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

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.

Increased gamma-aminobutyric acid levels in mouse brain induce loss of righting reflex, but not immobility, in response to noxious stimulation.

BACKGROUND: The general anesthetic state comprises behavioral and perceptual components, including amnesia, unconsciousness, and immobility. gamma-Aminobutyric acidergic (GABAergic) inhibitory neurotransmission is an important target for anesthetic action at the in vitro cellular level. In vivo, however, the functional relevance of enhancing GABAergic neurotransmission in mediating essential components of the general anesthetic state is unknown. Gabaculine is a GABA-transaminase inhibitor that inhibits degradation of released GABA, and consequently increases endogenous GABA in the central nervous system. Here, we examined, behaviorally, the ability of increased GABA levels to produce components of the general anesthetic state. METHODS: All drugs were administered systemically in adult male ddY mice. To assess the general anesthetic components, two end-points were used. One was loss of righting reflex (LORR; as a measure of unconsciousness); the other was loss of movement in response to tail-clamp stimulation (as a measure of immobility). RESULTS: Gabaculine induced LORR in a dose-dependent fashion with a 50% effective dose of 100 (75-134; 95% confidence limits) mg/kg. The behavioral and microdialysis studies revealed that the endogenous GABA-induced LORR occurred in a brain concentration-dependent manner. However, even larger doses of gabaculine (285-400 mg/kg) produced no loss of tail-clamp response. In contrast, all the tested volatile anesthetics concentration-dependently abolished both righting and tail-clamp response, supporting the evidence that volatile anesthetics act on a variety of molecular targets. CONCLUSIONS: These findings indicate that LORR is associated with enhanced GABAergic neurotransmission, but that immobility in response to noxious stimulation is not, suggesting that LORR and immobility are mediated through different neuronal pathways and/or regions in the central nervous system.

Propofol-induced anesthesia in mice is mediated by gamma-aminobutyric acid-A and excitatory amino acid receptors.

UNLABELLED: To elucidate the role of gamma-aminobutyric acid (GABA)(A) receptor complex and excitatory amino acid receptors (N-methyl-D-aspartate [NMDA] and non-NMDA receptors) in propofol-induced anesthesia, we examined behaviorally the effects of GABAergic and glutamatergic drugs on propofol anesthesia in mice. All drugs were administered intraperitoneally. General anesthetic potencies were evaluated using a righting reflex assay. The GABA(A) receptor agonist muscimol potentiated propofol (140 mg/kg; 50% effective dose for loss of righting reflex) induced anesthesia. Similarly, the benzodiazepine receptor agonist diazepam and the NMDA receptor antagonist MK-801 augmented propofol anesthesia, but the non-NMDA receptor antagonist CNQX did not. In contrast, the GABA(A) receptor antagonist bicuculline antagonized propofol (200 mg/kg; 95% effective dose for loss of righting reflex) induced anesthesia. However, neither the benzodiazepine receptor antagonist flumazenil, the GABA synthesis inhibitor L-allylglycine, nor the NMDA receptor agonist NMDA reversed propofol anesthesia. Conversely, the non-NMDA receptor agonist kainate enhanced propofol anesthesia. These results suggest that propofol-induced anesthesia is mediated, at least in part, by both GABA(A) and excitatory amino acid receptors. IMPLICATIONS: We examined behaviorally the effects of GABAergic and glutamatergic drugs on propofol-induced anesthesia in mice. The results suggest that propofol anesthesia is mediated, at least in part, by both GABA(A) and excitatory amino acid receptors.