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GENERAL ARTICLES

Evidence for GABA_A Receptor Agonistic Properties of Ketamine: Convulsive and Anesthetic Behavioral Models in Mice

Masahiro Irifune, DDS, PhD^*,, Tomoaki Sato, DDS, PhD^*, Yoshiko Kamata^*, Takashige Nishikawa, PhD^*, Toshihiro Dohi, PhD, and Michio Kawahara, MD, PhD

*Department of Pharmacology, Kagoshima University Dental School, Kagoshima; and Departments of Pharmacology and Anesthesiology, Hiroshima University School of Dentistry, Hiroshima, Japan

Address correspondence and reprint requests to Masahiro Irifune, DDS, PhD, Department of Anesthesiology, Hiroshima University School of Dentistry, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8553, Japan. Address e-mail to mirifun{at}hiroshima-u.ac.jp

	Abstract

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We examined the potentiation by ketamine of the -aminobutyric acid_A (GABA_A) receptor function using convulsive and anesthetic behavioral models in adult male ddY mice. General anesthetic potencies were evaluated by a rating scale, which provided the data for anesthetic scores, loss of righting reflex, duration, and recovery time. All drugs were administered intraperitoneally. Small subanesthetic doses of ketamine did inhibit tonic seizures induced by a large dose of the GABA_A receptor antagonist bicuculline (8 mg/kg). The 50% effective dose value was 15 (95% confidence limits 10–22) mg/kg. Even large anesthetic doses (100–150 mg/kg) did not suppress clonic seizures in 50% of the animals. The GABA_A receptor agonist, muscimol (0.32–1.12 mg/kg), potentiated ketamine-induced anesthesia in a dose-dependent fashion (P < 0.05). Similarly, the benzodiazepine receptor agonist, diazepam (1–3 mg/kg), augmented ketamine anesthesia in a dose-dependent manner (P < 0.05). Bicuculline (2–5 mg/kg) dose-dependently antagonized ketamine-induced anesthesia (P < 0.05). Neither the benzodiazepine receptor antagonist, flumazenil (2–20 mg/kg), nor the GABA synthesis inhibitor, L-allylglycine (200 mg/kg), affected the anesthetic action of ketamine. These results suggest that ketamine has GABA_A receptor agonistic properties and that ketamine-induced anesthesia is mediated, at least in part, by GABA_A receptors.

Implications: We examined the potentiation by ketamine of the -aminobutyric acid_A receptor function using convulsive and anesthetic behavioral models in mice. Subanesthetic doses of ketamine-inhibited tonic convulsions induced by the -aminobutyric acid_A receptor antagonist bicuculline. The -aminobutyric acid_A receptor agonist, muscimol, potentiated ketamine-induced anesthesia. Bicuculline antagonized ketamine anesthesia, but the benzodiazepine receptor antagonist, flumazenil, and the -aminobutyric acid synthesis inhibitor, L-allyglycine, did not. The effects of ketamine on the -aminobutyric acid_A receptors appear to correlate with its anesthetic actions.

	Introduction

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General anesthetics may act by binding directly to proteins rather than by perturbing lipid bilayers. In the central nervous system (CNS), anesthetics may influence protein activity by binding to pockets or clefts, causing small changes in protein conformation (1). In the mammalian CNS, -aminobutyric acid (GABA) functions as an inhibitory neurotransmitter. General anesthetics enhance central inhibitory neurotransmission mediated by the GABA_A receptor–channel complex. Thus, this complex may be a target for general anesthetics (2). Ketamine is an IV anesthetic whose primary mechanism of action is thought to be a blockade of the N-methyl-D-aspartate (NMDA) receptor channel (3). Yet, electrophysiological studies have shown that ketamine, in clinically relevant concentrations, potentiates the GABA receptor-mediated inhibitory postsynaptic current in guinea-pig olfactory cortical slices (4) and in rat hippocampal slices (5). In addition, at peak brain concentration during anesthesia, ketamine stimulates GABA-activated Cl^- currents elicited on GABA_A receptors expressed by Xenopus oocytes (6). These in vitro findings suggest that ketamine also enhances GABA_A receptor-mediated inhibition in the CNS. However, the effects of ketamine on the GABA_A receptor–channel complex has not been confirmed using an in vivo behavioral model.

