning and memory during withdrawal. This highlights NMDA receptor involvement in neurodevelopment and cognitive functions.
Area of Science:
- Neuroscience
- Developmental Neuroscience
- Behavioral Neuroscience
Background:
- Chronic developmental administration of N-methyl-D-aspartate (NMDA) antagonists has been shown to reduce synaptic development.
- Withdrawal from NMDA antagonism is characterized by a rebound period of synaptogenesis exceeding control levels.
- The NMDA receptor is implicated in crucial behavioral measures such as seizure activity and learning/memory.
Purpose of the Study:
- To explore the withdrawal period following chronic developmental NMDA antagonism.
- To examine the effects of phencyclidine (PCP), a noncompetitive NMDA antagonist, on NMDA-induced seizures and Morris water maze performance.
- To investigate the role of the NMDA receptor-channel complex in development and learning/memory.
Main Methods:
- Male Long-Evans rats received daily subcutaneous injections of 10 mg/kg PCP or saline from postnatal Day 5 to P20.
- Animals were assessed for sensitivity to NMDA-induced seizures at various time points post-PCP withdrawal (P21, P26, P36, P56).
- Learning and memory were evaluated using the Morris water maze, assessing acquisition performance and initial swim headings on multiple days post-withdrawal (P23, P26, P30, P38, P75).
Main Results:
- Chronic PCP treatment led to increased behavioral seizure activity after NMDA administration, observed up to 15 days post-withdrawal.
- PCP-treated rats exhibited heightened sensitivity of the NMDA receptor/channel complex during this withdrawal period.
- Animals treated with PCP required significantly more trials to reach criterion in the Morris water maze and showed less accurate initial swim headings.
Conclusions:
- Developmental exposure to PCP results in enduring alterations in NMDA receptor function.
- The withdrawal period from developmental NMDA antagonism is associated with increased seizure susceptibility and cognitive deficits.
- These findings underscore the critical role of the NMDA receptor-channel complex in normal neurodevelopment, learning, and memory processes.