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The theory of chemical transmission has proved to be a powerful tool in the analysis of many aspects of neurological function, and its implications loom large on the horizon of neurology and psychiatry. Neurotransmitters are released at neuronal endings, diffuse rapidly across the synaptic cleft, and then act upon receptor proteins embedded in the membrane of the post-synaptic neuron or gland. Drugs are evaluated for their ability to stimulate or to block specific receptors, and in that way modify activity of the postsynaptic organ in order to achieve some desirable therapeutic effect. This chapter is concerned with our knowledge of some of the principal neurotransmitters, namely the primary amines: dopamine, noradrenaline, and serotonin; the quaternary amine: acetylcholine; and the aminoacids: gamma-aminobutyric acid, glutamic acid and glycine. The historical background to the discovery of these molecules as physiological neurotransmitters is presented, and their relation to various clinical states is discussed.

This paper is concerned with some of the events in physiology that followed Otto Loewi's description of a substance that he named "Vagusstoff"; events that led eventually to the establishment of acetylcholine as a transmitter substance in the nervous system. Much of the work achieving this recognition of acetylcholine as a neurotransmitter took place in the middle third of the twentieth century; a period that witnessed the dislocation of many people as a result of National Socialist policies in Germany, that country's expansionist conquests, and the Second World War. A few of the people who were obliged to emigrate from Europe played prominent roles in these discoveries. This paper describes some of their achievements and, in a way, pays tribute to them.

This paper describes the work of five scientists who, among others, carried on the work of J. L. W. Thudichum, the pre-eminent investigator of brain chemistry in the latter half of the 19th century, after his death in 1901.

The Nobel Prizes for Physiology or Medicine have included a relatively large number of awards for work in the neurosciences, or for work construed to have made a contribution to neuroscience. These are recognized in this article by brief explanations of the particular contribution that warranted this magnificent (and munificent) award. The first prizes in neuroscience were awarded five years after the initiation of the Nobel Foundation's program. Up to 2005, 28 prizes have been awarded for achievements in neuroscience to 52 individuals.

The discovery of the Law of Conservation of Energy in the 1840s had consequences for psychological theory. Does the process of thinking involve a novel form of energy that is not recognized by physical science? E. L. Youmans (1821-1887) argued that "mental operations are dependent upon material changes in the nervous system." Kurd Lasswitz (1848-1910) introduced the term "psychophysical energy," based upon the electrical activity of the brain. At the beginning of the twentieth century Alfred Lehmann (1858-1921) claimed that intense mental effort leads to a net increase in oxygen utilization and regarded this as evidence of a specific psychic energy. His views were adopted and extended by Hans Berger (1873-1941). F. G. Benedict (1870-1957), drawing upon extensive experience with balance experiments conducted on humans in large-scale respiration calorimeters, concluded that mental effort probably had no effect upon the brain's metabolism. Modern approaches to the problem make use of PET imaging, which detects local changes in glucose utilization by the brain during cognitive activity.

Neurochemistry, the biochemistry of brain and nerve, had its identifiable scientific origins in France just before the French Revolution. Its main development remained in the hands of Parisian chemists over the next four decades. Thereafter, interest in the subject spread slowly through the German-speaking world. The most significant advances were made by a Hessian, practicing medicine and chemistry as an émigré in London in the second half of the 19th century. Some chemists had an intrinsic interest in exploring the brain by the techniques which they had applied to various organs of the body. However, there were others for whom social, medical, even philosophical, factors were the spur in their choice of study of the chemistry of the nervous system. This paper describes the early growth of neurochemistry as I have come to understand it during the course of historical research during the past 10 years.

Having described the spinal fluid, François Magendie (1783-1855) called upon a number of chemists in Paris to analyze the material, in the effort to decide if it was a special secretion of the nervous system or simply a filtrate of the blood. J.L. Lassaigne (1800-1859) and J.P. Couerbe (1805-1867) responded. Their results, and those of some earlier investigators, are described. In the ensuing years of the nineteenth century, other investigators similarly conducted analyses of spinal fluid, but these were usually of single constituents in poorly defined diagnostic conditions. In 1909-1912, William Mestrezat (1883-1928) took advantage of the recently introduced technique of lumbar puncture, which by now had become hospital routine, and introduced the modern era of systematic analysis of many components of the spinal fluid, correlated with specific disease states.

