AMPA receptor competitive antagonism reduces halothane MAC in rats

Various subtypes of receptors have been identified for glutamate, an excitatory neurotransmitter. Previous studies have shown that antagonism of glutamate at the NMDA receptors reduces minimum alveolar concentration (MAC) for volatile anesthetics. NBQX (2,3-dihydroxy-6-nitro-7-sulfamoyl- benzo(f)quinoxaline) is a selective antagonist at the glutamatergic AMPA receptor. The purpose of this experiment was to determine whether AMPA receptor antagonism influences halothane MAC in the rat. Sprague-Dawley rats were anesthetized with halothane in 50% O₂/balance N₂, tracheally intubated and the lungs were mechanically ventilated. Increasing doses of NBQX were intravenously infused in three groups while the control group was infused with vehicle (D₅W). Halothane MAC was then determined by the tail-clamp method. Halothane MAC was log-linearly related to plasma NBQX concentrations (MAC = -0.125 (In plasma concentration NBQX) + 1.035, r² = 0.77). A maximal 58% reduction of halothane MAC was achieved with an NBQX loading dose of 42 mg/kg followed by a continuous infusion rate of 36 mg · kg^-1 · h^-1 (control = 1.02 ± 0.07%; NBQX = 0.43 ± 0.12%; P < .01). Larger doses of NBQX were not possible because of the poor aqueous solubility of this compound. In a separate experiment, awake rats were randomly assigned to groups based on the dose of NBQX infused. Pa(CO₂) and mean arterial pressure were measured at time 0 and at 5 and 30 min after start of NBQX infusion. The infusion was then stopped. Time until recovery of the righting reflex was recorded. Pa(CO₂) values were unchanged by the lower doses of NBQX, but were increased by the largest dose of NBQX infused (control = 37.3 ± 2.1 mmHg; NBQX = 50.1 ± 12 mmHg; P < .01). Mean arterial pressure was not affected by any dose of NBQX. The righting reflex was impaired in the high-dose NBQX group only. We conclude that competitive antagonism of glutamatergic neurotransmission at the AMPA receptor reduces halothane MAC in the rat.