Carbon tetrachloride (CCl₄) as well as chloroform (CHCl₃), which is chlorinated hydrocarbon, has been well known to induce liver damage. CHCl₃ however has been used as an anesthetic. CCl₄ likewise acts directly on the central nervous system and has a narcotic effect even though the potency is considerably weaker than that of CHCl₃ (1).
It was reported that CHCl3 induced a reduction of ascorbic acid in the adrenal glands (2). This observation might imply an activation of the hypophyseo-adrenal axis by CHCl₃.
On the other hand, Brody et al. observed a decrease of catecholamine contents in the adrenal glands and an increase in the plasma and urine following administration of CCl₄ (3, 4). So they have assumed that CCl₄ acts directly on the hypothalamus and stimulates catecholamine release from the sympathetic nerve and the adrenal glands, and this phenomenon might be involved in the mechanism of CCl₄-induced toxicity.
From these facts, it can be presumed that CCl₄ acts directly on the hypothalamus and stimulates a release of corticotropin releasing factor from the hypothalamus and of adrenocorticotropic hormone (ACTH) from the pituitary gland. Consequently the plasma concentration of adrenocortical hormone might be increased.

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Concerning the cause of fatigue, there have been many assumptions on the basis of energy accumulation of substances inducing fatigue. There have been a lot of studies (1, 2) on piling up of the so-called fatigue substances. In the book edited by Katsunuma and Asahina (3), it was reported that the so-called fatigue substances were found by Ueda, Weichart, Pieron, Knipping, Denisenko, Asahina, Ozawa, Vorobew, Pravdic and Neminsky. They assumed that these substances were the metabolites from degraded protein.
As mentioned above, there are many reports concerning the cause of fatigue, but we cannot but conceive some questions for their chemical nature.
In our investigation on the appearance of fatigue due to physical exercise, the fact that a certain kind of metabolic substance was produced and accumulated from the energy source consumed by the physical exercise.
Our investigation was begun to study the relationship between the change of this metabolic product and the change of glucuronic acid metabolism due to physical exercise in the body.
The first experiment was done by Tamura in participation in Abe's studies (4, 5) on agents relieving fatigue and increasing efficiency, in 1942. The summary of this study is as follows: the rat was made to run as long as possible on the rotating belt and the time being almost impossible to run was adopted as running time. The running was repeated three times after a short rest.
This running test revealed that the central stimulants such as caffeine and amphetamine prolonged only the 1st running time, while glucose and glucuronic acid prolonged all of the 1st, the 2nd and the 3rd running time. In other words, the reducing agents such as glucose and glucuronic acid much more prevented the appearance of fatigue than the central stimulants.

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It has been shown that the heart of the mammals contains relatively large amount of catecholamines, mainly consisting of noradrenaline (1-5). The cardiac tissue takes up exogenously administered noradrenaline (6-8) and stores it for relatively long periods of time (6, 9, 10).
The sympathectomy causes marked depletion of catecholamines in the sympathetic nerve terminal. Remarkable depletion of the cardiac catecholamines caused by the stellate ganglionectomy in the cat (11) suggests the dominant participation of the postganglionic fibers originating in, or craniad to, the stellate ganglion, to the sympathetic innervation on the heart. In the dog, on the other hand, cardiac catecholamines are hardly depleted by bilateral resection of the stellate ganglion and thoracic sympathetic chain and ganglia, but depleted by extensive resection of the nerve plexus adjacent to the heart (12). On the basis of the physiological studies, Pannier (13) has indicated that the sympathetic cardiac accelerance nerves of the dog, at least in some part, pass through the stellate ganglion without changing neuron.
The following experiments were performed in an attempt to know how is the capacity of the dog heart to take up and store exogenously administered noradrenaline affected by the stellate ganglionectomy which causes only partial decreases in endogenous noradrenaline levels.

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Das Carnosin wurde 1900 von Gulewitsch und Amiradzibi (1) im Rinderfleischextrakt entdeckt, welcher es in reichlicher Menge enthät. Danach wurden die Methylverbindungen des Carnosins, Anserin (2) und Ophidin (3), aus Fleischextrakten von Gans und Schlange abgetrennt und identifiziert. 1961 wurde Homocarnosin (4) aus Rinderhirn isoliert, aber ist in Muskulatur nicht enthalten.
Die Wirkungen der Dipeptide, welche von ω-Aminosären, Histidin oder dessen Derivaten abstammen können, sind immer wieder erötert worden, ohne dass es gelang, eine einheitliche Auffassung zu erzielen. Bei der Entdeckung der Dipeptide wurde anfangs ihre Artspezifität in der Muskulatur in Rechnung gestellt. Durch die nachherigen Untersuchungen stellte sich heraus, dass die Muskulatur nahezu aller Tiere nur ein Dipeptid nicht enth%auml;t, sondern die beiden verschiedenartigen Dipeptide. Überdies ist Gehalt der Muskulatur an den beiden Dipeptiden verschieden. Under den Dipeptiden befinden sich Carnosin ohne Methylgruppe und seine Methylverbindungen, aber immer findet sich Carnosin neben Anserin oder Ophidin. Das zusammengetroffene Vorhandensein von Anserin und Ophidin, welche sätlich zu Methylverbindungen des Carnosins gehören, kann noch nicht nachgewiesen werden. Bisher liess sich an die physiologische Bedeutung dieser Dipeptide in Muskeln mit der Begrüdung denken, dass sie in etwas grösserer Anreicherung in Muskeln anzutreffen sind (5-10). Aber aus anderen Organen und Geweben als der Muskulatur wurden diese Dipeptide dargestellt. In hiesigem Institut sind derzeit nahere Untersuchungen über das Vorkommen dieser Dipeptide im lebenden Organismus der verschiedenen Tiere und ihre pharmakologischen Wirkungen im Gange.