The purpose of this study was to elucidate in vivo the potentiation by ketamine of GABA_A receptor function. For this purpose, we used two behavioral models. First, to test the potentiation action of ketamine on GABAergic inhibitory neurotransmission, we used a convulsive behavioral model. Bicuculline, a selective GABA_A receptor antagonist, blocks GABAergic neurotransmission (Fig. 1) and induces tonic-clonic convulsions. The GABA_A receptor agonist, muscimol, blocks the convulsions induced by bicuculline (7), but not those induced by the NMDA receptor agonist NMDA (8). Conversely, the competitive NMDA receptor antagonist, 2-amino-7-phosphonoheptanoic acid, antagonizes convulsions produced by the agonist NMDA, but not those produced by the GABA_A receptor antagonist, bicuculline (9). These findings suggest that the effects of the selective GABA_A and NMDA receptor ligands on convulsive behavior are specific to their sites of action. Second, to determine whether the actions of ketamine on GABAergic neurons occur presynaptically or postsynaptically, we used an anesthetic behavioral model. L-Allylglycine is a GABA synthesis inhibitor that depletes GABA from presynaptic nerve terminals (Fig. 1). If ketamine presynaptically facilitates GABAergic neurons and induces anesthesia, L-allylglycine should inhibit ketamine-induced anesthesia. However, if ketamine acts postsynaptically on the GABA_A receptor–channel complex, GABA_A receptor modulators (Fig. 1) should modulate ketamine anesthesia.

View larger version (18K): [in this window] [in a new window]   Figure 1. Schematic illustration of a -aminobutyric acidergic (GABAergic) synapse indicating possible sites of drug action. Site 1: Glutamic acid decarboxylase (GAD) is the enzyme responsible for the conversion of L-glutamate (L-GLU) to GABA. L-Allylglycine is a selective inhibitor of GAD and depletes GABA from presynaptic nerve terminals. Site 2: Muscimol is an effective GABAA receptor-stimulating drug. Activation of the GABAA receptor by muscimol results in the opening of the chloride channel. The ensuing influx of chloride anions inhibits the firing of the neurons by hyperpolarization. Bicuculline blocks the action of GABA at postsynaptic receptors. Site 3: GABAA and benzodiazepine (BDZ) receptors are part of the same GABAA receptor–channel complex. Diazepam is a specific agonist at the BDZ binding site and increases the frequency of channel conductance or duration of opening. Flumazenil is a selective BDZ receptor antagonist.

	Methods

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Ketamine hydrochloride and muscimol hydrobromide were purchased from Research Biochemicals, Inc. (Wayland, MA). (+)-Bicuculline and L-allylglycine were obtained from Sigma Chemical Co. (St. Louis, MO). Diazepam was obtained from Wako Pure Chemical Industries Ltd. (Osaka, Japan). Flumazenil was generously supplied by Yamanouchi Pharmaceutical Co. (Kyoto, Japan). The possible sites of action of these drugs (except ketamine) are shown in Fig. 1. Ketamine, muscimol, and L-allylglycine were dissolved in 0.9% saline solution. Bicuculline was dissolved in a few drops of 0.1 N HCl, diluted with distilled water, and adjusted to approximately pH 3.0 to stabilize its effects. Diazepam and flumazenil were suspended in 1.0% carboxymethyl cellulose sodium salt solution. Each drug was freshly prepared on the day of the experiment. All drugs were administered intraperitoneally (IP) in a volume of 5 mL/kg.

