Amines and the brain

Amines and the brain

103 TIBS - March 1983 50 Years Ago Amines and the brain J. H. Quastel There is no doubt, today, of the fact that a that defied experimentation. Ther...

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103

TIBS - March 1983

50 Years Ago Amines and the brain J. H. Quastel There is no doubt, today, of the fact that a that defied experimentation. There was an variety of biogenic amines are not only pre- indifference, even an antagonism, to the sent in mammalian brain but that they per- thought that chemical, or physicoform roles in the molecular processes chemical, mechanisms may underlie characterizing the conscious nervous sys- abnormal mental behaviour. Such attitudes tem that underlie many aspects of cerebral greatly delayed experimental work on isohehaviour. Some of them are now known to lated brain, especially in hospitals or inshe transmitters in the nervous system, e.g. titutions devoted to the care of the mentally acetyl choline, the catecholamines and 5- disturbed. How could work on isolated hydroxya'yptamine. Dihydroxyphenylethyl- brain, be it from mouse or man, at whatever amine has attained a signal importance in time it might he acquired following demise the study and treatment of Parkinsonism of the animal, throw light on the origin of and allied nervous disorders. Much of human mental disorder and even lead to modern neurochemical research is devoted improvements or changes in mental to the consideration, however indirect, of therapy ? As I look back on those difficult days I the cerebral amines; for example, investigations of their locations and the conditions fully realize how justified my colleagues controlling their formation in brain cells must have felt in their scepticism of the and the circumstances governing their value of laboratory work on animal brains. uptake, storage and removal following Nevertheless, I knew that some fresh release from their sites of storage. In recent approach was needed that could lead to a years, /3-phenylethylamine, p-tyramine, possibly acceptable view of the conditions m-tyramine and tryptamine have been that might give rise to mental disorders - a found in small amounts in the mammalian view that would he open to experirnentation brain and it is known that their concentra- and might make it possible to predict recovtions are increased following administra- ery, or even alleviation of the disorder. I had shown in 1932 that clinically active tion of monoamine oxidase (MAO) inhlbitors; for example, administration of barbiturates, which had dire effects on brain the MAO inhibitors, ephedrine and hehaviour (as anaesthetics) had highly iproniazid, suppress the metabolism of inhibitory effects on the respiration of isonoradrenaline and 5-hydroxytryptamine lated brain tissue incubated in a gluand increase their concentrations in the cose-saline medium, whereas clinically brain stem. The amines are stored at special ineffective barbiturates (used at the same sites in the brain, indicating that their local concentrations) had little or no effect. influence may he far greater than their Moreover the action of the potent barbituoverall concentrations would lead one to rates was reversible; a simple washing of believe. Much work is being done to dis- the brain tissue restoring the initial respiracover their exact locations in the nervous tory value of the isolated brain. Again, this system. inhibitory effect was specific, for it was not How did this vast field of investigation evident when the glucose in the medium originate? What special circumstance was substituted by succinate, a highly caused attention to be focused on the cere- oxidizable substrate of the brain. The conbral amines? It was by no means rare, in centrations of barbiturates used were high older times, for many of those who did their (0.1%), far above that necessary for anaesbest to ease the lot of their mentally afflicted thesia. The reason for this only became patients to consider that some mental dis- clear some years later when it was realized turbances were due to the ingestion, or to that the rate of respiration of isolated brain the formation in the body, of substances cortex (examined as slices) was only about that had toxic effects in the central nervous half that found in vivo but that stimulation system. But for many medical men, the of the brain tissue in vitro by a variety of 'functional' psychoses, such as schizo- means increased the respiratory rate to phrenia, seemed to be explained by concepts almost the normal value. Examples of such stimulation were the applications of electriJ. H. Quastel is at the Department of Neurochemiscal pulses or exposure to a potassium ion try, University of British Columbia, Vancouver, concentration about equal to that in the Canada.

