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Diethyldithiocarbamate, a dopamine beta hydroxylase inhibitor, decreases biosynthesis of norepinephrine in the brain. The effects of this inhibitor coincide with alterations in memory as demonstrated in single-trial passive avoidance in C57BL/6J mice.

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Dopamine-ft-hydroxylase activity is present in mouse neuroblastoma C-1300 tumors. The activity is proportional to the weight of the tumor. Serum activity is markedly increased in mice that bear the tumors. Treatment of mice with 5-bromodeoxyuridine causes marked inhibition of tumor growth and decrease of dopamine-p-hydroxylase activity in the serum. The histochemical studies reveal that 1-5% of the cells in mouse C-1300 neuroblastoma tumors contain catecholamines and that catecholamine-containing processes terminate mainly around blood vessels of the tumor. Dopamine-j3-hydroxylase is present in clonal neuroblastoma cell lines. The cell line with the greater tendency to form axon-like processes has a higher activity of this enzyme. Dopamine-g-hydroxylase (hydroxylase) (EC 1.14.2.1) is found in normal animals only in adrenal glands and in adrenergic neurons (1, 2). It catalyzes the hydroxylation of dopamine to norepinephrine in the only physiologically significant pathway for the formation of this neurotransmitter. We now present data on the activity of this enzyme in mouse C-1300 neuroblastoma tumors and in cultured cell lines derived from this tumor. have not appreciably changed during the year in which the experiments were performed. After trypsinization and centrifugation, cells (about 0.1 ml) were washed 3-times with 10 ml of tyrosine and phenylalanine-free Eagle's medium containing 10% calf serum and twice with saline solution; cells were then sonicated and aliquots were taken for enzyme assay. Cell numbers were determined in duplicate with the hemocytometer; after dilution in 0.4% trypan blue, 95-98% of cells regularly excluded the dye. Hydroxylase in tumor, cell cultures, and plasma was assayed (7-9) by a sensitive procedure. In the first of coupled enzymatic reactions, tyramine is converted by the enzyme to octopamine; in the second reaction the octopamine is further converted by added phenylethanolamine: N-methyl transferase (EC 2.2.1.-) to N-methyl octopamine. The first reaction was done for 20 min and the second for 30 min (8). Tumors to be used for hydroxylase assay were homogenized in 5 mM Tris buffer (pH 6.8) containing 0.1% Triton X-100 and, the homogenates were centrifuged at 10,000 X g for 10 min. Aliquots of the supernatant containing 0.1-0.2 mg of tissue in 0.1-0.2 ml were assayed. For assay of the enzyme in serum, aliquots of 0.05-0.1 ml of serum (diluted 1: 10 with water) were used, and for assay in cultured cells, 0.1-to 0.2-mg aliquots of the homogenate (50-100,gg of protein) were used. In all incubations, tyramine (0.4 Amol) served as a substrate for the enzyme and S-adenosyl-i-[methyl-4C]methionine (43 mCi/mol) served as methyl donor. METHODS

Abstract.-The effects of centrally acting drugs on tremor were investigated in monkeys with ventromedial tegmental lesions exhibiting hypokinesia or hypokinesia and tremor. In monkeys with resting tremor, the administration of DL-5-HTP (5-hydroxytryptophan) or of DL-DOPA (3,4-dihydroxyphenylalanine) relieves the tremor, but the simultaneous administration of DL-5-HTP or DL-DOPA and atropine results in a much more pronounced relief. These results point to an imbalance between the cholinergic and adrenergic-serotonergic systems in parkinsonism.In monkeys exhibiting hypokinesia, the administration of harmaline evokes a marked resting tremor of the extremities contralateral to the tegmental lesion. The production of tremor by harmaline is not abolished by lowering the striatal amine levels with specific inhibitors of amine synthesis. Administration of DL-5-HTP protects monkeys from tremors induced by harmaline, which might affect the functions of the central nervous system by interaction with receptors for serotonin. The present results further demonstrate the apparent role of biogenic amines in the extrapyramidal dysfunctions.Model syndromes of extrapyramidal dysfunction have been produced in monkeys by introduction of unilateral lesions into the ventromedial area of the brain stem, after which the destruction of the pars compacta of the substantia nigra is associated with low concentrations of dopamine and serotonin in the corresponding basal ganglia.' Reduction of the biogenic amines in the striatum is concomitant with an impairment in the storage of dopamine and serotonin and with a decrease in the activities of tyrosine hydroxylase and DOPA decarboxylase.2-4To determine further the role of biogenic amines in extrapyramidal dysfunction, we have investigated the effects of centrally acting drugs on tremor in monkeys with mesencephalic lesions.Methods. -Green monkeys (Cercopithecus sabaeus) were used and unilateral radio-frequency lesions were induced in the ventromedial tegmental region of the brain stem as previously described.1' 2 Hypokinesia of the contralateral extremities appeared immediately afterward. In some monkeys a resting tremor (4 to 6 cycles per sec) developed five to seven days later. The lesions were induced at least one month prior to the beginning of the experiments. Tremograms were obtained by means of a transducer attached to the extremities and recorded on an electroencephalograph. The effects of centrally acting drugs were investigated in monkeys with ventromedial tegmental lesions with a slight spontaneous resting tremor of the contralateral extremities (group I) and in monkeys exhibiting hypokinesia of the contralateral extremities but no resting tremor (group II). Localization of the lesion in each brain was verified by gross examination and by histological studv. The locus and the extent of the lesion were similar to those reported previously.' Gross examination revealed that the lesion in the monkeys from group I was 1113

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