Norepinephrine, 3-methoxy 4-hydroxyphenylethyleneglycol and homovanillic acid levels were similar in the locus ceruleus of 13 controls and 8 parkinsonian patients with no intellectual deterioration, but were decreased in 7 demented patients. The concentration of dopamine was similarly diminished in non-demented and demented parkinsonians, and binding of 3H-desmethylimipramine and 3H-rauwolscine was not abnormal in parkinsonians. These data indicate that norepinephrine metabolism in the locus ceruleus is subnormal only in demented parkinsonians.

The high-affinity binding of triatiated imipramine to platelet membranes was compared in samples from 16 untreated depressed women and 21 age-matched controls of the same sex. The maximal binding in the depressed group was significantly lower than that of the controls, although the affinity constants were similar. These results suggest that binding of tritiated imipramine in human platelets may represent a biochemical index of depression, possibly reflecting similar changes in the brain.

In 1960, Ehringer and Hornykiewicz (1) published a seminal article describing a reduction in dopamine levels in the striatum and substantia nigra of patients with Parkinson's disease. This observation had two consequences: the discovery of the mesostriatal system in the human brain, and the possibility of improving parkinsonian motor disability by restoring dopaminergic transmission with levodopa. It was only several years later that a decrease in dopamine levels was discovered in other brain structures, suggesting that the hypothalamic, mesolimbic, and mesocortical dopaminergic systems also degenerated to a certain extent. The principal studies demonstrating loss of dopaminergic neurons and changes in dopamine receptors are summarized in Tables 1-3. During the same period, decreases in noradrenaline and serotonin concentrations were detected in the basal ganglia and cerebral cortex, suggesting that the long ascending noradrenergic (Table 4) and serotoninergic ( Table 5 ) pathways, originating in the locus ceruleus and the raphe nuclei, respectively, were dysfunctional. Another 20 years passed before the discovery that the subcorticocortical cholinergic neurons (Table 6) and several peptidergic systems (Table 7) were also affected. We still know little about the fate of receptors (Table 8) and of neurons using amino acids as transmitters, except perhaps for those containing y-aminobutyric acid (Table 9). This succession of discoveries has been the object of a large and growing body of literature. A number of reviews summarize the data (8,12,18,23,40,47,(88)(89)(90)(91)(92)(93)(94). There is even a review of the reviews (2)! Therefore, instead of elaborating a new and exhaustive description of the biochemistry of Parkinson's disease, we intend rather to show how advances in our understanding of brain function have changed our pharmacological conception of the disease (discover and compensate for a neurotransmitter deficiency) to a physiological one (understand how dysfunction of neuronal systems produce symptoms). It has indeed been discovered through anatomical and biochemical studies that the lesions underlying the symptoms are more numerous and their consequences more complicated than originally thought. Progress has

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Inhibition of the binding of [3H]imipramine and inhibition of the uptake of [3H]serotonin and [3H]norepinephrine by a series of antidepressants and other drugs were studied in the rat hypothalamus. No correlation was found between the potencies of these drugs for the inhibition of [3H]imipramine binding and the inhibition of [3H]norepinephrine uptake. There was, however, a highly significant correlation between the potencies of these drugs for the inhibition of [3H]serotonin uptake. These results suggest that high-affinity [3H]imipramine binding might be associated with the mechanism of serotonin uptake in the brain.