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): 3b. Contributions of Interviewees
Four interviewees (Garattini, Dingell, Sulser and Frazer) contributed to the neuropharmacology of antidepressants. In the late 1950s Silvio Garattini, in collaboration with Costa and Valzelli, found that imipramine reversed reserpine-induced hypothermia and ptosis. In the early 1960s reserpine reversal was introduced in the screening for potential antidepressants (Costa, Garattini and Valzelli 1960). In the late 1960s Garattini showed that oxazepam was a pharmacologically active metabolite of diazepam (Marcucci, Fanelli, Mussi and Garattini 1970).
In the early 1960s James Dingell, a second-generation disciple of Brodie and a pupil of Gillette, isolated desmethylimipramine (desipramine, DMI), a secondary amine metabolite of imipramine (Gilette, Dingell, Sulser, Kuntzman and Brodie 1961). In collaboration with Sulser and Gillette, Dingell demonstrated that DMI has a longer half-life than its parent substance (Dingell, Sulser and Gillette 1962). He had also shown that chronic administration of imipramine to rats led to accumulation of DMI (and not of imipramine) in tissues, including the brain (Dingell, Sulser and Gillette 1964).
Fridolin Sulser, another Brodie disciple, was first in the early 1960s to recognize that reserpine reversal was dependent on the availability of NE (Sulser, Bickel and Brodie 1964). He found that DMI no longer reversed the effects of reserpine after depleting brain NE by α-methyltyrosine (Sulser 1998). In the mid-1970s, in collaboration with Jerzy Vetulani, Sulser discovered that chronic treatment with tricyclic and MAOI antidepressants (as well as with ECT) decreased the number of β-adrenoreceptors and reduced the responsiveness of the β-adrenoreceptor-coupled adenylate cyclase system to NE in limbic and cortical structures in the rat brain (Vetulani and Sulser 1975). Pursuing this line of research further, with a shift in emphasis from pre-synaptic to post-synaptic mechanisms, he found in collaboration with Sanders-Bush that both NE, through the activation of the cyclic AMP – protein kinase A pathway, and 5HT, through the activation of the diacylglycerol (DAG) - protein kinase C pathway, caused phosphorylation of nuclear CREB (cyclic adenosine monophosphate regulated element binding protein) (Sanders-Bush, Conn and Sulser 1975). Furthermore, in collaboration with Manier and Shelton, he also revealed that chronic treatment with noradrenergic antidepressants produced a highly significant reduction (down–regulation) of CREB - P, the biologically active form of the transcription factor (Manier, Shelton and Sulser 2002).
The finding of β-receptor down regulation in chronic treatment with noradrenergic antidepressants was further refined by Alan Frazer who had shown, with the employment of quantitative-autoradiography, that desipramine preferentially down-regulated β- adrenoreceptors (Ordway, Gambrena and Frazer 1988). Frazer was first to demonstrate that chronic treatment with SSRIs down-regulated SERT (serotonin transporter) and that the ovarian hormones, estradiol and progesterone could inhibit the ability of SSRIs to slow the clearance of 5HT (Benmansour, Cecchi, Morilak, Gerhardt, Javors, Gould and Frazer 1999; Frazer; Benmansour, Pietrowski, Altamarino and Frazer 2009). Screening for potential antidepressants with the forced swimming test, Frazer and his associates found a dose-dependent improvement of “behavioral despair” with leptin, a hormone with receptors in limbic structures, secreted by adipose tissues (Lu, Kim, Frazer and Zhang 2006).
Two interviewees (Wurtman and Sanders-Bush) contributed to the neuropharmacology of serotonin. In the early 1970s Richard Wurtman, in collaboration with John Fernstrom, demonstrated that administration of tryptophan increased brain 5HT (Fernstrom and Wurtman 1971). They had also shown an increase in brain serotonin following ingestion of a carbohydrate diet (Fernstrom and Wurtman 1972). Wurtman, a disciple of Axelrod, discovered in the mid-1960s that melatonin is synthesized in the pineal gland and the synthesis of melatonin is controlled by light (Wurtman1985; Wurtman, Axelrod and Fisher 1964). He also revealed that the NE content of the pineal gland changes during the 24-hour diurnal rhythm (Wurtman and Axelrod 1966).
Elaine Sanders-Bush, a disciple of Sulser, was one of the first to demonstrate that there are multiple serotonin receptors; she also described their regional distribution (Blackshear, Steranka and Sanders-Bush 1981). In the mid-1980s Sanders-Bush discovered that calcium was a second messenger of the 5HT-2 family of 5HT receptors (Sanders-Bush and Conn 1987).
