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

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Abstract
We examined the potentiation by ketamine of the γ-aminobutyric acidA (GABAA) 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 GABAA 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 GABAA 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 GABAA receptor agonistic properties and that ketamine-induced anesthesia is mediated, at least in part, by GABAA receptors. Implications We examined the potentiation by ketamine of the γ-aminobutyric acidA receptor function using convulsive and anesthetic behavioral models in mice. Subanesthetic doses of ketamine-inhibited tonic convulsions induced by the γ-aminobutyric acidA receptor antagonist bicuculline. The γ-aminobutyric acidA receptor agonist, muscimol, potentiated ketamine-induced anesthesia. Bicuculline antagonized ketamine anesthesia, but the benzodiazepine receptor antagonist, flumazenil, and the γ-aminobutyric acid synthesis inhibitor, l-allyglycine, did not. The effects of ketamine on the γ-aminobutyric acidA receptors appear to correlate with its anesthetic actions.