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Effect of MK-801 on seizures induced by exposure to hyperbaric oxygen: comparison with AP-7
M Chavko1, J C Braisted, A L Harabin
1Naval Medical Research Institute, Bethesda, Maryland 20889-5607, USA.
Abstract:
The effect of the noncompetitive N-methyl-d-aspartate (NMDA)-receptor antagonist MK-801 on seizures induced by hyperbaric oxygen in relation to changes in cerebral blood flow (CBF) was investigated. Rats were injected with MK-801 (0.005-8 mg/kg) 30 min before exposure to 100% O2 at 5 atm (gauge pressure). MK-801 administration resulted in a biphasic response in seizure latency. Doses of 0.1-4 mg/kg significantly decreased time to EEG and motor seizures, while 8 mg/kg had no effect on seizure latency. MK-801 had no effect on seizure duration. In a dose range 0.1-8 mg/kg MK-801 increased CBF in awake animals, which might be responsible for the decreased seizure latency. The gradual increase in seizure latency with increasing MK-801 doses suggests involvement of an additional factor probably related to the drug's anticonvulsive effect. Unlike MK-801, a competitive NMDA receptor antagonist, AP-7, at a dose 250 mg/kg had no effect on latency to seizures or CBF.
Insights
The NMDA-receptor antagonist MK-801 reduced seizure latency in rats exposed to hyperbaric oxygen, likely due to increased cerebral blood flow. Higher doses suggest an additional anticonvulsive effect.
Area of Science:
- Neuroscience
- Pharmacology
- Hyperbaric Medicine
Background:
- N-methyl-D-aspartate (NMDA) receptors play a crucial role in neuronal excitability.
- Hyperbaric oxygen (HBO) can induce seizures, and understanding the underlying mechanisms is vital for patient safety.
- Cerebral blood flow (CBF) regulation is critical during oxygen exposure.
Purpose of the Study:
- To investigate the effect of the NMDA-receptor antagonist MK-801 on hyperbaric oxygen-induced seizures.
- To examine the relationship between MK-801 administration, seizure latency, and changes in cerebral blood flow (CBF).
- To compare the effects of a noncompetitive NMDA antagonist (MK-801) with a competitive antagonist (AP-7).
Main Methods:
- Rats were administered varying doses of MK-801 (0.005-8 mg/kg) 30 minutes prior to exposure to 100% oxygen at 5 atm.
- EEG and motor seizures were monitored to determine seizure latency and duration.
- Cerebral blood flow (CBF) was measured in awake animals.
- A competitive NMDA antagonist, AP-7 (250 mg/kg), was used as a comparator.
Main Results:
- MK-801 exhibited a biphasic effect on seizure latency; doses of 0.1-4 mg/kg significantly decreased latency, while 8 mg/kg had no effect.
- MK-801 did not alter seizure duration.
- MK-801 (0.1-8 mg/kg) increased CBF, potentially contributing to the reduced seizure latency.
- Increasing MK-801 doses suggested an additional anticonvulsive mechanism beyond CBF changes.
- AP-7 had no significant effect on seizure latency or CBF.
Conclusions:
- The noncompetitive NMDA antagonist MK-801 lowers seizure threshold during hyperbaric oxygen exposure, primarily through increased CBF.
- A dose-dependent anticonvulsive effect of MK-801 may involve mechanisms beyond its impact on cerebral blood flow.
- Noncompetitive NMDA receptor antagonism differs in its effect on HBO-induced seizures compared to competitive antagonism.