Actions of Fluorinated Alkanols on GABAA Receptors

Abstract

Previous work demonstrates that various anesthetics enhance the effect of gamma-aminobutyric acid (GABA), and this enhancement has been proposed as an explanation for how anesthetics cause anesthesia. This explanation extends to both fluorinated and unfluorinated alkanols. In the present study, we tested the capacity of fluorinated alkanols to enhance the function of the GABA_A receptors expressed in Xenopus oocytes. CF₃ CH₂ OH, CF₃ (CF₂)₂ CH₂ OH and CF₃ (CF₂)₄ CH₂ OH potentiated GABA_A receptor function, but CF₃ (CF₂)₅ CH₂ OH did not. The degree of potentiation decreased in proportion to the chain length of the alkanols. These findings were not specific for receptors expressed in oocytes, as similar results were obtained with muscimol-stimulated³⁶ Cl^- uptake using mouse brain membrane vesicles. Although CF₃ (CF₂)₅ CH₂ OH has been reported to enhance the capacity of desflurane to produce immobility in vivo, in our in vitro studies, this compound reduced potentiation of GABA-gated response by anesthetics such as isoflurane, enflurane, and pentobarbital. CHF₂ (CF₂)₅ CH₂ OH, which has in vivo anesthetic effects, also failed to potentiate GABA_A receptor function. These results indicate that the GABA_A receptor is not the only receptor affected by fluorinated alkanols and that other receptors contribute to the capacity of alkanols to produce immobility. In particular, CF₃ (CF₂)₅ CH₂ OH and CF₃ CH₂ OH inhibited N-methyl-D-aspartate receptor-mediated responses, which raises the possibility that this receptor is important for actions of fluorinated alkanols. Implications: We find a consistent parallel between the immobilization produced by fluorinated alkanols and their actions on N-methyl-D-aspartate receptors but do not find a consistent parallel between immobilization and effects on gamma-aminobutyric acid type A receptors. Thus, we suggest that N-methyl-D-aspartate, but not gamma-aminobutyric acid type A, receptors may mediate the capacity of anesthetics to produce immobilization. (Anesth Analg 1999;88:877-83)