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 γ-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.

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The effect of amiodarone, a cationic amphiphilic drug, on cytokine release from, and on protein kinase C (PKC) activity of, mouse alveolar macrophages, bone marrow macrophages, and blood monocytes was examined. In addition, its effect on three enzymes in these cells was also determined. Amiodarone suppressed the growth of all cell types at high doses. As regards cytokine release, amiodarone caused an increase in interleukin-1 (IL-1)α, IL-1β, and tumor necrosis factor (TNF) a release from alveolar macrophages but not from bone marrow macrophages and monocytes. PKC activity was increased by amiodarone only in alveolar macrophages. And the treatment with amiodarone severely suppressed the H⁺-ATPase, sphingomyelinase, and phospholipase A₂ activities in alveolar macrophages. But these enzyme activities in bone marrow macrophages and monocytes were not suppressed so much as in alveolar macrophages. This current study indicated that mouse alveolar macrophages treated with amiodarone undergo suppression of H⁺-ATPase, resulting in suppression of sphingomyelinase and phospholipase A₂ activity, and in activation of PKC activity and release of cytokines. It also showed that changes in activities of all three enzymes in alveolar macrophages are different from those in bone marrow macrophages and monocytes with respect to reactivity toward amiodarone.

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We investigated the effect of a noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist, (+)-5-methyl-10, 11-dihydro-5H-dibenzo[a, d]cyclohepten-5, 10-iminehydrogen maleate (dizocilpine, MK-801), on hippocampal norepinephrine release in morphine-treated rats in order to clarify the relationship between NMDA receptors and the development of morphine dependence. Naloxone hydrochloride injected subcutaneously (s.c.) into morphine-dependent rats, induced an immediate increase in hippocampal norepinephrine release, which was associated with a typical morphine withdrawal syndrome. The increased norepinephrine levels persisted for at least 2 hr, even after the disappearance of the behavioral withdrawal syndrome. This striking effect of naloxone on hippocampal norepinephrine release was dependent on the duration of the intraberebroventricular (i.c.v.) morphine infusion. Pretreatment with dizocilpine (s.c.) before naloxone challenge reduced the rate of the rise in hippocampal norepinephrine release induced by naloxone in morphine-treated rats. Concurrent infusion (i.c.v.) of dizocilpine and morphine decreased the level of hippocampal norepinephrine release after a naloxone challenge. Both pretreatment with dizocilpine (s.c.) before naloxone injection and infusion (i.c.v.) of dizocilpine suppressed rearing and teeth-chattering signs, but not wet-dog shakes in morphine-treated rats. These results suggest that dizocilpine attenuates the development of morphine dependence through NMDA receptors, and thus that interaction between opioid receptors and NMDA receptors may be involved in the development of morphine dependence.

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The lethal effects of combining cocaine and ethanol administration in mice and the protective effects of buprenorphine, a mixed opioid agonist-antagonist, were examined with consideration to the involvement of cocaethylene. In Experiment 1, buprenorphine (0.25 or 0.5 mg/kg, i.p.) protected against a dose of cocaine exceeding the LD₅₀ value (75 mg/kg, i.p.) combined with ethanol (3 g/kg, i.p.), although this attenuated lethality was not lower than the non-ethanol group (acute administration experiment). In Experiment 2, daily administrations of non-lethal doses of cocaine (40 mg/kg, i.p.) were combined with ethanol (1.5 g/kg, i.p.) for up to 5 days (repeated administration experiment). In Experiment 3, one dose of cocaine (75 mg/kg, i.p.) was administered after the ad libitum ingestion of an ethanol liquid diet, created by replacing 35% of the total calories with ethanol, for five days (ethanol liquid diet experiment). In all the three experiments, 2 lethal groups could be discerned: an immediate lethal group (IL group) and a delayed lethal group (DL group). These groups were differentiated based on their survival times after the cocaine administrations, observed respiratory and locomotive disorders, and drug concentrations. The number of the DL group animals was elevated only in the combined cocaine-ethanol groups of Experiment 1. Buprenorphine (0.25 mg/kg, i.p.) administered before each cocaine injection attenuated the total percent lethality to levels not higher than the total percent lethality of the non-ethanol groups in the latter two experiments. This supports the validity of the protective effects of buprenorphine on cocaine toxicity amplified by non-lethal doses of ethanol. Quantitative postmortem drug analyses of mice from the IL groups, in which the drug levels were high enouth to be determined, suggested that buprenorphine had a protective effect against combined cocaine-ethanol lethality without significantly decreasing the drug distributions, except for the concentration of cocaethylene in the brain.

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