Evidence of the neurotransmitter role of dopamine has come from research employing a variety of modalities. These have made use of the techniques of pharmacology, toxicology, clinical pathology, clinical chemistry and experimental neurology. This article deals more specifically with the contributions of the author and his collaborators in establishing the function of dopamine as the chemical mediator of the nigrostriatal tract

The drug treatment of Parkinson's disease since the original description of the malady in 1817 is described. Consideration is given to the historic use of alkaloids of the belladonna, harmala, and aporphine families, and of amphetamine. The introduction of the L-dopa treatment is described. The modes of action of the various drugs employed in the past as well as those in current use are described in the context of knowledge of the functioning of the nigrostriatal tract.

Georges Cabanis (1757-1808), through his writings on the relation of the physical and moral, or psychological, aspects of man, left a legacy that made the study of mental activity a part of physiology. His views on the importance of phosphorus to the function of the brain thrust that element into a prominent stream of research that involved many investigators in several countries. Although that particular stream eventually dried up, its influence remained: by the beginning of the twentieth century basic medical science had become well set on studies of the mind-body relationship.

Kernicterus, described in the period just before Kinnier Wilson's publication of his study of hepatolenticular degeneration, served him as a model of liver dysfunction associated with neurological disorder. The work of the early investigators of kernicterus, especially their descriptions of the pathological changes in the brain, led Wilson to postulate that a hepatotoxin was responsible for the neurological entity that he elucidated.

When Georges Cabanis presented his views to the National Institute of France in 1797 on the physiological basis of human psychology, he introduced the concept that phosphorus was of special importance in the workings of the brain. The presence of phosphorus in that organ had only recently been described by A F Fourcroy, a finding that impressed Cabanis because of the association of light (phosphorescence) and heat (evolved during oxidation) with the element. Furthermore, he hypothesised that the electrical activity of the brain represented a parallel and interacting system with that of phosphorus. Cabanis was one of the leading exponents of "ideology", the principal school of philosophy at the time of the French Revolution. Ideology promoted the systematisation of knowledge in every sphere--social, scientific and medical, for example-- and Cabanis's views about cerebral phosphorus evolved from those teachings.

The period between 1600 and 1800 was one of great change in the history of science, generally, and in the history of chemistry, specifically. It opened with Francis Bacon's visionary recognition of the benefits to mankind that would accrue from the expansion of scientia and closed with the overthrow of the phlogiston hypothesis. New chemical knowledge resulted from the efforts of the alchemists, especially in Paracelsians, and of the phlogistic philosophers, some of it recorded by writers of magic books (Thorndike, 1958; Camporesi, 1989). The authors of these works reflected 'the general mentality ... imbued with magic, occult beliefs, unreal suggestions, 'voices', and 'rumours', ... 'errors' and 'prejudices'. In respect to brain chemistry there appeared, beside the fantastic, elements of fact that characterise this period as embracing the 'pre-history' of neurochemistry.

From 1865 to about 1910 studies of the chemistry of the brain were afflicted by the hypothesis that cerebral lipid matter consisted of a giant molecule from which all the simpler lipids were derived as breakdown products. In successive periods the main proponents of this 'protagon' theory were Oscar Liebreich, Arthur Gamgee and William Cramer. The theory was disproved by the careful and detailed studies of JLW Thudichum whose work on the brain was described in many papers, government reports, and two outstanding monographs. The controversy involved rough moments, generated by both sides, but by 1910, a few years after his death, Thudichum was fully vindicated in his opposition to the protagon concept and his classification of brain lipids became the accepted standard for biochemistry as a whole.

Chloral hydrate was introduced into therapeutics more than 120 years ago, and soon became popular as a somnifacient. It is the first synthetic CNS depressant. Its metabolite, urochloralic acid, was detected early. Studies of the biochemical pharmacology of chloral hydrate have engaged the attention of many investigators in succeeding years. Its mode of action in producing sleep was initially attributed to the possibility that it gives rise to chloroform in vivo. Although this hypothesis did not stand up to scientific scrutiny, it led to efforts to establish how chloral hydrate brings about its action. This seems to be through its reduced metabolite, trichloroethanol. The precise mode of action on the nervous system remains to be worked out.

Alpha-methyltryptophan (AMTP), a synthetic amino acid, is metabolized by the rat in vivo to alpha-methylserotonin (AM5HT), which appears in the pineal gland just as it does in the brain. Pineal AM5HT assumes the same diurnal rhythm as serotonin does in control animals. Administration of AMPT results in a decrease of the serotonin content of the pineal gland, but not of its melatonin content. Pharmacological evidence indicates that the uptake of AMTP into the gland is influenced by noradrenergic innervation. No evidence was obtained for formation in vivo of alpha-methyl-N-acetylserotonin or the alpha-methyl analogue of melatonin.

