Historical Development of the Dopamine Hypothesis of Schizophrenia

This review examines the history of discoveries that contributed to development of the dopamine hypothesis of schizophrenia. The origin of the hypothesis is traced to the recognition that neuroleptic drugs interfere with brain dopamine function. This insight was derived from two distinct lines of research. The first line originated from the discovery in 1956 that reserpine depletes brain serotonin. This finding resulted in a sequence of studies that led to the discovery that brain dopamine is involved in neuroleptic-induced extrapyramidal motor disturbances. The second line of research was aimed at determining the mechanism of action of psychomotor stimulants. This research produced evidence that stimulants directly or indirectly activate brain dopamine receptors. Because nonreserpine neuroleptics such as chlorpromazine block stimulant-induced movement, these findings suggested that neuroleptics were dopamine antagonists. Most previous accounts of the development of the dopamine hypothesis of schizophrenia emphasize the first line of research and ignore the second.     

History of the Discovery of the Antipsychotic Dopamine D2 Receptor: A Basis for the Dopamine Hypothesis of Schizophrenia

The 1975 publication of Seeman et al. (Proc Nat Acad Sci, USA), reporting the discovery of the antipsychotic receptor in the brain, is a classic example of translational medicine research. In searching for a pathophysiological mechanism of psychosis, the team sought to identify sites that bound the antipsychotic drug haloperidol. Their criterion was that haloperidol bound to the site at one to two nanomoles per liter, corresponding to haloperidol concentrations found in spinal fluid or plasma water in treated patients. They requested de novo synthesis of tritiated haloperidol, and it readily detected specific haloperidol binding sites in brain striatum. With dopamine binding the haloperidol-labeled sites with higher potency than other neurotransmitters, the sites were named antipsychotic/dopamine receptors (now designated dopamine D2 receptors). Most significantly, they found that all antipsychotics bound these sites at concentrations and with a rank order of potencies that were directly related to the mean daily antipsychotic dose taken by patients with schizophrenia. Their findings enabled screening for new antipsychotics, initiated D2 receptor measurements in brain of living patients, and determination of minimum occupancy (65%) of D2 receptors for antipsychotic benefit. The collective work is generally viewed as providing a fundamental basis for the dopamine hypothesis of schizophrenia.     

The myth of reserpine-induced depression: role in the historical development of the monoamine hypothesis

For five decades it has been generally accepted that reserpine, an antihypertensive and antipsychotic drug, causes depression. The discovery that reserpine depletes brain monoamines was an important factor in the development of the monoamine hypothesis of depression, and it continues to be widely cited in support of this hypothesis. The present paper argues that, contrary to prevailing belief, reserpine is not depressogenic. The reason for perpetuation of this myth is reluctance to discard the monoamine hypothesis. This hypothesis ushered the modern biochemical paradigm into psychiatry and is still of great importance. It serves as a heuristic to guide research, it enhances psychiatry's prestige, and it helps to validate and promote drug therapy for depression and other mental disorders.     

The Myth of Reserpine-Induced Depression: Role in the Historical Development of the Monoamine Hypothesis

For five decades it has been generally accepted that reserpine, an antihypertensive and antipsychotic drug, causes depression. The discovery that reserpine depletes brain monoamines was an important factor in the development of the monoamine hypothesis of depression, and it continues to be widely cited in support of this hypothesis. The present paper argues that, contrary to prevailing belief, reserpine is not depressogenic. The reason for perpetuation of this myth is reluctance to discard the monoamine hypothesis. This hypothesis ushered the modern biochemical paradigm into psychiatry and is still of great importance. It serves as a heuristic to guide research, it enhances psychiatry’s prestige, and it helps to validate and promote drug therapy for depression and other mental disorders.     

Serendipity and the Cerebral Localization of Pleasure

Most accounts of the discovery of “pleasure” circuits in the brain begin with the observation by James Olds and Peter Milner in 1953 that electrical brain stimulation can condition operant responses in rats. Less well-known, pleasurable brain stimulation was previously observed in schizophrenic patients by Robert Heath. However, Heath failed to recognize the significance of this observation, at least in part, because of preconceived notions he held about the etiology of schizophrenia. This episode in the history of neuroscience illustrates the importance of sagacity in serendipitous scientific discoveries. It also shows that “mental preparedness” can be an obstacle to progress.     

Serendipity and the cerebral localization of pleasure

Most accounts of the discovery of "pleasure" circuits in the brain begin with the observation by James Olds and Peter Milner in 1953 that electrical brain stimulation can condition operant responses in rats. Less well-known, pleasurable brain stimulation was previously observed in schizophrenic patients by Robert Heath. However, Heath failed to recognize the significance of this observation, at least in part, because of preconceived notions he held about the etiology of schizophrenia. This episode in the history of neuroscience illustrates the importance of sagacity in serendipitous scientific discoveries. It also shows that "mental preparedness" can be an obstacle to progress.     