Two interviewees (Berger and Lal) contributed to the neuropharmacology of anxiolytics. In the mid-1940s Frank Berger found that mephenesin produced reversible flaccid paralysis in mice (Berger and Bradley 1946). He also noted that animals became quiet and “tranquilized” after small doses of the drug (1998). Berger was instrumental in synthesizing, developing and introducing meprobamate, a substance with a similar pharmacological profile to mephenesin but with a longer duration of action (Berger 1954, 1977).
Harbans Lal developed a pentylenetetrazol-induced model of anxiety for studying the anxiolytic effect of drugs (Jung, Lal and Gatch 2002; Lal and Shearman 1982). Lal was first to show that centrally acting anti-muscarinic drugs antagonized the effect of neuroleptics on apomorphine induced aggression but not of the effect of morphine (Gianutsos and Lal 1976).
Three interviewees (Iversen, Paul and Enna) contributed to the neuropharmacology of γ-aminobutyric acid. Leslie Iversen, a disciple of Axelrod was first, in the 1960s, to demonstrate a calcium dependent release of GABA in crustaceans in response to stimulation of an inhibitory nerve (Iversen 1978; Iversen, Mitchell and Srimivasan 1971; Osuka, Iversen, Hall and Kavitz 1966). He was also first to demonstrate GABA uptake mechanisms in the mammalian brain (Iversen and Neel 1968). In the 1970s Iversen found that naloxone, an opiate antagonist, blocked morphine’s suppressant effect on the release of Substance P from the sensory nuclei of the brain and spinal cord (Dingledine, Iversen, and Breuker 1976; Iversen, Jessell and Kanazawa 1976).
In the late 1970s Steven Paul and his associates demonstrated the action of benzodiazepines, ethyl alcohol and barbiturates on the GABA receptor system (Hammer, Skolnick and Paul 198). Paul was first to show the binding of imipramine to the 5HT transporter in man (Paul, Rehavi, Rice, Ittah and Skolnick 1981). In the late 1980s he had discovered neuroactive progesterone metabolites in the brain and showed that these metabolites interacted with the GABA receptor system (Paul and Purdy 1982; Puia, Santi, Vicini, Pritchett, Purdy and Paul 1990).
Salvatore Enna contributed to the delineation of the of biochemical properties of the GABA receptor system and to the demonstration of correspondence between GABA receptors and benzodiazepine recognition sites (Enna and Möller 1987). In collaboration with Sands and Reisman, Enna was first to demonstrate the effect of antidepressants on GABA function (Sands, Reisman and Enna 2004).
Two interviewees, Fuxe and Dahlström, both students of Nils-Ǻke Hillarp, mapped the major DA, NE and 5HT pathways in the brain with the use of fluorescence histochemistry, a technique developed by Falck and Hillarp (Anden, Carlsson, Dahlström, Fuxe and Hillarp 1964; Anden, Dahlström, Fuxe, Larsson, Olson and Ungerstedt 1966; Falck, Hillarp, Thieme and Torp 1962). In the late-1960s Kjell Fuxe, in collaboration with Anden, Corrodi and Hökfelt, had shown that hallucinogenic drugs of the indolylalkylamine types, such as LSD, activated post-synaptic 5HT receptors in the brain (Anden, Corrodi, Fuxe and Hökfelt 1968). In the mid-1970s, in collaboration with Luigi Agnati, he demonstrated that bromocriptine was a dopamine agonist. In the early 1980s Fuxe and Agnati introduced the concept of intra-membrane, receptor-receptor interactions; and in the mid-1980s they demonstrated a slow, “volume transmission,” in the brain that involves the diffusion and “convection” of transmitters and modulators in the extra-cellular and cerebrospinal fluid (Agnati, Fuxe, Zoli, Zini, Toffano and Ferraguti 1986; Fuxe 2002; Fuxe and Agnati 2006; Fuxe, Agnati, Benfenati, Celani, Zini, Zoli and Mutt 1983).
Annica Birgitta Dahlström and Kjell Fuxe were first in the mid-1960s to demonstrate the presence of monoamines in the cell bodies of brain stem neurons (Dahlström and Fuxe 1964). They were also first to show experimentally-induced changes in the intraneuronal amine levels of bulbospinal neurons systems (Dahlström and Fuxe 1965). In the late 1960s Dahlström discovered axonal transport mechanisms and identified two groups of adenosine triphosphatase molecules, one involved in the fast transport from the cell body to the nerve endings and the other in “retrograde transport” (Dahlström 1966, 1971).
Three interviewees (Pert, Akil and Barchas) contributed to the neuropharmacology of neuropeptides and endorphins. In 1973 Candace Pert, a student of Solomon Snyder, was one of the first to discover the opiate receptor (Pert and Snyder 1973). She also localized in the rat brain the receptor with the employment of autoradiography (Pert, Kuhar and Snyder 1976). In 1986 Pert identified T (thymus) peptide that blocks HIV (human immunodeficiency virus) infection (Pert, Hill, Ruf, Berman and Robey 1986).
