Isoflurane Antagonizes the Capacity of Flurothyl or 1,2-Dichlorohexafluorocyclobutane to Impair Fear Conditioning to Context and Tone

Abstract

In animals, the conventional inhaled anesthetic, isoflurane, impairs learning fear to context and fear to tone, doing so at concentrations that produce amnesia in humans. Nonimmobilizers are inhaled compounds that do not produce immobility in response to noxious stimulation, nor do they decrease the requirement for conventional inhaled anesthetics. Like isoflurane, the nonimmobilizer 1,2-dichlorohexafluorocyclobutane (2N) impairs learning at concentrations less than those predicted from its lipophilicity to produce anesthesia. The capacity of the nonimmobilizer di-(2,2,2,-trifluoroethyl) ether (flurothyl) to affect learning and memory has not been studied. Both nonimmobilizers can cause convulsions. We hypothesized that if isoflurane, 2N, and flurothyl act by the same mechanism to impair learning and memory, their effects should be additive. We found that isoflurane, 2N, and flurothyl (each, alone) impaired learning fear to context and fear to tone in rats, with the nonimmobilizers doing so at concentrations less than those that cause convulsions. (Fear was defined by freezing [volitional immobility] in the presence of the conditioned stimulus [context or tone].) However, the combination of isoflurane and 2N or flurothyl produced an antagonistic rather than an additive effect on learning, a finding in conflict with our hypothesis. And flurothyl was no less potent than 2N (at least no less potent relative to the concentration of each that produced convulsions) in its capacity to impair learning. We conclude that conventional inhaled anesthetics and nonimmobilizers impair learning and memory by different mechanisms. The basis for this impairment remains unknown. Conventional inhaled anesthetics and nonimmobilizers are antagonistic in their effects on learning and memory, and this finding suggests that they impair learning and memory, at least in part, by different mechanisms.