Anticonvulsant Activity Estimations
The mice were examined individually in a circular glass beaker (13.5 cm diameter x 19 cm high). Tonic-clonic convulsions were induced by IP administration of 8 mg/kg of the GABA_A receptor antagonist bicuculline in all animals. Ketamine was injected 5 min before bicuculline. A tonic seizure was defined as a hindlimb extension in excess of 90° from the plane of the body. Abolition of the hindlimb tonic extensor component was used as the end point in this tonic test. A clonic seizure was defined as forelimb clonus of 3-s duration. Abolition of even a minimal threshold seizure (3 s of clonus) was considered the end point in this clonic test. Data were evaluated in an all-or-none manner. The animals were observed for a maximum of 60 min after the bicuculline injection by a person who was blind to the treatments. As soon as the mice reached the end point in these tests, they were killed by using diethyl ether. The dose of ketamine required to produce an anticonvulsant effect (50% effective dose [ED₅₀]) in 50% of animals and associated 95% confidence limits were calculated by the method of Litchfield and Wilcoxon (10).

Anesthetic Potency Estimations
The GABA_A receptor agonist muscimol and the benzodiazepine receptor agonist diazepam were administered IP 30 min before the IP administration of ketamine. Mice were treated with bicuculline simultaneously with ketamine. The benzodiazepine receptor antagonist, flumazenil, was administered 30 min before 100 mg/kg of ketamine. In a preliminary study, 200 mg/kg of L-allylglycine, a glutamic acid decarboxylase inhibitor that inhibits GABA synthesis, induced convulsions approximately 90 min after injection in two mice. This result was almost identical to the data of Orlowski et al. (11). A similar dose of L-allylglycine produces a significant decrease in the GABA level at 30 min after the injection, progressing to an approximately 40% decrease at 60 min, but no further substantial change at 2 h (12,13). Therefore, 200 mg/kg of L-allylglycine was given 60 min before 100 mg/kg of ketamine. The anesthetized animals were kept warm with an overhead heat lamp. Concurrent control groups were used in each experiment. Subjects in a given group were always assigned to treatments over two or more days. Some of these treatments, including the control, were performed on the same experimental day.

The mice were examined individually in a circular glass beaker (13.5 cm diameter x 19 cm high). After administration of ketamine, we tilted the beaker by hand to an angle of approximately 45° with a horizontal plane in triplicate at each recording time. Righting reflex was assessed and recorded every 3 min after injection for a maximum of 2 h by a blinded observer. Anesthetic scores were evaluated according to the rating scale of Boast et al. (14), with minor modifications: a score of 0 indicated a normal righting reflex; +1 indicated that the mouse righted itself within 2 s on all three trials (slightly impaired righting reflex); +2 indicated that the latency to righting was >2 s, but <10 s at the best response in three trials (moderately or severely impaired righting reflex); +3 corresponded to the absence of this reflex (no righting within 10 s on all three trials).

Total anesthetic scores were the total of the scores recorded every 3 min after the ketamine injection for a maximum of 2 h. Animals were considered to have lost their righting reflex when they scored +3. The time between the loss of the ability to right themselves (shown as a score of +3) and the time they regained that ability (shown as a score of +2) was considered the duration of loss of the righting reflex (min). The time required to return to a normal righting reflex (shown as a score of 0) was considered the recovery time (min).

Because the reflex response is an all-or-none response, the number of animals losing the righting reflex (scored +3) of the total that received a specific treatment was used to calculate the percentage of loss of the righting reflex. ED₅₀ for loss of the righting reflex, 95% confidence limits of that value, and the significance of differences in ED₅₀ values between groups were determined according to the method of Litchfield and Wilcoxon (10).

Data are presented as mean ± SEM. The all-or-none data were analyzed by using the method of Litchfield and Wilcoxon (10). Data other than the all-or-none data were analyzed by Kruskal-Wallis one-way analysis of variance, followed by Dunn’s test for multiple comparisons. The results were considered statistically significant when P < 0.05.

	Results

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Ketamine produced a potent protection against tonic seizures induced by IP administration of 8 mg/kg of bicuculline with an IP ED₅₀ of 15 (95% confidence limits 10–22) mg/kg. In contrast, even a large anesthetic dose (150 mg/kg) of ketamine showed no anticonvulsant effect against clonic seizures in 50% of mice (Fig. 2).

