Monday, 06.04.2020

Thomas A. Ban
Neuropsychopharmacology in Historical Perspective
Education in the Field in the Post-Neuropsychopharmacology Era

Background to An Oral History of the First Fifty Years
Neuropharmacology (Volume Three): 1. Neurotransmitters
(Bulletin 40)

 

          In 1957 Ralph Gerard coined the term “psychotropic drugs” for chemicals which can control or induce mental pathology (Gerard 1957). Neuropharmacology studies the molecular substrate involved in the mode of action of these drugs.

          Interviewees, in the first two volumes of this series, reflected on their contributions to the delineation of the effects of psychotropic drugs on behavioral measures (Volume 1) and neurophysiologic parameters (Volume 2). In Volume 3 the emphasis shifts and interviewees reflect on their contributions to the development of neuropharmacological research. Since neuropharmacological research may provide information on the biochemical underpinning of mental pathology, neuropharmacology has been the moving force of psychotropic drug development during the 50 years covered in Volume 3.

          Development of neuropharmacology was triggered in the 1950s by the serendipitous discovery of the first set of effective psychotropic drugs: chlorpromazine, reserpine, meprobamate, iproniazid and imipramine in the treatment of mental pathology (Ban 1967).The commercial success of these drugs, especially chlorpromazine and meprobamate, stimulated the pharmaceutical industry to develop substances with similar effects. By the end of the 1950s there were 12 effective drugs for the treatment of psychoses, seven for the treatment of depression and two for the treatment of anxiety.

          Drugs for the treatment of psychoses at the end of the 1950s: chlorpromazine, chlorprothixene, haloperidol, methotrimeprazine (levomepromazine), perphenazine, prochlorperazine, reserpine, thiopropazate, thioproperazine, thioridazine, trifluoperazine and triflupromazine.

          Drugs for the treatment of depression by the end of the 1950s: amitriptyline, imipramine iproniazid, isocarboxazid, nialamide, phenelzineand tranylcypromine.

          Drugs for the treatment of anxiety by the end of the 1950s: hydroxyzine and meprobamate.

          In 1967 an “expert committee” of the World Health Organization (WHO) classified psychotropic drugs into five categories: neuroleptics (major tranquilizers, antipsychotics), anxiolytic sedatives (minor tranquilizers), antidepressants, psychostimulants and psychodysleptics (psychomimetics)(WHO 1967). By the end of the 20th century two further categories were added; mood stabilizers and cognitive enhancers. Each of these categories was broad, and within each category there were substances with different pharmacological actions. The WHO classification has had a major impact on neuropharmacology and on psychotropic drug development.

          The initial targets of neuropharmacological research were neurotransmitters. By the end of the 1950s there were six neurotransmitters identified: acetylcholine, norepinephrine (noradrenalin), serotonin, dopamine, γ-aminobutyric acid and substance P.

          Acetylcholine (ACh) was first detected at parasympathetic nerve endings in 1914 by Henry Dale (Dale 1914). The effect of the substance on cells adjacent to the nerve endings was first noted by Otto Loewi in 1921 (Loewi 1921). In 1936-1937 ACh was isolated from brain homogenates by Juda Quastel and his associates, and Stedman and Stedman (Quastel 1936; Stedman and Stedman 1937). The effect of ACh on neuronal transmission in the spinal cord was demonstrated by Eccles and his associates in 1954 (Eccles, Fatt and Koketsu 1954).

          Sympathin was first detected at sympathetic nerve endings in 1904 by R.T. Elliott (Elliott 1905; Healy 1997). The substance was identified as noradrenaline (NA)/norepinephrine (NE) and separated from adrenaline/epinephrine by Ulf Von Euler in 1946 (Sourkes 1962; Von Euler 1946). In 1954 Marthe Vogt reported on the concentration of NE in different parts of the brain in normal conditions and after the administration of drugs (Vogt 1954).

