MK-801 enhances gabaculine-induced loss of the righting reflex in mice, but not immobility

Abstract

Purpose: gamma-Aminobutyric acid (GABA) and N-methyl-D-aspartate (NMDA) receptors are important targets for anesthetic action at the in vitro cellular level. Gabaculine is a GABA-trans-aminase inhibitor that increases endogenous GABA in the brain, and enhances GABA activity. We have recently shown that unconsciousness is associated with the enhanced GABA activity due to gabaculine, but that immobility is not. MK-801 is a selective NMDA channel blocker. In this study, we examined behaviourally whether gabaculine in combination with MK-801 could produce these components of the general anesthetic state. We further compared the effect of MK-801 with ketamine, another NMDA channel blocker.

Methods: All drugs were administered intraperitoneally to adult male ddY mice. To assess the general anesthetic components, two endpoints were used. One was loss of the righting reflex (LORR; as a measure of unconsciousness) and the other was loss of movement in response to tail-clamp stimulation (as a measure of immobility).

Results: Large doses of MK-801 alone (10-50 mg.kg(-1)) induced neither LORR nor immobility in response to noxious stimulation. However, even a small dose (0.2 mgxkg(-1)) significantly enhanced gabaculine-induced LORR (P < 0.05), although gabaculine in combination with MK-801 (0.2-10 mgxkg(-1)) produced no immobility. However, gabaculine plus a subanesthetic dose of ketamine (30 mgxkg(-1)), which acts on NMDA, opioid and nicotinic acetylcholine receptors and neuronal Na(+) channels, suppressed the pain response, but did not achieve a full effect. Ketamine alone dose-dependently produced both LORR and immobility.

Conclusion: These findings suggest that gabaculine-induced LORR is modulated by blocking NMDA receptors, but that immobility is not mediated through GABA or NMDA receptors.