View larger version (16K): [in this window] [in a new window]   Figure 2. Anticonvulsant action of ketamine against tonic (open circles) and clonic (closed circles) seizures induced by bicuculline in mice. Various doses of ketamine were administered IP 5 min before IP injection of 8 mg/kg of bicuculline, which produced tonic-clonic seizures in 100% of mice. A tonic seizure was defined as a hindlimb extension in excess of 90° from the plane of the body. Abolition of the hindlimb tonic extensor component was used as the end point in this tonic test. A clonic seizure was defined as forelimb clonus of 3-s duration. Abolition of even a minimal threshold seizure (3 s of clonus) was considered the end point in this clonic test. The percentage of animals that showed no convulsion is plotted on a probability scale graph. Each point represents a percentage of 7–10 animals per dose of ketamine (see text for ED50 values).

View larger version (18K): [in this window] [in a new window]   Figure 3. Effects of muscimol and bicuculline on ketamine-induced loss of righting reflex in mice. Muscimol at a dose of 1.12 mg/kg (closed triangles) was administered IP 30 min before IP injection of various doses of ketamine. Bicuculline at a dose of 5 mg/kg (closed circles) was given IP simultaneously with ketamine. Control animals (treated with ketamine alone; open circles) were pretreated with vehicle solution. The percentage of animals who lost righting reflex is plotted on the probability scale graph. Each point represents a percentage of 6–11 animals per dose of ketamine (see text for ED50 values).

	Discussion

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In this convulsive behavior study, we found that small subanesthetic doses of ketamine inhibited bicuculline-induced tonic seizures, but even large anesthetic doses did not suppress clonic seizures in 50% of the animals (Fig. 2). These results are consistent with the data of Veliskova et al. (17) and Wardley-Smith et al. (18). The effects of the selective GABA_A and NMDA receptor ligands on convulsive behavior are specific to their sites of action (7–9). Therefore, it is likely that, although ketamine acts as a channel blocker at the NMDA receptor (3), the anticonvulsant activity of ketamine against bicuculline-induced convulsions is mediated by enhancing inhibitory neurotransmission via GABA_A receptors, not by its NMDA receptor antagonism. The reason for the difference in ketamine’s anticonvulsant effect on tonic and clonic convulsions remains uncertain. However, although the precise mechanism of the difference is unclear, it has been reported that tonic seizures induced by bicuculline are more susceptible to the actions of drugs that potentiate GABA_A receptor function than are clonic seizures (19). This finding strongly suggests the involvement of GABAergic neurotransmission in the tonic seizures rather than the clonic component.

L-Allylglycine, a GABA synthesis inhibitor, induced seizures at a dose of 200 mg/kg, suggesting that this dose reduced GABA in presynaptic nerve terminals to a point lower than the level required physiologically in the brain. However, this dose of L-allylglycine did not affect ketamine-induced anesthesia (Table 2). This finding indicates that ketamine’s potentiation of GABAergic neurotransmission is not presynaptic or is not caused by indirect effects mediated through neuronal networks. Similar convulsive doses of L-allylglycine decrease the GABA level by approximately 40% (12,13). Thus, this level of GABA might be sufficient to allow activation of the postsynaptic GABA_A receptors by ketamine. In fact, an electrophysiological study has revealed that ketamine enhances a low concentration (5 µM) of GABA-induced Cl^- currents (6).

The selective benzodiazepine receptor antagonist, flumazenil, did not affect ketamine-induced anesthesia, notwithstanding the involvement of GABA_A receptors in ketamine anesthesia (Table 3). The ß-subunit of the GABA_A receptor forms a functional Cl^- channel that contains sites for the direct activation of GABA and general anesthetics such as propofol, pentobarbital, and etomidate (20). In addition, propofol enhances GABA_A receptor function in a manner that does not depend on the presence of the -subunit in the receptor, in contrast to benzodiazepines (21). These findings suggest that general anesthetics may have their sites of action on the ß-subunit that includes the GABA binding site, and that their action might be independent of the -subunit (20). Furthermore, in vivo behavioral studies have shown that the benzodiazepine receptor antagonist, flumazenil, does not reverse anesthesia induced by volatile and IV anesthetics (22,23). Thus, ketamine might produce anesthesia in a manner similar to the action of these general anesthetics on the GABA_A receptor–channel complex, and the effect may be independent of benzodiazepine receptor activation.