From DOPA to Parkinson's disease: the early history of dopamine research

Dopamine is among the most well-researched neurotransmitters at the present time. For the first half-century of neurotransmitter research, however, interest in dopamine was minimal, and only a few scattered groups of researchers studied it. It was their research that stimulated current interest, and provided the background for our present understanding of this important substance. By the late 1950s, it was clear to these individuals that dopamine served an important physiological role in mammalian brains, and that its role was most likely that of a central nervous system agonist. Soon after this, dopamine, or more specifically the depletion of dopamine, was clearly implicated in Parkinson's disease. This paper looks at the early history of the physiological roles of this intriguing compound.     

The Tulane Electrical Brain Stimulation Program a historical case study in medical ethics

In 1950 physicians at Tulane University School of Medicine began a program of research on the use of electrical brain stimulation that would span three decades and involve approximately 100 patients. Initially, electrical brain stimulation was used to treat of schizophrenia, but later it was applied to a variety of other conditions. Throughout its history the Tulane research was well publicized in both the professional and lay literature, and for almost twenty years, with rare exception, these accounts were laudatory. However, in the early 1970s this work began to draw sharp public criticism. Despite its public and controversial nature, the Tulane electrical brain stimulation program has received relatively little attention from historians. This review recounts the history of the Tulane program with particular emphasis on the ethical propriety of the work. Factors that shaped the historical context in which the Tulane experiments were conducted are discussed.     

The serotonin hypothesis of schizophrenia: a historical case study on the heuristic value of theory in clinical neuroscience

Clinical examination of the reliability and coherence of the evidence concerning modern neurochemical theories of mental disorders has led some scholars to conclude that support for many of these theories is weak. Nevertheless, these theories continue to be widely promoted. One explanation that has been offered for continued adherence to questionable theory is that it stimulates and gives direction to research. The heuristic value of theory is examined in the present paper by tracing the discoveries that followed from an old theory of schizophrenia, which is--by current consensus--false. It is shown that the original serotonin hypothesis of schizophrenia did, in fact, lead to significant advances in neuropharmacology, neurology and psychiatry.     

Ivane Beritashvili: founder of physiology and neuroscience in Georgia

This paper is dedicated to one of the outstanding scientists of the twentieth century--Ivane Beritashvili. He was a Georgian physiologist who graduated from St. Petersburg University and worked under the supervision of N. Wedensky. He founded the Department of Physiology and the Institute of Physiology at the University of Tbilisi, Georgia. Among his numerous contributions was the discovery of the rhythmical course of reciprocal inhibition in spinal reflexes, the first demonstration of the excitatory and inhibitory reactions in the brain stem neuropil. But Beritashvili's most significant contribution was the discovery of the mediation of animal psychoneural behavior by image-driven memory.     

Maritime Archaeology and the Early Atlantic Trade: research at Elmina,Ghana

This article details recent maritime archaeological research off the town of Elmina in coastal Ghana. Founded in 1482, Elmina Castle was the first and largest European outpost in sub‐Saharan West Africa, and remained a centre of maritime trade for almost four centuries. Survey and diver investigations led to the discovery of several sites, including a shipwreck dating to the mid 17th century, which is characterized by a mass of trade goods, cannon and buried hull remains. A second Dutch vessel dating to c.1700 was documented after its discovery during dredging operations in the Benya Lagoon adjacent to Elmina. These sites present an opportunity to study ships and cargoes involved in the West African trade.     

Memories of John Eccles

This article contains an account of the career of John Eccles that can be divided into two parts. The first extends from 1925, when he won a Rhodes scholarship to Magdalen College Oxford, to 1975, when he took voluntary retirement from the State University of New York at Buffalo. During this period, he set up six different laboratories in which he carried out research on synaptic mechanisms that provide the basis of neuroscience. The second period is the 20 years between his retirement and death in Switzerland, which he spent on the problem of the relationship between mind and brain.     

Ivane Beritashvili: Founder of Physiology and Neuroscience in Georgia

This paper is dedicated to one of the outstanding scientists of the twentieth century—Ivane Beritashvili. He was a Georgian physiologist who graduated from St. Petersburg University and worked under the supervision of N. Wedensky. He founded the Department of Physiology and the Institute of Physiology at the University of Tbilisi, Georgia. Among his numerous contributions was the discovery of the rhythmical course of reciprocal inhibition in spinal reflexes, the first demonstration of the excitatory and inhibitory reactions in the brain stem neuropil. But Beritashvili's most significant contribution was the discovery of the mediation of animal psychoneural behavior by image-driven memory.     

Neurognostics Question

Abstract

Dopamine is among the most well‐researched neurotransmitters at the present time. For the first half‐century of neurotransmitter research, however, interest in dopamine was minimal, and only a few scattered groups of researchers studied it. It was their research that stimulated current interest, and provided the background for our present understanding of this important substance. By the late 1950s, it was clear to these individuals that dopamine served an important physiological role in mammalian brains, and that its role was most likely that of a central nervous system agonist. Soon after this, dopamine, or more specifically the depletion of dopamine, was clearly implicated in Parkinson's disease. This paper looks at the early history of the physiological roles of this intriguing compound.     