The use of bromides in medicine dates back to the beginning of the 19th century. The salts were used in neurological and mental diseases, particularly in epilepsy, up until their partial replacement by phenobarbital and ultimate displacement by dilantin. This article reviews the analytical methodology as it developed historically, and traces the application of chemical analysis of body fluids to monitoring for bromide toxicity (bromism) and then to investigation of the blood-brain barrier in various disorders of the central nervous system.

1. Alpha-methyltryptophan, on administration to experimental animals gives rise to cerebral alpha-methylserotonin, which substitutes for serotonin in certain behavioral and functional tests. 2. Such results are consistent with the similarity of the properties of the two indoleamines with respect to storage, uptake and release, as well as with the 5HT2-receptor agonist activity of alpha-methylserotonin. 3. It is proposed that alpha-methyltryptophan be regarded as a candidate drug for the provision of alpha-methylserotonin as a substitute for serotonin in disorders where the latter amine is thought to be deficient.

In vivo measurements by positron emission tomography of the brain serotonin synthesis rates in the normal dog, in the dog with increased plasma tryptophan concentration, and in the dog under different arterial oxygen tensions are described. The method described here permits repeated measurements in the same brain for the first time. An increase in the plasma tryptophan concentration from 16.6 to 191.5 and then to 381 microM resulted in close to a linear increase in the brain serotonin synthesis rate. When PaO2 was raised from 76 +/- 2 to 106 +/- 1 mm Hg, the rate of serotonin synthesis in the dog brain increased from 39 +/- 8 to 54 +/- 10 pmol g-1 min-1. The estimates of the Michaelis-Menten constants, Kappm and Vmax, for the transport of tryptophan through the blood-brain barrier are 303 +/- 54 microM and 63 +/- 10 nmol g-1 min-1, respectively.

We describe here a practical autoradiographic method to estimate the rate of serotonin synthesis in brain. A two-time point method (60 and 150 min after injection of alpha-[14C]methyl-L-tryptophan) was first evaluated in 14 normal rats (7 at each time point). After this the method was tested in lithium-treated rats. In normal rats the rate of serotonin synthesis measured by the two-time point method generally correlated with known concentrations of tryptophan hydroxylase. The rate of synthesis in lithium-treated rats was compared with that in sham-treated rats (NaCl treatment). The results showed a significant increase in the synthesis rate in some cerebral structures. The greatest increases in the serotonin synthesis rate, attributable to the lithium treatment, were observed in the parietal cortex (52%) and caudate nucleus (47%). This is the first investigation to demonstrate, with autoradiographic resolution (approximately 100 microns), the differential changes in the rate of serotonin synthesis in the brain. Lithium had no significant effect on the rate of synthesis in the pineal gland.

A biological model for the measurement of the rate of serotonin synthesis in rat brain with alpha-[14C]methyl-L-tryptophan is described. The rate of serotonin synthesis in several grossly dissected brain structures is reported. The half-life of the precursor pool, estimated from kinetic data, is between 20 and 25 min. The method allows, for the first time, measurement of the brain serotonin synthesis rate without any pharmacological manipulation and does not require separation of metabolites. Autoradiographic data are also presented to demonstrate anatomical resolution of this method. The synthesis rate can be estimated in a large number of discrete structures when autoradiography is applied. Long retention of the tracer in brain is also demonstrated.

?-Methylserotonin, an analogue of serotonin formed in vivo from ?-methyltryptophan, is able to stimulate phosphoinositide turnover (up to 190% of the basal rate) in slices of rat cerebral cortex in vitro. Desensitization of the cortical slices by ?-methylserotonin or serotonin significantly decreases serotonin-stimulated (but not norepinephrine-stimulated) phosphoinositide turnover, thus indicating an interaction of ?-methylserotonin with serotonin receptors. Ketanserin, a serotonin(2)-receptor antagonist, blocks ?-methylserotonin-stimulated phosphoinositide turnover. This suggests that this action is mediated by serotonin(2)-receptors. The chronic administration to rats of p-chlorophenylalanine, which depletes stores of brain serotonin, increases serotonin-stimulated phosphoinositide turnover, as detected in vitro. In contrast to this, the chronic administration of ?-methyltryptophan, which also depletes brain serotonin, does not increase the in vitro serotonin-stimulated phosphoinositide turnover. This suggests that accumulated ?-methylserotonin formed in the brain substitutes for serotonin and prevents the up-regulation of serotonin-receptor-mediated phosphoinositide hydrolysis. The present study explains the molecular basis for the functional activity of ?-methylserotonin in serotonergic neurons.

