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): 3a. Contributions of Interviewees
(Bulletin 42)
The information in Bulletins 40 and 41 provides the necessary orientation points for identifying the place of the contributions of the 33 interviewees whose transcripts in Volume 3 record the development of neuropharmacology. All transcripts are based on videotaped interviews.
Of the 33 interviewees five (Carlsson, Dahlström, Jarvik, Knoll and Pletscher) have an MD and PhD; 14 (Agranoff, Barchas, Barondes, Berger, Fuxe, Garattini, Kandel, Kopin, Langer, Paul, Sandler, Snyder, Sulser and Wurtman) are MDs; and 14 (Akil, Axelrod, Dingell, Enna, Fibiger, Frazer, Greengard, Iversen, Karczmar, Lal, Pert, Sanberg, Sanders-Bush and Spector) are PhDs. All but two interviewees (Dahlström and Knoll) are ACNP members. Four interviewees (Axelrod, Greengard, Jarvik and Karczmar) are founders and four other interviewees (Akil, Kopin, Paul and Sulser) are past-presidents.
All interviews were conducted from 1995 to 2008 and, with the exception of five, at annual meetings of the College. Three (Dingell, Spector and Sulser) of the five interviews done between annual meetings were conducted in Nashville, Tennessee; one (Pletscher) in Riehen, Switzerland; and one (Knoll) in Budapest, Hungary.
The thirty-three interviews were conducted by 16 interviewers. Eleven interviewers (Akil, Braslow, Cook, Costa, Koslow, Meador-Woodruff, Nestler, Sulser, Tone, Watson and Wayner) conducted one interview; three (Bromley, W. Bunney and Healy) conducted two; one (Hollister) six; and another one (Ban) nine. One interviewee (Barondes) was interviewed by two interviewers (Tone and Ban.)
By the time Volume 3 was publishedin 2011, four of the interviewees (Axelrod, Berger, Jarvik and Pletscher) and one of the interviewers (Hollister) passed away (Sulser 2011).
The 33 interviewees were involved in 10 different broadly defined areas of research related to neuropharmacology. Most of the interviewees contributed to several areas (Ban 2011).
The research of one interviewee, Alexander Karczmar, was focused entirely on the cholinergic system. In the 1950s Karczmar, in collaboration with Koketsu, Nishi and Dun, identified three ganglionic receptor sites of acetylcholine (Ach): nicotinic, muscarinic (metabotropic) and peptidergic (Karczmar 1986).Also, in the 1950s, in collaboration with Lang, he demonstrated the structural similarity between peripheral and central muscarinic acetylcholine receptors (Karczmar 1998).
The research of three interviewees (Pletscher, Sandler and Knoll) involved monoamine oxidase (MAO) and its inhibitors (I). Alfred Pletscher was first to demonstrate that administration of iproniazid, a MAOI, increased brain serotonin (5HT) levels (Pletscher 1998). Pletscher was a member of Brodie’s team which revealed that reserpine released 5HT from its vesicular storages in pre-synaptic 5HT neurons (Pletscher 2006).
Merton Sandler’s research was focused on MAO, the enzyme itself. In the mid-1960s, in collaboration with Moussa Youdim, he provided electrophoretic evidence that MAO was present in the brain in multiple forms (Youdim 2006). In the early 1970s, in collaboration with Vivette Glover, he demonstrated that dopamine (DA) was metabolized by the type-B isoenzyme of MAO (Sandler 2004).
The first MAO-B inhibitor, deprenyl (selegiline,) was synthesized and developed during the 1960s by Joseph Knoll and his team (Knoll2005).Knoll’s discovery was based on his recognition that deprenyl differs from other MAOIs by inhibiting, instead of potentiating, the blood pressure increasing effect of amphetamine and tyramine (Knoll, Vizi and Somogyi 1968). Knoll had also shown that deprenyl increased longevity and sexual activity in rats (Knoll, Dallo and Yen 1989).
Three interviewees (Axelrod, Kopin and Spector) contributed to the elucidation of catecholamine metabolism. In the 1950s Julius Axelrod, one of the Nobel Laureates (1970) of Brodie’s school, identified two enzymes, catechol-O-methyl transferase (COMT) and phenylethanolamine-N-methyl transferase (PNMT), involved in catecholamine metabolism (Axelrod 1959). In 1961, in collaboration with Whitby and Hertting, he discovered that the action of NE was terminated by reuptake into pre-synaptic noradrenergic neurons (Hertting, Axelrod and Whitby 1961). The demonstration by Axelrod and his team that cocaine and imipramine blocked the reuptake of NEwas instrumental to the development of the neuropharmacology of tricyclic antidepressants (Axelrod 1998).
Irwin Kopin was a member of Axelrod’s team which established that neuronal reuptake was important in the inactivation of NE (Hertting, Kopin, Axelrod and Whitby 1861).Kopin’s findings that NE metabolizes into dihydroxyphenylglycol (DHPG) and that DHPG converts through 3-methoxy-4-hydroxy-phenyl glycol (MHPG) into 3-methoxy-4-hydroxymandelic acid (vanilmandelic acid-VMA) filled a gap in catecholamine metabolism (Kopin, Axelrod and Gordon 1961).
