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Objective: To investigate the role of GABA A receptor in nikethamide-induced respiratory enhancement in the medullary slices of neonatal rats., Methods: Ex vivo medullary slices of neonatal rats (1 to 3 days old) containing the medial region of the nucleus retrofacialis with the hypoglossal nerve rootlets were prepared and perfused with modified Kreb's solution to record respiration-related rhythmic discharge activity (RRDA) from the hypoglossal nerve rootlets using suction electrodes. Thirty RRDA-positive slices were randomized into 5 equal groups and perfused with nikethamide (at concentrations of 0.5, 1, 3, 5, 7, and 10 microg/ml with the optimal nikethamide concentration determined), GABA (at 10, 20, 40, and 60 micromol/ to determine the optimal concentration), 10 micromol/ bicuculline, 10 micromol/ bicuculline plus 40 micromol/L GABA, and 5 microg/ml nikethamide followed by 5 microg/ml nikethamide plus 10 micromol/ bicuculline after wash out, respectively., Results: Nikethamide increased RRDA at the concentrations of 0.5-7 microg/ml, and 5 microg/ml nikethamide showed the most distinct effect on the inspiratory time (TI), integral amplitude (IA), and respiratory cycle (RC). GABA at 40 micromol/ showed the most effective inhibition of RRDA in terms of TI, IA, and RC. Bicuculline at 10 micromol/ could increase the IA, TI and RC, but the combination of 10 micromol/ bicuculline and 40 micromol/ GABA had no significant effects on RRDA. Compared with nikethamide used alone, nikethamide plus bicuculline significantly increased TI and IA without affecting RC., Conclusion: Nikethamide can enhance RRDA of the hypoglossal nerve rootlets in the medullary slices of neonatal rats, and the effect can be partially mediated by the GABA A receptor.

A study was made of the nature and specificity of the increase in biphenyl 2-hydroxylase activity after preincubation of liver microsomal preparations with various carcinogens in vitro. This enhancement of enzyme activity in vitro was investigated in mouse, hamster and rat, and although the rat appears to be atypical in the variation of the pattern of 2- and 4-hydroxylation with age, similar enhancements were detectable in each species examined. An increase in biphenyl 2-hydroxylase activity was apparent 2h after intraperitoneal administration of safrole or benzopyrene to mature Wistar albino rats and appeared to be similar in nature to that observed after preincubation of liver microsomal preparations with the same chemical in vitro. Investigation of other drug-metabolizing enzyme systems suggests that the enhancing effects of carcinogens in vitro are specific for biphenyl 2-hydroxylase. No correlation between the enhancement of biphenyl 2-hydroxylase and inhibtion of biphenyl 4-hydroxylase was apparent.

The effect of erabutoxin (ETX) was examined on respiration of rabbits. A single dose of 15 microgram/kg or 25 microgram/kg of ETX did not cause respiratory paralysis, but repeated administration of 15 microgram/kg of ETX at 3 hour intervals (three times) or 25 microgram/kg at 4 hour intervals (twice) caused fatal respiratory paralysis. Furthermore, a single administration of 50 microgram/kg of ETX caused fatal respiratory paralysis within 2 hours after the administration in all animals. This respiratory paralysis caused by ETX was reversible and of long duration (10-20 hour). This respiratory paralysis was not blocked by the administration of anticurare agents (neostigmine, edrophonium) or respiratory stimulants (nikethamide, picrotoxin, dimorpholamine). Since ETX had no influence on the circulatory system, death caused by ETX was prevented with application of artificial respiration.

1. When administered to intact white mice, the central depressants-diphenhydramine, promethazine, chlorpromazine, gammahydroxybutyrate, gammabutyrolactone, hyoscine, and pethidine-produced sedation in small doses, but excitement and convulsions in higher doses. When given to mice pretreated with subanaesthetic doses of phenobarbitone these drugs abolished the righting reflex both in convulsant doses (hyoscine excepted) and in non-convulsant doses. These effects are similar to the effects previously observed with local anaesthetics.2. Meprobamate, diazepam and chlorpromazine produced a loss of righting reflex both when given alone and following phenobarbitone. When given alone in higher doses, chlorpromazine induced convulsions.3. The central stimulants bemegride and picrotoxin antagonized the loss of righting reflex produced by phenobarbitone, but nikethamide, caffeine and strychnine did not alter the depressant effects of phenobarbitone.4. On the basis of these and previous studies with intact white mice a tentative classification of drugs having generalized depressant and stimulant effects on the central nervous system was proposed and discussed.

1. In the neuronally isolated cortex of the cat, local application of bemegride, picrotoxin, nikethamide, caffeine and strychnine facilitated the surface positive response of the isolated cortex and lowered the stimulus threshold for this response. Excepting nikethamide, they all produced convulsive discharge in the isolated cortex unrelated to the applied stimulus.2. Local application of glutamate to the cortex produced spreading depression, which was sometimes preceded by spontaneous positive bursting.3. In contrast to the "general depressants" which produce a relatively consistent pattern of effects on the electrical responses of isolated cortex, the "general stimulants", although they all have excitatory effects on isolated cortex, each produced a greatly different type of electrical response in the isolated cortex, suggesting that several different mechanisms of action are responsible for their effects.

1. The effects of central stimulant drugs injected intraperitoneally were examined on the release of acetylcholine (ACh) from the cerebral cortex of the anaesthetized rat. The effects of the drugs in increasing ACh release were approximately parallel to the increases produced in the electrical activity of the brain.2. Leptazol in a dose of 150 mg/kg increased the release of ACh by 2.9 times the resting release and in a dose of 300 mg/kg by 7.5 times; on the e.e.g. the injection produced a large increase in the electrical activity.3. Picrotoxin in a dose of 12 mg/kg increased the release of ACh by 7.5 times and on the e.e.g. caused a large increase in activity.4. Strychnine in doses of 8 mg/kg and 12 mg/kg increased the release of ACh by 2.0 and 2.4 times and produced a small increase in the activity of the e.e.g.5. Dexamphetamine in a dose of 100 mg/kg increased the release of ACh by 1.9 times and had no appreciable effect on the e.e.g.6. Nikethamide in a dose of 2 g/kg increased the release of ACh by 2.3 times and produced no appreciable change in the e.e.g.7. Caffeine in a dose of 100 mg/kg produced no significant effect on the release of ACh.