We describe here an autoradiographic method to measure the in vivo rate of serotonin synthesis in rat brain. The method is based on the use of the L-tryptophan analogue alpha-methyl-L-tryptophan (alpha-MTrp), which is converted in vivo into alpha-methylserotonin (alpha-M5HT). Since alpha-M5HT is not a substrate for monoamine oxidase, it is accumulated in the brain tissue. Data are presented to confirm time-dependent conversion of alpha-MTrp into alpha-M5HT in the dorsal raphe nucleus and also in the pineal body, an organ outside the blood-brain barrier. It has also been shown that washing brain slices in 10% trichloroacetic acid results in less than 3% incorporation of alpha-MTrp into brain proteins. The rates of synthesis are calculated in several grossly dissected brain structures by using tracer kinetics and a three-compartment biological model. The half-life of the precursor pool is estimated to be approximately 20 min. The rate of serotonin synthesis is highest in the pineal body.

1. Administration to rats of alpha-methyltryptophan (AMTP) gives rise to alpha-(AM5HT) in the brain along with a decrease of cerebral 5HT. 2. Analysis of fractions prepared from brains of AMTP-injected rats shows that AM5HT occurs mainly in the synaptosomes. 3. The synaptosomal content of AM5HT in proportion to the total AM5HT in the brain represents the same ratio as for the corresponding fractions of 5HT.

The concentrations of polyamines and the activities of ornithine decarboxylase (ODC) and of S-adenosylmethionine decarboxylase (SAM-DC) were measured in the adrenal glands of rats during development. Adrenal spermine content increases gradually during the first month of life whereas spermidine and putrescine decrease. A low spermidine/spermine ratio is obtained. The developmental pattern of adrenal SAM-DC resembles that of spermine content. The activity of adrenal ornithine decarboxylase increases after birth and attains a peak at 17 days of age. It declines sharply thereafter. Induction of adrenal ODC following the stress of immobilization is already observed in the rat at 4 days of age but the induction caused by maternal deprivation or cold exposure is obtained only at 17 days. The results suggest that the developmental pattern of ODC activity is independent of its responsivity to various stressors.

Administration of the dopamine receptor agonists apomorphine (APM) and piribedil increases adrenocortical ornithine decarboxylase (ODC) activity. In this paper alterations in the sympathoadrenal system, and in the central dopaminergic and serotonergic systems have been produced to study the possible mechanism of action of APM on adrenocortical ODC. Unilateral splanchnicotomy, unilateral rhizotomy, and bilateral demedullation each attenuated the response of adrenocortical ODC to APM. Intracerebroventricular 6-hydroxydopamine and 5,6-dihydroxytryptamine, intraperitoneal p-chlorophenylalanine and electrolytic lesion of the medial raphe nucleus reduced the APM-induced increase. None of these treatments produced any changes in the endogenous ODC activity of the adrenal cortex. It is postulated that dopaminergic brain structures participate directly in the stimulatory effect on the hypophyseo-adrenal system to increase adrenocortical ODC activity. An intact central serotonergic system seems to be necessary for APM to exert its effect on adrenocortical ODC activity, particularly the medial raphe nucleus.

The administration of the dopamine antagonist haloperidol (HLP) to rats produced a temporary increase in adrenomedullary and cortical ornithine decarboxylase (ODC) activity. The time-course of stimulation of ODC activity by HLP showed different patterns in both structures. Medullary ODC activity was highest at 2.5 h, decreasing at later times; cortical ODC activity was not affected by the drug at 2.5 h, but then increased up to at least 6.5 h. The medullary increase observed at 2.5 h was dose-related and could be prevented by splanchnicotomy. Hypophysectomized rats, on the contrary, showed an enhanced response to HLP. The results suggest that haloperidol-induced increase of adrenomedullary ODC activity is caused by a reflex increase in preganglionic nerve activity, and that the pituitary gland can modulate this response. Cortical ODC response to HLP, as previously demonstrated, is mediated entirely by the hypophysis.

Concentrations of homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA) were significantly higher in CSF obtained after injection of air during pneumoencephalography (PEG) than in lumbar CSF, as drawn before the injection. There was a high correlation between levels in the `mixed' and lumbar samples of CSF in the case of each of the two acids. The concentration of lumbar HVA, but not that of 5-HIAA, was negatively correlated with CSF pressure. 5-HIAA levels were low in both samples of CSF in a group of epileptics, by comparison with controls. In two patients with Kufs disease and in one with Niemann-Pick disease, the concentration of HVA was very low in the lumbar sample. The application of a standardized PEG technique in the study of monoamine metabolism in man is suggested.