Systemic administration of the GABA_A receptor agonist muscimol induces depressant effects, such as impairment of motor coordination and sedation, especially in large doses (7). There is a possibility, therefore, that synergy between muscimol and ketamine may occur via action at different sites. Indeed, this type of synergy is an acknowledged phenomenon (e.g., ₂-adrenergic receptor agonists and general anesthetics). Moreover, the GABA_A receptor antagonist, bicuculline, may antagonize the depressant action of ketamine, regardless of its site of action, because bicuculline is a potent neuroexcitant and convulsant. These possibilities suggest that ketamine may produce anesthesia in parallel and independent of GABA_A receptor-mediated pathways. In fact, ketamine is a channel blocker at the NMDA receptor, a specific subtype of the excitatory amino acid (EAA) receptor, and blocks the excitatory transmission mediated by the EAA receptor in the CNS (3). If ketamine did not enhance the inhibitory neurotransmission mediated by GABA_A receptors, it would not prevent convulsions induced by bicuculline. Furthermore, bicuculline would augment ketamine-induced anesthesia, because mice lose the righting reflex during tonic-clonic convulsions. Kainate and quisqualate are agonists for the other subtypes of EAA receptors (kainate and AMPA [-amino-3-hydroxy-5-methyl-4-isoxazole proprionic acid] receptors). They are also potent neuroexcitants and convulsants. Ketamine suppressed neither kainate- nor quisqualate-induced convulsions, but the largest subconvulsive dose of both kainate and quisqualate failed to reverse ketamine anesthesia, in contrast to bicuculline (24).

These findings suggest that the effects of these GABA_A and EAA receptor ligands on ketamine anesthesia occur via their specific sites of action. Furthermore, it has been reported that NMDA causes a significant increase in GABA content in the striatum of rats measured with in vivo microdialysis, and NMDA-evoked release of GABA is blocked by a specific NMDA receptor antagonist (25). It is unlikely, therefore, that the activating effect of ketamine on GABA neurons is attributed to secondary pharmacology via its NMDA receptor antagonism. Thus, ketamine-induced anesthesia appears to involve an enhancement of GABA_A receptor-mediated neurotransmission.

Ketamine acts on several receptors (NMDA, muscarinic cholinergic, and opioid receptors) (3). We found in a previous behavioral study that ketamine-induced anesthesia involves, at least in part, NMDA receptor antagonism (24). Furthermore, it has been reported that ketamine may produce anesthesia by blocking central cholinergic neurotransmission (3). Therefore, ketamine-induced anesthesia may be mediated both by enhancing central inhibitory transmission (e.g., GABAergic neurons) and by blocking excitatory neurotransmission (e.g., glutamatergic and muscarinic cholinergic neurons). This speculation is supported by the electrophysiological finding that ketamine reduces NMDA receptor-mediated responses and enhances GABA_A receptor-mediated responses (26).

In conclusion, ketamine has GABA_A receptor agonistic properties, and ketamine-induced anesthesia is mediated, at least in part, by GABA_A receptors.

	Acknowledgments

 
This work was supported, in part, by a Grant-in-Aid for Scientific Research (C) (No. 10671740) from the Ministry of Education, Science, Sports, and Culture of Japan.

We thank Mr. Steven L. Leeper, Transnet, Inc., for English language editing. We also acknowledge Yamanouchi Pharmaceutical Co. for the donation of flumazenil.

	References

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Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins with the assistance of Stanford University Libraries' HighWire Press®. Copyright 2006 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999