Altered responses to propofol, but not ketamine, in mice deficient in the 65-kilodalton isoform of glutamate decarboxylase.
GABA is synthesized by two isoforms of glutamate decarboxylase (GAD), GAD65, and GAD67. However, the relative contributions of GAD65-mediated GABA synthesis to the in vivo actions of anesthetics remain unknown. To address this issue, we used mice deficient in the 65-kDa isoform of GAD and tested the hypothesis that partial reduction of GABA content in GAD65-deficient mice [GAD65(-/-)] would contribute to hypnotic and immobilizing actions of the anesthetics. The open field test, loss of righting reflex (LORR), loss of tail-pinch withdrawal response (LTWR), and locomotor activity were compared between wild-type (WT) mice and GAD65(-/-) mice. Effects of general anesthetics on both phasic and tonic GABAergic currents were examined using the patch-clamp method in frontal cortex pyramidal neurons in brain slices. The duration of propofol (100 mg/kg i.p.)-induced LORR and the duration of propofol (150 mg/kg i.p.)-induced LTWR in GAD65(-/-) mice were significantly reduced compared with WT mice. In contrast, no difference was seen for ketamine. Preinjection of the GABA transporter 1 inhibitor, NO-711 (C(21)H(22)N(2)O(3).HCl) (0.75 mg/kg i.p.), reinstated diminished actions of propofol in GAD65(-/-) mice. Cortical pyramidal neurons in GAD65(-/-) mice had smaller tonic conductances, and propofol-induced enhancement of tonic inhibition was smaller than in WT mice, suggesting that genotype differences in GAD65-mediated GABAergic inhibitory tone may be, at least in part, a cellular basis underlying behavioral differences. In conclusion, GAD65(-/-) mice show a diminished response to propofol, but not ketamine, indicating that GAD65-mediated GABA synthesis plays an important role in hypnotic and immobilizing actions of propofol.
Kubo
Kazuhiro
K
Department of Anesthesiology, Gunma University Graduate School of Medicine, Maebashi City, Japan.
Nishikawa
Koichi
K
Hardy-Yamada
Makiko
M
Ishizeki
Junko
J
Yanagawa
Yuchio
Y
Saito
Shigeru
S
D018686:Anesthetics, Intravenous / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D004594:Electrophysiology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D005625:Frontal Lobe / Q000187:drug effects / Q000378:metabolism; D005968:Glutamate Decarboxylase / Q000172:deficiency* / Q000235:genetics; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D007649:Ketamine / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D015742:Propofol / Q000008:administration & dosage / Q000494:pharmacology*
D018686:Anesthetics, Intravenous; D007649:Ketamine; D005968:Glutamate Decarboxylase; C401141:glutamate decarboxylase 2; D015742:Propofol