Induction of adrenal ornithine decarboxylase (ODC) was studied in rats that had previously undergone hemisection of the spinal cord at the C5-C6 level. Control rats were sham-operated. In the latter, the stress of immobilization produced symmetrical increases in ODC of the adrenal medulla. In rats with cord hemisection a quantitatively similar increase was observed only on the intact side, the response of adrenomedullary ODC of the lesioned side being significantly smaller. Induction of adrenomedullary ODC in hemisected rats by administration of apomorphine or of 2-deoxyglucose resulted in the same pattern of response as after immobilization. Induction of adrenocortical ODC by immobilization or apomorphine was not affected by cord hemisection. The results demonstrate the existence of both ipsilateral and contralateral components of descending spinal pathways for the induction of adrenomedullary ODC, the ipsilateral fibres exerting a preponderant effect.

The increase in activity of adrenocortical ornithine decarboxylase (ODC) elicited by the administration of apomorphine (APM) was studied in rats, four days after transection of the spinal cord or 24 h after various types of brain surgery: transection of the mesencephalon or of the diencephalon, or hypothalamic deafferentation (creation of a "hypothalamic island"). Section of the cord elevated endogenous adrenocortical ODC activity and potentiated the induction of the enzyme by APM. Incomplete sections of the brain at the level of the mesencephalon or diencephalon produced no change in either endogenous or induced ODC activity. In contrast to this, interruption of the mesencephalic-diencephalic connections by complete diencephalic transection produced profound decreases of endogenous ODC and of the response to APM. Deafferentation of the hypothalamus raised endogenous ODC concentrations of the adrenal cortex and potentiated the response to APM. The results strongly suggest that APM acts at the level of the diencephalon (hypothalamus) to increase adrenocortical ODC activity. Diencephalic-mesencephalic connections must be intact for this to occur. Peripheral and extrahypothalamic influences play a modulatory role in this effect.

Motor and autonomic effects of n-pentylamine in mice have been evaluated in relation to aminergic mechanisms by combining administration of the amine with drugs having well known effects on such mechanisms. Some evidence has been found to indicate the importance of dopaminergic pathways in the actions of pentylamine; these actions are modifiable by central blockade of muscarinic receptors with atropine. Serotonin-regulated pathways do not seem important for the effects of pentylamine that have been studied.

The effect of induction of adrenal tyrosine hydroxylase (TH) by various centrally acting drugs on catecholamine levels in adrenal and plasma was investigated in rats. All the drugs tested, namely oxotremorine, Piribedil, B-HT 920, and HA-966, produced significant increases in adrenal dopamine content and plasma epinephrine level. Denervation of the adrenal abolished the increase in adrenal dopamine as it did the induction of tyrosine hydroxylase. The results suggest that the induced increase of adrenal TH activity, as mediated by certain drugs, results in an elevation of the plasma epinephrine level and that the adrenal dopamine content is a better indicator of the catecholamine-synthesizing capacity of the adrenal medulla than are the other catecholamines.

The catabolism of 14C-putrescine (1,4-tetramethylene-diamine) to labeled CO2 in small laboratory animals has been studied extensively in order to establish the influence of nutritional, endocrine and other factors on this process. Special attention has been paid to treatments that are known to affect the activity of diamine oxidase (DAO, histaminase, EC, 1.4.3.6), a copper-containing enzyme characteristically inhibited by semicarbazide. Thus, copper-deficient rats metabolize putrescine more slowly than their controls. Antimalarial drugs that inhibit histamine N-methyltransferase also inhibit putrescine catabolism in vivo and DAO activity in vitro. Adrenalectomized rats metabolize the diamine at a reduced rate, a result consistent with the previously demonstrated decrease of DAO in the tissues of several species of animal. There is no effect on the rate of catabolism of putrescine when thyroid state is altered. Heparin (up to 15,000 U/kg), which releases DAO from the small (0.1 mg/kg), intestine, and aminoguanidine (0.1 mg/kg), which inhibits the enzyme powerfully, both cause decreased rates of catabolism of the diamine in rats. The putrescine-catabolizing ability returns with a half-time of recovery of 15-18 h, corresponding to the estimates of SHAFF and BEAVEN [36] for recovery of intestinal DAO activity following administration of heparin or cycloheximide. Together with out other results this suggests that what is being measured by putrescine catabolism depends to a significant extent on the activity of DAO in vitro.