A Concert Hall for Stringed Musical Instruments Under the Splenium of the Corpus Callosum

This article contains an account of the career of John Eccles that can be divided into two parts. The first extends from 1925, when he won a Rhodes scholarship to Magdalen College Oxford, to 1975, when he took voluntary retirement from the State University of New York at Buffalo. During this period, he set up six different laboratories in which he carried out research on synaptic mechanisms that provide the basis of neuroscience. The second period is the 20 years between his retirement and death in Switzerland, which he spent on the problem of the relationship between mind and brain.     

The Future of Collective Farms' Built Social Infrastructure: Choosing Between Central Place and Network Theories

The aim of this paper is to discuss local and regional planning and development practices in a post‐socialist country such as Estonia. Two approaches — central places and network theories — are used as a conceptual basis. According to the first hypothesis, planning and development of social infrastructure (e.g. schools, sports halls) has remained based on the central place theory — as an outdated planning approach — in Estonia. The second hypothesis argues that while, on the one hand, the application of the network paradigm and increased cooperation between local communities would considerably save public resources, on the other hand, because of the path dependency of Soviet centralized planning and development practices, the networking and lobbying takes place vertically rather than horizontally. This restricts both administrative cooperation and networking on the local and regional levels. The paper consists of three parts. The first part describes the turn in Western planning theory: the shift from normative top‐down planning to a bottom‐up approach and networking. The second part analyses critically the Soviet and post‐Soviet planning theory and practices: the planning and development culture created during the Soviet era. Finally we present a case study of a community planning procedure in the Suure‐Jaani locality — a good example of the influence of historical changes in the settlement system and planning culture of the past on current development.     

Exotic Celtic Coinage in Britain

This paper examines the c. 250 'exotic' Celtic coins found in Britain, defined as coins originating beyond Armorican and Belgic Gaul. The coins are considered in relation to their typology, their contexts of discovery and their distribution. Several key themes emerge: the occasional import of early continental staters, perhaps in the third century BC; the arrival of fine copies of Massiliot bronze issues during the second century BC, leading to the development of British potin coinage; and, from the first half of the first century BC, the importation of an increased number of exotic coins, mostly from central Gaul, primarily to Chichester, north-east Kent and the territories north of the Thames.     

The search for an endogenous schizogen: the strange case of taraxein

In 1956, Dr. Robert Galbraith Heath, Chair of Psychiatry and Neurology at Tulane University School of Medicine in New Orleans, announced that he and colleagues had discovered a protein they called taraxein in the blood of schizophrenic patients that caused symptoms of schizophrenia when injected into healthy volunteers. Heath's claim received wide public and professional attention. Researchers quickly tried to confirm the discovery. These efforts, which were rigorous and in some cases conducted in consultation with the Tulane researchers, failed. Nevertheless, for the next four decades Heath continued to defend his claim. This article recounts the scientific developments that led up to Heath's putative discovery and it explores the scientific findings for and against the taraxein theory of schizophrenia.     

Recording the brain at work: the visible, the readable, and the invisible in electroencephalography

The electroencephalogram (EEG), the graphic recording of the electric activity of the human brain, kindled far-reaching speculations about the imminent deciphering of mind and brain in the 1930s. Regardless of the thousands of neurons in the human cortex, recording from a person at rest produced a surprisingly regular line oscillating at 10 per second that disappeared at the moment of mental activity. With ever more groups specializing in electroencephalography, however, the deciphering of mind and brain did not materialize but moved further away in the information produced. In the various approaches employed in EEG research, such as the analysis of the graphic code, the search for pathognomic patterns or the imaging of cognitive processing, visualization guided research as well as theorizing, its productivity continued to keep the epistemological question open.     

Metalworking and Recycling in Late Bronze Age Cyprus – the Evidence from Kition

Excavations at the sacred precinct of the Late Bronze Age city of Kition uncovered the remains of metalworking workshops which were clearly associated with the temples. The results of the excavation as well as a number of specialist reports of the archaeometallurgical finds have already been published. Since their publication, however, archaeological research has progressed and new evidence has come to light regarding the Late Bronze Age in general and metalworking in particular. The object of this paper is to present the finds from these workshops and reconsider some of the issues that their discovery has raised. The results of the previous studies of the archaeometallurgical studies are critically assessed and the evidence reinterpreted based on what is available today. One of the issues addressed is that of metal recycling during the Late Bronze Age. This communication was presented at a research workshop organized by the Israel Science Foundation and the University of Haifa on 'Recycling, Hoarding and Trade in Bronze, 13th–11th centuries BCE' (Haifa 26–28 April, 1998). The first part of the paper was written by Karageorghis, the second part by Kassianidou.