neurone itself. The increased external concentration of potassium ions increased, indirectly, the rate of formation of acetylCoA from pyruvate thereby making the citric acid cycle the rate-limiting process for glucose oxidation. The respiratory rate then became highly sensitive to substances which impede the citric acid cycle. The respiration of the isolated brain tissue, stimulated in this manner, was inhibited by barbiturates at their anaesthetic concentrations. It seemed to me that there might well he a correlation between the facts that clinically potent barbiturates could he respiratory inhibitors of brain respiration in vitro and that clinically ineffective barbiturates were, under similar experimental conditions, without inhibitory effect. Such a correlation could help to explain the well-known mental disturbances that usually accompany the onset of cerebral anoxia. Following this line of thought, it seemed possible that there might exist substances, native to the body, that will also effect brain cell metabolism, or cerebral physicochemical mechanisms, if their localized concentrations were substantially changed in mentally ill patients. During the period 1932-1933 1 decided to see if amines, which I suspected as being products of bacterial breakdown of amino acids in the human intestine would, like barbiturates, suppress or modify cerebral glucose oxidation in vitro. I chose a group of substances, many of them so far as I knew at the time, not yet discovered in the brain, including phenylethylamine, tyramine, tryptamine, isoamylamine, putrescine, cadaverine and histamine. I had samples of these compounds and I decided to test all of them. I found that only putrescine, cadaverine and histamine, all used at the same physiologically high concentrations, had little or no inhibitory effects. The effects of the other amines seemed to be very similar to those of the barbiturates. The results were published in 1933 (Ref. 1) but drew little attention as the effective amines were not known at that time to he brain constituents. Nevertheless, the results made further work with these substances desirable. The work with isoamylamine was of particular interest to me, for I had noticed that in all experiments involving aerobic incubation of this amine with animal brain tissue there arose, after incubation, the distinctive odour of isoamylalcohol. It had become clear to me at that time isoamylamine must under-

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104 go chemical change in the isolated brain presumably oxidation to the corresponding aldehyde followed by its reduction to the alcohol. This observation gave rise to a line of investigation which resulted in the finding 2 that an aliphatic amine oxidase must exist in mammalian brain. The experimental problems involved were purely technical (e.g. that of estimating ammonia in the presence of a volatile amine) and were solved without great difficulty. The complete findings were published early in 1937 but, in the meantime, it had become clear that amine oxidase could attack the inhibitory arylamines forming the corresponding aldehydes, which were the actual respiratory inhibitors. Their effects greatly exceeded those of the parent amines. The cerebral amine oxidase was apparently identical to a tyramine oxidase already known to exist in liver and it became known subsequently as -

T I B S - March 1983

monoamine oxidase. These results were published late in 1937 (Ref. 3), curiously enough in the same issue of the Biochemical Journal containing an article by Blaschko, Schlossman and Richter which presented very similar results. Subsequent work" showed that phenylisopropylamine (amphetamine) was a competitive inhibitor of monoamine oxidase and this amine brought about a relief of the respiratory inhibition due to the biogenic amines. It was suggested' that the well-known pharmacological effects of amphetamine may be due to its competition with monoamine oxidase, resulting in increased levels in the brain of the biogenic amines, a suggestion supported by the later work of Oota5. Thus the idea arose that the brain cell levels of biogenic amines are related to some aspects of cerebral behaviour. Nowadays, it is believed that the excita-

tory effects of amphetamine are mediated through brain catecholamines and are due both to its ability to inhibit monoamine oxidase and to its ability to prevent reuptake of the released amine. The oxidase plays a significant role in controlling the amount of dopamine (and other amines) stored in the brain. Since 50 years ago there has now arisen a vast literature on the pharmacological effects of biogenic amines monoamine oxidase and other enzymes involved in cerebral amine metabolism. References

1 Quastel, J. H. and Wheatley, A. H. M. (1933) Biochem. J. 27, 1609-1613 2 Pugh, C. E. M. andQuastel, J. H. (1937)Biochem. J. 31,286-291 3 Pugh, C. E. M. and Quastel, J. H. (1937)Biochem. J. 31, 23(16-2321 4 Mann, P. J. G. and Quastel, J. H. (1940) Biochem. J. 34,414--431 5 0 o t a , Y. (1946)J. Chem. Soc. Japan 67, 45-51