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In Japan, it is well known that Fugu-poisoning holds the first rank in the mortality from the food-intoxication. This fact also could be confirmed by Ogura (1) in the statistical survey on the Fugu-poisoning that have happened in the past eighty years. This shows that the cases of this intoxication are over one hundred patients every year, and the mortality amounted to more than sixty per cent. The death was due to central and peripheral respiratory failure. The neurotoxic principle is localized in general in the liver and ovaries of noxious Fugu. In 1909, Tahara (2) succeeded in obtaining fairly pure toxin, and named it “Tetrodotoxin”. After that, Yokoo (3) in 1950 first reported the isolation of crystalline toxin, and Tsuda et al. (4) in 1952 established the method of mass-production of this crystalline toxin in a different precedure. The chemical structure of this toxin, as illustrated in Fig. 1, was presented by Tsuda et al. (5) in 1964, and at the same time supported with Hirata et al. (6) and Woodward (7). Recently, according to Mosher et al. (8), tarichatoxin, isolated from the eggs of the California newt, Taricha torosa, has also the same structure as tetrodotoxin.
A series of pharmacological studies of crystalline tetrodotoxin in our laboratory have been carring out since 1955. In these investigations, we were the first to find that, on the experiments of the isolated guinea pig ileum, tetrodotoxin suppressed completely the contractile response to nicotine and partly that to 5-hydroxytryptamine, but in this concentration no influence to acetylcholine and histamine (9, 10). Thereafter, the experi ments have carried forward the inhibitory action on the autonomic ganglion by tetrodo toxin (11-17). It was concluded that tetrodotoxin had an inhibitory action on the process of transmission in the ganglion.

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In the past few years it has been found that various carcinogenic hydrocarbons (e.g. 3, 4-benzpyrene and 3-methylcholanthrene) and drugs (e.g. phenobarbital and aminopyrine) increase markedly the activity of the enzyme systems in liver microsomes which metabolize several foreign compounds (1). About 16 μg (average of 10 reports) of 3, 4benzpyrene has been reported to be contained in smoke of 1, 000 cigarettes (2), but studies on the relationship between nicotine and the carcinogens have not been done from the standpoint of drug metabolism. During the course of pharmacological investigations of nicotine in our laboratory (3-5), the effect of the carcinogens on nicotine metabolism and the converse, the effect of nicotine on the carcinogen metabolism were subjected to be investigated.
Data presented in this paper indicates that 2-acetylaminofluorene, 3, 4-benzpyrene and 3-methylcholanthrene enhanced the activity of nicotine metabolizing enzyme and that nicotine also increased the activity of metabolizing enzymes toward 2-acetylaminofluorene and 3, 4-benzpyrene in rat liver microsomes.

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It is a well-known fact that the repeated administration of psychotropic drugs often leads to the development of tolerance in animals. As to tranquillizers, it has been reported by some investigators that the tolerance phenomenon was observed in rats or cats following the chronic treatment with chlorpromazine (1) and meprobamate (2, 3). The present paper deals with the effect of some tranquillizers on the conditioned avoidance response observed with the use of the Miller-Mowrer-type apparatus as well as the development of tolerance to these drugs in the rat.

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In the preceding paper, it was shown that the rat became tolerant to some psychotropic drugs when blockage of the conditioned avoidance response was estimated as an index of tranquillizing activity (1). In the course of these studies, a statistically significant difference was obtained between male and female rats in the development of tolerance upon the repeated administration of chlordiazepoxide and thioridazine. The purpose of the present study was to determine whether sex hormones are primarily concerned with this apparent sex difference in the development of the drug tolerance.

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Previously, it was reported that in in vivo anaphylaxis there were observed a fall in adenosine triphosphate (ATP) level and a rise in adenosine monophosphate (AMP) level of guinea-pig liver, but no changes in the values of ATP and other adenine nucleotides in the lung of in vivo shock. However, the fall of ATP in liver was not observable in in vitro anaphylactic reaction (1).
The fall of ATP level in tissues has been also reported in the animals treated with certain drugs (2-5) or with X-ray irradiation (6, 7). In the latter case, aside from a fall of ATP level, a significant decrease is shown in the P³² incorporation into nucleotide fraction of spleen and thymus in the mice transplanted with mammary carcinoma.
The present paper describes the result of an investigation on the adenine nucleotide contents and on the P³² incorporation into the nucleotides of guinea-pig liver in in vivo anaphylaxis, as determined by the ion exchange chromatographic method.
The experiments were also conducted on the animals treated with histamine, since histamine is known as a mediator in anaphylaxis in guinea pig, producing anoxia by constricting bronchial muscle, which is a phenomenon practically undistinguishable from anaphylactic shock.

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We have already reported that picric acid (1, 2) and phenyl acetate (3) provoke a contraction of the guinea pig ileum through acetylcholine liberation from the cholinergic nerve ; the effect of picric acid is inhibited by morphine but the response to phenyl acetate is not affected by morphine. So we speculated that two mechanisms could be responsible for the acetylcholine liberation: one is concerned with the actions of 5-hydroxytryptamine and picric acid and is affected by morphine, the other is brought in the action by phenyl acetate and is resistant to the inhibitory action of morphine (3). In this report the mechanisms concerned with acetylcholine liberation from the cholinergic nerve element of guinea pig ileum are studied, using strychnine, derivatives of phenyl acetate, catecholamines and reserpine.

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