          In 1884 Stevens and Lee described a vasoconstrictor substance in the blood (Stevens and Lee 1884). Rapport, Green and Page crystallized the substance in 1948 from ox serum and identified it as 5-hydroxytryptamine (5HT), referred to as serotonin (Rapport, Green and Page 1948). In 1937 Vittorio Erspamer extracted a substance from the enterochromaffin cells of the intestinal mucosa of rabbits he referred to as enteramine (Erspamer and Vialli1937). In 1952 he recognized that enteramine was a structurally identical indoleamine with serotonin (Erspamer and Asero 1952). In 1953 Twarog and Page demonstrated the presenceand in 1954 Amin, Crawford and Gaddum described the distribution of 5HT in the brain (Amin, Crawford and Gaddum 1954; Twarog and Page 1953).

          Dopamine (DA), an intermediary in the synthesis of NE from tyrosine, was detected in the brain in 1957 by Kathleen Montagu (Montagu 1957). The same substance was identified in 1958 by Arvid Carlsson and his associates (Carlsson, Lindqvist, Magnusson and Waldeck 1958). In 1959 Carlsson described the distribution of dopamine in the central nervous system. He also demonstrated that DA was not just an inactive intermediary, a precursor of NE, but an active neurotransmitter in the brain (Carlsson 1959). The distribution of dopamine was further elaborated by Bertler and Rosengren,and Sano and his associatesin the same year (Bertler and Roseengren 1959; Sano, Gano, Kakimoto et al 1959).

          The presence of γ-aminobutyric acid (GABA) in plants and bacteria has been known since the late 19th century. In 1950 Awapara and his associates, and Roberts and Frankel detected the presence of GABA in the brain (Awapara, Landua, Fuerst and Seale 1950; Roberts and Friedel 1950). Seven years later in 1957, Purpura and his associates and Curtis and his associates demonstrated its marked depressant action on nerve terminals and identified GABA as an inhibitory neurotransmitter (Curtis, Eccles and Eccles 1957; Purpura, Girado and Grundfest 1957).

          Substance P (SP) was detected in the intestine and in the brain in 1931 by Von Euler and Gaddum (Von Euler and Gaddum 1931).In 1952 Zetler had shown the presence of the substance in high concentration in the human cerebral cortex; in 1959 he demonstrated that SP is a centrally acting transmitter of inhibitory neurons (Zetler 1953, 1959).

          The Aminco Bowman spectrophotofluorimeter(SPEC) was introduced in 1955 and employed in the same year by Bernard Brodie and his associates for measuring the concentration of neurotransmitter monoamines, such as NE, 5-HT and DA and their metabolites in the brain. SPEC complemented paper, gas and high-speed liquid chromatography and was instrumental in opening up research in neuropharmacology (Bowman, Caulfield and Udenfriend 1955).

          The enzyme monoaminoxidase (MAO), involved in the oxidative deamination of monoamines, was first detected in the liver by Blaschko and his associates in 1937 (Bernheim1931; Blaschko, Richter and Schlossman 1937).The same year MAO was also detected in the brain by Pugh and Quastel (Pugh and Quastel1937). In 1938 MAO oxidase was separated from diamine oxidase by Zeller (Zeller 1938).

 

References:

Amin AH, Crawford TB, Gaddum JH. The distribution of substance P and 5-hydroxytryptamine in the central nervous system of the dog.  J Physiol 1954; 126: 596-618.

Awapara J, Landua AJ, Fuerst R, Seale B. Free γ-aminobutyric acid in brain. J Med Chemistry 1950; 187: 35-9.

Ban TA. The role of serendipity in drug discovery. Dialogues in Clinical Neuroscience 2006; 8: 337-44.

Bertler A, Rosengren E.  Occurrence and distribution of dopamine in brain and other tissues.  Experientia 1959; 15: 10-1.

Bernheim NLC. Tyramine oxidation. II.The course of oxidation. J Biol Chem 1931; 155: 299-309.

Blaschko H, Richter D, Schlossman H. The oxidation of adrenaline and other amines. Biochem J 1937; 31: 2187-96.

Bowman RL, Caulfield PA, Udenfiend S. Spectrophotofluorometry in the visible and ultraviolet spectrum. Science 1955; 122: 32-3.

Carlsson A. The occurrence, distribution and physiological role of catecholamines in the nervous system. Pharmacol Rev 1959; 11: 490-3.

