Thomas A. Ban
Neuropsychopharmacology in Historical Perspective
Education in the Field in the Post-Neuropsychopharmacology Era
Alfred Pletscher Autobiography – On the Eve of the Birth of the Neurotransmitter Era in Biological Psychiatry
The story of serotonin and norepinephrine, the first monoamine neurotransmitters identified begins with the detection of a vasoconstrictor substance in the blood in the mid-1880s by Stevens and Lee (1884). The substance was crystallized from ox serum by Rapport, Green and Page (1948) and its chemical structure identified, in the late 1940s, as 5-hydroxytryptamine (5HT), referred to as serotonin. Independent of this development, in the mid-1930s Erspamer with Vialli (1937) extracted a substance from the enterochromaffin cells of the intestinal mucosa of rabbits, they referred to as enteramine. In the early 1950s Erspamer recognized that “enteramine” was a structurally-identical “indoleamine” with serotonin (Erspamer and Asero 1952). Then, in 1953, Twarog and Page demonstrated the presence of 5HT in the brain and one year later, in 1954, Amin, Crawford and Gaddum described its distribution in the brain.
Simultaneously with this development, but starting about 20 years later, in the early years of the 20th century, R.T. Elliott (1905) detected a substance at sympathetic nerve endings he referred to as “sympathin.” In the mid-1940s the substance was identified as noradrenaline (NA)/norepinephrine (NE) and separated by Ulf von Euler (1905-1983) from adrenaline/epinephrine (Euler1946). In 1954, the same year as Amin, Crawford and Gaddum described the distribution of 5HT in the brain, Marthe Vogt (1903–2003) reported on the concentration of NE in different parts of the brain in normal conditions and after the administration of drugs (Ban 2011; Vogt 1954).
Recognition of the function of monoamine oxidase (MAO), the enzyme involved in the oxidative deamination of monoamines is linked to the name of Felix Blaschko (1900–1993). While studying the metabolism of adrenaline in the mid-1930s Blaschko and his associates found that it was metabolized by “tyramine oxidase,” an enzyme first described in 1928 by MLC Hare in the liver (Blaschko, Schlossmann and Richter 1937a; Kopin 2006). Subsequently, they had also shown that it was the same enzyme that metabolized noradrenaline, dopamine and all aliphatic amines (Knoll 2014). Hence, they changed its name from “tyramine oxidase” to “amine oxidase.” Furthermore, in 1937 Blaschko, Schlossmann and Richter (1937b), provided further substantiation on the presence of the enzyme in the liver. In the same year, amine oxidase was also detected in the brain by Pugh and Quastel (1937). One year later, in 1938, after Albert Zeller’s separation of “diamine oxidase” from “amine oxidase,” the name of “amine oxidase” was changed to “monoamine oxidase” (MAO) to indicate that its function is restricted to the oxidative deamination of monoamines (Knoll 2014).
Developments which led to the introduction of substances with an inhibitory effect on the activity of the MAO enzyme began in1945 with V. Chorine’s discovery that nicotinamide had a bacteriostatic effect (Kopin 2006). The search that followed for related drugs that might be useful in the treatment of tuberculosis led, in the early 1950s, to the synthesis of isoniazid and iproniazid, its hydrazide derivative, by Fox and Gibbs (1953) at Hoffmann La Roche Laboratories in the USA (Pletscher 2006). It was noted that both energized patients and produced euphoria in tubercular patients with (Flaherty 1952). In 1952, antidepressant effects were reported with isoniazid by Delay, Laine and Buisson, and Robitzek, Selikoff and Orenstein. In the same year (1952) Zeller and his associates discovered that both isoniazid and iproniazid were inhibitors of the activity of the MAO enzyme (Zeller and Barsky 1952; Zeller, Barsky and Fouts 1952). From the two substances iproniazid was more potent. It was an irreversible inhibitor of MAO (Pletscher 2006).
Instrumental to further developments was the construction and introduction of the Aminco Bowman spectrophotofluorometer (SPEC) in 1955 with the necessary sensitivity to measure the concentration of neurotransmitter monoamines, such as NE and 5-HT and their metabolites in the brain (Bowman, Caulfield and Udenfriend 1955). The SPEC was ready for use in the laboratory of Bernard Brodie (1907–1989) at the National Institutes of Health (NIH) of the United States without delay.
This was the state of affairs in March 1955 when Alfred Pletscher (1917-2006), an employee of Hoffmann La Roche, the company that developed isoniazid and iproniazid, joined Brodie’s Laboratory as a visiting scientist. His findings, with the employment of SPEC that the tranquilizing (sedative) action of reserpine, a substance that can arguably induce depression (See Bulletin 14) is associated with a dose dependent depletion of brain 5HT, reported with Brodie and Parkhurst Shore, in the same year (Pletscher, Brodie and Shore 1955) opened up worldwide research on the neurobiology of monoamine neurotransmitters and led ultimately to the monoamine hypotheses of affective disorders. His discovery that pre-treatment with iproniazid, a substance that can arguably induce elation, not only attenuated the tranquilizing (sedative) effect of reserpine, but reversed it by producing behavioral stimulation, provided the scientific rationale for the introduction of MAO inhibitors in the treatment of depression. It also heralded, in 1956, the beginning of the “neurotransmitter era,” the first epoch in the history of neuropsychopharmacology (Ban 2011; Ban and Ucha Udabe 2006; Besendorf and Pletscher 1956; Brodie, Pletscher and Shore 1956; Brodie, Shore and Pletscher 1956; Pletscher 1956; Pletscher, Shore and Brodie 1955, 1956; Sulser 2011).
The autobiographic essay of Alfred Pletscher in which the story of his major contributions to biochemical neuropsychopharmacology in the 1950s are discussed was first published in 1998 with the title “On the eve of the neurotransmitter era in biological psychiatry” in The Rise of Psychopharmacology and the Story of CINP edited by Thomas A. Ban, David Healy and Edward Shorter. Parts of the story is also covered in one of Pletscher’s other autobiographic essays, published in 2004, with the title “From inside the pharmaceutical industry” in Reflections on Twentieth–Century Psychopharmacology by the same editors (Ban, Healy and Shorter 1996, 2004.)
There are also two interviews with Pletscher which contain information on his contributions to neuropsychopharmacology, one conducted by Ban and the other by Andrea Tone, both published in 2011, in volumes Three (Neuropharmacology, edited by Fridolin Sulser) and Nine (Update, edited by Barry Blackwell) in An Oral History of Neuropsychopharmacology, a series edited by Ban (Ban 2011; Blackwell 2011; Sulser 2011).
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April 26, 2018