Sleeping time after phenobarbital treatment and the brain levels of gamma-aminobutyric acid and phenobarbital at the regaining of righting response point in ethionine-induced liver-disordered mice.
The mechanism of prolongation of sleeping (anesthesia) time after phenobarbital (PB) treatment was assessed in mice with ethionine (ET)-induced liver disorders (ET-treated group). The brain gamma-aminobutyric acid (GABA), glutamic acid (GLU), lactic acid (LA), and pyruvic acid (PA) levels were significantly higher in the ET-treated group than the control group. The ET-treated group showed an abnormal neurotransmission and a decrease in energy metabolism. After administration of PB (175 mg/kg, i.p.), sleeping time and the brain GABA, GLU, LA, PA, and PB levels at the awakening point were compared between ET-treated and control groups. Sleeping time in the ET-treated group was two times longer than that in the control group. At the awakening point, the brain GABA and LA levels in the ET-treated and control groups and the PA level in the ET-treated group were significantly lower than those without PB treatment; and the GLU level in the ET-treated group was significantly higher than that without PB treatment. The brain concentrations of PB in both groups remained the same for seven hr after PB treatment. There was no difference in the brain PB concentration between the two groups at the awakening point, although the ET-treated group showed impairment of excretion of PB at 18 hr of PB treatment. In conclusion, awakening is not directly correlated with a decrease in PB in the brain, but rather to changes in the brain GABA, GLU, and other substances, and an inhibition of the neurotransmission and decreased energy metabolism in the brain are considered to be involved in the prolongation of PB-induced sleeping time in the ET-treated mice.
Noguchi
M
M
Safety Research Laboratory, Tanabe Seiyaku Co., Ltd., Osaka, Japan.
Kawai
Y
Y
D000758:Anesthesia; D000762:Anesthesia Recovery Period; D000818:Animals; D001923:Brain Chemistry / Q000187:drug effects*; D002273:Carcinogens; D056486:Chemical and Drug Induced Liver Injury; D005001:Ethionine; D005260:Female; D018757:GABA Modulators / Q000032:analysis / Q000493:pharmacokinetics / Q000494:pharmacology*; D018698:Glutamic Acid / Q000032:analysis; D019344:Lactic Acid / Q000032:analysis; D008107:Liver Diseases / Q000378:metabolism* / Q000503:physiopathology; D051379:Mice; D010634:Phenobarbital / Q000032:analysis / Q000493:pharmacokinetics / Q000494:pharmacology*; D019289:Pyruvic Acid / Q000032:analysis; D012890:Sleep / Q000187:drug effects*; D005680:gamma-Aminobutyric Acid / Q000032:analysis
D002273:Carcinogens; D018757:GABA Modulators; D019344:Lactic Acid; D018698:Glutamic Acid; D005680:gamma-Aminobutyric Acid; D019289:Pyruvic Acid; D005001:Ethionine; D010634:Phenobarbital