Sydney Spector, another Brodie disciple, identified tyrosine hydroxylation as the rate limiting step in the formation of catecholamines. He demonstrated, in the mid-1960s, that blocking the activity of tyrosine hydroxylase by α-methyltyrosine depleted NE in the brain(Spector and Sjoersdma and Udenfriend1965). Spector, with the employment of radioimmunoassay, developed antibodies to psychotropic drugs which could distinguish between the isomers of a substance (Spector 1974). With the use of antibodies, he isolated in the mid-1970s an endogenous morphine-like substance in the brain (Gintzler, Levy and Spector 1976; Spector 2002).
Six interviewees (Carlsson, Snyder, Langer, Greengard, Fibiger and Sanberg) contributed to the neuropharmacology of dopamine (DA).Arvid Carlsson, another Nobel Laureate (2000) from Brodie’s school, had shown in the late 1950s that the reserpine-induced depletion of monoamines was not restricted to 5HT but included NE (Carlsson, Rosengren, Bertler and Nilsson 1957).He had also shown that reserpine-induced akinesia was reversed by the administration of 3,4-dihydroxyphenylalanine (DOPA), the precursor of DA and NE (Carlsson, Lindqvist and Magnusson 1957).In 1959 Carlsson demonstrated the neurotransmitter function of DA and in 1963, in collaboration with Lindqvist, he revealed that administration of chlorpromazine and haloperidol increased the metabolites of NE and DA in the mouse brain (Carlsson 1988).Carlsson’s recognition that dopamine receptor blockade was possibly the crucial step in the mode of action of antipsychotic drugs was instrumental to the development of the neuropharmacology of neuroleptics. It also triggered research which led to the formulation of the dopamine hypothesis of schizophrenia (Van Rossum 1967). In the development of zimelidine in the 1970s, the first SSRI antidepressant introduced for clinical use (in the early 1980s), Carlsson played a pivotal role (Carlsson and Wong 1997).
Solomon Snyder, a student of Joel Elkes and a disciple of Julius Axelrod, was among the first to demonstrate DA receptor blockade with neuroleptics (Burt, Creese and Snyder 1976).He was also among the first in the 1970s to isolate endorphins in the mammalian brain and to elucidate their structure (Simantov and Snyder 1976).In the 1990s Snyder recognized nitric oxide (NO) as a new class of gaseous neurotransmitterand as a physiologic mediator of penile erection (Burnett, Lowenstein, Bradt and Snyder 1992; Snyder1992).
Salomon Langer was first to describe pre-synaptic autoreceptors for DA, 5HT, ACh, GABA and glutamate (Langer 1974, 1987). He was also among the first in the 1970s to demonstrate co-transmission: the release of several types of neurotransmitters from one nerve terminal. Langer played a pivotal role in developing the atypical antipsychotic, aripiprazole (Langer1980; Langer and Pinto 1976).
Paul Greengard, another Nobel Laureate included in this volume, was first to show that interaction between DA and its receptors leads to the activation of specific cAMP (cyclic adenosine monophosphate) dependent protein kinases which, through phosphorylation, activate some proteins in the neuron (Yanz, Feng, Fienberg and Greengard 1999). His discovery of the presence of neurotransmitter-sensitive adenyl cyclase on the cell membrane opened the path to study the second messenger system in signaltransduction (Kebabian and Greeengard 1971).In the 1980s Greengard identified DARP-32 (dopamine and cyclic adenosine monophosphate response element binding protein) in striatal cells (Desdouits, Siciliano, Greengard and Grault1995; Hemmings, Greengard, Tung and Cohen 1984). DARP-32 is regulated by dopaminergic and glutamatergic stimulation in the opposite direction;its identification has stimulated interest in molecular genetic research in schizophrenia.
Hans Christian Fibiger and his associates were first to demonstrate that destruction of DA terminals in the nucleus accumbens stopped animals self-administering cocaine(Fibiger and Phillips 1986).They also showed DA release in the nucleus accumbens during various stages of sexual behavior in male rats (Damsma, Pfans, Wenkstem, Phillips and Fibiger 1992). The findings of Fibiger and his associates indicate that DA, and not NE, is the biochemical substrate of self-perpetuating reward, pleasure seeking behavior. In the 1980s Fibiger contributed to the mapping of muscarinic (cholinergic) neurons;and in the 1990s he was instrumental in introducing early gene (cFos) expression in screening for psychotropic drugs (Fibiger 1987, 1994; Fibiger and Vincent 1987).
Paul Sanberg found that nicotine enhanced the cataleptogenic effect of haloperidol, a dopamine antagonist, in rats(Sanberg et al. 1993).He also demonstrated that transdermal nicotine could reduce by about 50% the dose of haloperidol in treatment of Tourette’s syndrome (Sanberg et al. 1997; Silver, Shytle, Philipp, Wilkinson, McConville and Sanberg 2001).
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