Increased gamma-aminobutyric acid levels in mouse brain induce loss of righting reflex, but not immobility, in response to noxious stimulation.
BACKGROUND
The general anesthetic state comprises behavioral and perceptual components, including amnesia, unconsciousness, and immobility. gamma-Aminobutyric acidergic (GABAergic) inhibitory neurotransmission is an important target for anesthetic action at the in vitro cellular level. In vivo, however, the functional relevance of enhancing GABAergic neurotransmission in mediating essential components of the general anesthetic state is unknown. Gabaculine is a GABA-transaminase inhibitor that inhibits degradation of released GABA, and consequently increases endogenous GABA in the central nervous system. Here, we examined, behaviorally, the ability of increased GABA levels to produce components of the general anesthetic state.


METHODS
All drugs were administered systemically in adult male ddY mice. To assess the general anesthetic components, two end-points were used. One was loss of righting reflex (LORR; as a measure of unconsciousness); the other was loss of movement in response to tail-clamp stimulation (as a measure of immobility).


RESULTS
Gabaculine induced LORR in a dose-dependent fashion with a 50% effective dose of 100 (75-134; 95% confidence limits) mg/kg. The behavioral and microdialysis studies revealed that the endogenous GABA-induced LORR occurred in a brain concentration-dependent manner. However, even larger doses of gabaculine (285-400 mg/kg) produced no loss of tail-clamp response. In contrast, all the tested volatile anesthetics concentration-dependently abolished both righting and tail-clamp response, supporting the evidence that volatile anesthetics act on a variety of molecular targets.


CONCLUSIONS
These findings indicate that LORR is associated with enhanced GABAergic neurotransmission, but that immobility in response to noxious stimulation is not, suggesting that LORR and immobility are mediated through different neuronal pathways and/or regions in the central nervous system.
Katayama
Sohtaro
S
Department of Dental Anesthesiology, Division of Clinical Medical Science, Programs for Applied Biomedicine, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima, Japan.
Irifune
Masahiro
M
Kikuchi
Nobuhito
N
Takarada
Tohru
T
Shimizu
Yoshitaka
Y
Endo
Chie
C
Takata
Takashi
T
Dohi
Toshihiro
T
Sato
Tomoaki
T
Kawahara
Michio
M
D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D003509:Cyclohexanecarboxylic Acids / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D007103:Immobilization / Q000379:methods; D008297:Male; D051379:Mice; D010812:Physical Stimulation / Q000379:methods; D012018:Reflex / Q000187:drug effects / Q000502:physiology*; D005680:gamma-Aminobutyric Acid / Q000096:biosynthesis* / Q000378:metabolism
D003509:Cyclohexanecarboxylic Acids; C012987:gabaculine; D005680:gamma-Aminobutyric Acid