Carlsson A, Lindquist M, Magnusson T, Waldeck B. On the presence of 3-hydroxytyramine in brain. Science 1958; 127: 471-2.

Curtis DR, Eccles JC, Eccles RM. Pharmacological studies on spinal reflexes. J Physiol 1957; 136: 420-4.

Dale HH. The action of certain esters and ethers and choline, and their relation to muscarine. J Pharmacol 1914; 6: 147-90.

Eccles JC, Fatt P, Koketsu K. Cholinergic and inhibitory synapses in a pathway from motor-axon collaterals to motoneurons. J Physiol 1954; 126: 524-62.

Elliott TR. The action of adrenalin. J Physiol 1905; 32:  401-2. 

Erspamer V, Asero B. Identification of enteramine, specific hormone of enterochromaffin cells as 5-hydroxtryptamine. Nature 1952; 169: 800-1

Erspamer V, Vialli M. Ricerchesulsecretodelle cellule enterocromaffini. Boll d Soc Med-chir Pavia 1937; 51: 357-63.

Gerard RW. Drugs for the soul; the rise of psychopharmacology. Science 1957; 125: 201-3

Healy D. The Antidepressant Era. Cambridge (Massachusetts): Harvard University Press;1997. p.145.

Loewi O. Über humorakeűbertragbarkeit der Herzenwirkung. PflűgersArchiv 1921; 189: 232-42.

Montagu KA. Catechol compounds in rat tissues and in brains of different animals. Nature 1957; 180: 240-1.

Pugh C, Quastel JH. Oxidation of aliphatic amines by brain and other tissues.  Biochem J 1937; 31: 286-91.

Purpura DP, Girado M, Grundfest H. Selective blockade of excitatory synapses in the cat brain by γ-aminobutyric acid. Science 1957: 125: 1200-1.

Quastel JH, Tennenbaum M, Wheatley AH.  Choline ester formation and choline esterase activities of tissues in vitro. Biochem J 1936; 30: 1068-70.

Rapport MM, Green AA, Page IH. Crystalline serotonin. Science 1948; 108: 329-30.

Roberts E, Friedel S. γ-aminobutyric acid in brain: its formation from glutamic acid. J Biol Chem 1950; 187: 55-63.

Sano I, Gano T, Kakimoto Y, Taniguchi K, Takagad H, Nishinuma K. Distribution of catechol compounds in human brain. BiochimBiophys Acta 1959; 32: 586-7.

Sourkes TL. Biochemistry of Mental Diseases. New York: Harper & Row Publishers; 1962. p. 306-23.

Stedman E, Stedman F. Mechanism of biological synthesis of acetylcholine: isolation of acetylcholine produced by brain tissue in vitro. Biochem J 1937; 31: 817-20.

Stevens LT, Lee FS.  Action of intermittent pressure and of defibrinated blood upon blood vessels of frog and terrapin. Johns Hopkins Bulletin 1884; 3: 99-100.

Twarog BM, Page IH. Serotonin content of some mammalian tissues and urine and a method for its determination.  Am J Physiol 1953; 175: 157-61.

Vogt M. Concentration of sympathin in different parts of central nervous system under normal conditions and after administration of drugs. J Physiol 1954; 123: 451-81.

Von Euler US. A specific sympathomimetic ergone in adrenergic nerve fibers (sympathin) and its relation to adrenaline and noradrenaline. Acta PhysiolScand 1946; 12: 73-9.

Von Euler US, Gaddum JH. An unidentified depressant substance in certain tissue extracts. J Phsiol (London) 1931; 1: 72-4.

WHO. Research in Psychopharmacology. World Health Organization Technical Report Series No.371. Geneva: WHO; 1967.

Zeller EA. Über den enzymatischen Abbau von Histamin und Diaminen. Helvetia Chem Acta 1938; 21: 881-90.

Zetler G. Substance P in the central nervous system. Naturwissenschaften 1953; 40: 559-60.

Zetler G. Experiments on the anticonvulsive effectiveness of the polypeptide substance P.  Arch Exp Path Pharmacol  1959; 237: 11-5.

 

October 18, 2018