Huda Akil in the mid-1970s found that analgesia induced in rats by electrical stimulation of the brain was blocked by the administration of naloxone, a morphine antagonist (Akil, Mayer and Liebeskind 1976). She was the first to demonstrate that stress increased endorphin levels (Akil, Madden, Patrick and Barchas 1976). Akil, in collaboration with Stanley Watson, mapped the distribution of different endorphins in the brain (Akil and Watson 1987).
Jack D. Barchas was member of the team which demonstrated the presence of dynorphin 1-8 in hypothalamic magnocellular neurons in the1980s (Weber, Roth, Evans, Chang and Barchas 1982). He was also member of the team which isolated metorphamide, an amidated octapeptide, from bovine brain (Weber, Esch, Bohlen, Patterson, Corbett, McKnight, Kosterlitz Barchas et al. 1983). Focusing on neuropeptides, Barchas and his associates had shown the release of BAM 18, a product of peptide E, in response to stimulation (Boarder, Evans, Adams, Erdelyi, Barchas et al. 1987). They had also shown that dynorphin 1-8, an α-endorphin, is localized in the same cerebral systems (Barchas, Tatemoto, Faull, Evans, Valentino and Eberwine 1987).
Four interviewees (Agranoff, Barondes, Jarvik and Kandel) contributed to the elucidation of the biochemistry of memory. Bernard Agranoff in the 1950s discovered cytidine diphosphate-diacylglycerol, a substance important as an intermediate in the phosphoinositide cycle and in signal transduction (Agranoff, Bradley and Brady 1958). He also demonstrated a competition between dietary choline and inositol in growing chicks (Agranoff and Fox 1959). In the mid-1960s Agranoff had shown that administration of actinomycin D, a substance that blocks RNA synthesis, impaired retention (Agranoff, Davis, Casola and Lim 1967). He had also shown that administration of puromycin, a substance that blocks protein synthesis, produced retrograde amnesia in goldfish (Agranoff, Burrell, Dokas and Springer 1978; Agranoff, Davis and Brink 1965).
The relationship between protein synthesis and memory storage was further substantiated by Samuel Barondes’ demonstration that cycloheximide produced impairment of long-term memory in mice (Barondes 1968; Barondes and Cohen 1966, 1967; Squire and Barondes 1970). During the 1970s and 1980s Barondes discovered sugar binding proteins, called lectins, in slime molds and suggested that lectins play a role in cellular connections and interactions (Barondes 1984; Barondes, Catronova and Cooper 1994). He also identified a family of animal β-galactoside–binding lectins, he referred to as galactins, in chicken, mouse, frog and human tissues, including the brain (Barondes 1984; Barondes and Jarvik 1964).
Murray E. Jarvik collaborated with Barondes in studying the effect of actinomycin D on brain RNA synthesis and memory (Flood, Jarvik, Benntte, Orme and Rosenzweig 1977). He corroborated evidence for the negative effect of protein synthesis inhibition on memory (Barondes and Jarvik 1964; Jarvik, Jaffe and Jarvik 1978). In the 1980s Jarvik’s research shifted from memory to smoking and in the 1990s he introduced a “nicotine patch” that released nicotine through the skin (Jaffe and Jarvik 1964). Jarvik was first to show that bromocriptine, a dopamine agonist, decreased smoking (Jarvik, Caskey, Wirshing et al. 2000).
Eric Kandel, a Nobel Laureate, explored biochemical and molecular mechanisms involved in learning in Aplysia, demonstrating that the gill withdrawal reflex can undergo second order conditioning. In a series of elegant experiments, Eric Kandel identified serotonin as a critical transmitter that produced cyclic AMP which, when injected into sensory neurons, produced facilitation. In collaboration with Paul Greengard they injected a purified catalytic subunit of protein kinase A into presynaptic sensory neurons and found it simulated the actions of serotonin or cyclic AMP. These studies provided the first molecular insight into the process of learning (Karen, Walters and Kandel 1981; Kandel 2001, 2007; Sulser 2011).
Interviewees included in Volume 3 entered the field at different stages in the development of neuropsychopharmacology. Hence, the transcripts cover 50 years of history, from the introduction of the spectrophotofluorometer to the introduction of molecular genetic techniques. During these 50 years research in neuropharmacology extended from synaptic events, measured by neurotransmitter metabolism, to intracellular events, measured by protein synthesis and breakdown, and from the first to the third messenger systems in defining the action of psychotropic drugs.
Fridolin Sulser, the editor of this volume, was one of the leaders in the field during the neurotransmitter era. His research has been a moving force in the elucidation of the mode of action and in the development of antidepressants. His Introduction and Dramatis Personae complement the information covered in the interviews (Ban 2011).
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