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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

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.

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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