"Rational hope" in the early treatment of Parkinson's disease.

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.

An element of thought: phosphorus and mental philosophy in the nineteenth century.

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.

Newborn infants with yellow brains: the discovery of kernicterus in Germany, 1875-1908.

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.

Light and enlightenment: Cabanis, ideology, and the role of phosphorus in the brain.

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.

Seventeenth- and eighteenth-century commentators on the chemical composition of the brain.

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.

The protagon phoenix.

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.

Early clinical neurochemistry of CNS-active drugs. Chloral hydrate.

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 metabolism in rat pineal gland and brain.

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.

Early clinical neurochemistry of CNS-active drugs. Bromides.

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.

Serotonin synthesis rate measured in living dog brain by positron emission tomography.

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.

Alpha-methyltryptophan as a therapeutic agent.

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.

Biological model for the in vivo measurement of rate of serotonin synthesis in the brain.

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.

A new method to measure brain serotonin synthesis in vivo. I. Theory and basic data for a biological model.

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.