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Possible mechanism of anticonvulsant effect of ketamine in mice
A Manocha1, K K Sharma, P K Mediratta
1Department of Pharmacology, University College of Medical Sciences & GTB Hospital, Shahdara, Delhi.
Abstract:
The study was designed to investigate the effect of ketamine on convulsive behaviour using maximal electroshock (MES) test. An attempt was also made to study the possible receptor mechanisms involved. MES seizures were induced in mice via transauricular electrodes (60 mA, 0.2sec). Seizure severity was assessed by the duration of tonic hindlimb extensor phase and mortality due to convulsions. Intraperitoneal administration of ketamine produced a dose-dependent (5-50 mg/kg) protection against hindlimb extensor phase. The anticonvulsant effect of ketamine was antagonized neither by naloxone (low as well as high doses) nor sulpiride, but was attenuated by haloperidol, a dopamine (D2)/sigma receptor antagonist. Co-administration of gamma-aminobutyric acid (GABA)-ergic drugs (GABA, muscimol, diazepam and baclofen) and N-methyl-D-aspartate (NMDA) receptor antagonist, dizocilpine (MK801) with ketamine facilitated the anticonvulsant action of the latter drug. In contrast, flumazenil, a benzodiazepine (BZD)-GABAA receptor antagonist, reversed the facilitatory effect of diazepam on the anti-MES effect of ketamine. Similarly, delta-aminovaleric acid (DAVA), antagonized the facilitatory effect of baclofen on anti-MES action of ketamine. These BZD-GABAergic antagonists, flumazenil or DAVA per se also attenuated the anti-MES effect of ketamine given alone. The results suggest that besides its known antagonistic effect on NMDA channel, other neurotransmitter systems i.e. sigma, GABAA-BZD-chloride channel complex and GABAB receptors may also be involved in the anti-MES action of ketamine.
Insights
Ketamine demonstrates anticonvulsant effects against seizures by interacting with sigma, GABAergic, and GABAB receptors, beyond its known NMDA antagonism. These findings reveal broader mechanisms for ketamine
Area of Science:
- Neuroscience
- Pharmacology
- Convulsive Behavior Research
Background:
- Ketamine is known for its anesthetic and antidepressant properties.
- Its anticonvulsant effects and underlying mechanisms require further elucidation.
- The maximal electroshock (MES) test is a standard model for evaluating anticonvulsant activity.
Purpose of the Study:
- To investigate the anticonvulsant effects of ketamine using the MES test in mice.
- To explore the potential receptor mechanisms involved in ketamine's anti-convulsive action.
Main Methods:
- Maximal electroshock (MES) seizures were induced in mice.
- Ketamine was administered intraperitoneally at varying doses (5-50 mg/kg).
- The effects of various receptor antagonists (naloxone, sulpiride, haloperidol, flumazenil, DAVA) and co-agonists (GABA, muscimol, diazepam, baclofen, MK801) were assessed.
Main Results:
- Ketamine exhibited dose-dependent protection against hindlimb extensor seizures.
- Haloperidol, a dopamine (D2)/sigma receptor antagonist, attenuated ketamine's effect.
- GABAergic drugs and NMDA antagonist dizocilpine (MK801) facilitated ketamine's anticonvulsant action.
- Benzodiazepine-GABAA receptor antagonists (flumazenil) and GABAB antagonists (DAVA) reversed facilitatory effects and attenuated ketamine's action alone.
Conclusions:
- Ketamine's anti-MES action involves more than just NMDA receptor antagonism.
- Sigma receptors, GABAA-benzodiazepine-chloride channel complex, and GABAB receptors play a role in ketamine's anticonvulsant effects.
- These findings suggest a complex interplay of neurotransmitter systems in ketamine's therapeutic action.
