Block of Cerebral Actions of L-Dopa with Methyl Receptor Substances

Cotzias, George C.; Tang, Lei-Han; Ginos, James Z.; Nicholson, Alex; Papavasiliou, Paul S.

doi:10.1038/231533a0

Cited by 23 publications

(8 citation statements)

References 11 publications

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“…When, however, these pretreatments were followed by the injections of ibdopa, all the saline-treated animals developed the characteristic curving, but none of the inhibitor-treated ones did. In intact mice (Tables 2, 3, and 4) the following were found: (1) All inhibitors of protein synthesis diminished the behavioral effects of i.-dopa regardless of the end point used, even when the i-dopa was potentiated with a-methyldopa hydrazine (13). (2) The degree of diminution was roughly the same for each inhibitor and with each measurement.…”

Section: Observationsmentioning

confidence: 77%

“…The opposite suggestion might, however, emerge from the following. Nicotinamide, an inhibitor of tRNA transmethylase (12), has blocked the cerebral effects of -dopa (13), while such effects were minimal in the mouse mutant pallid, in which cerebral uptake of large neutral amino acids was slow (14). It was, thus, interesting to determine whether any of these suggestions was germane.…”

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confidence: 99%

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Changing the Actions of Neuroactive Drugs by Changing Brain Protein Synthesis

Tang¹,

Cotzias²,

Dunn³

1974

Proc. Natl. Acad. Sci. U.S.A.

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Diminution of cerebral protein synthesis diminished the cerebral responses of mice to some neuroactive drugs, while an increase in synthesis increased the responses. Protein synthesis in whole brains (tested in vitro ) was diminished by giving living mice different inhibitors by different routes. The inhibitors tested (chloramphenicol, cycloheximide, and puromycin) diminished the behavioral responses of the mice to levodopa without affecting either its cerebral uptake or its conversion to dopamine. A diminution of the reactions of dopaminergic receptors was suggested by the diminished responses to the dopaminergic drug, apomorphine, while participation of cholinergic ones was suggested by experiments with oxotremorine. Proof that receptors had been specifically involved was secured on homogenized caudate nuclei from chloramphenicol-treated mice, in which the dopamine-activated production of cyclic AMP was markedly diminished. A stimulator of cerebral protein synthesis, the artificial double-stranded RNA, poly(I)·poly(C), increased the behavioral responses to these three drugs while it increased the dopamine-activated production of cyclic AMP. Since all these experimental increases or decreases in the responses to drugs required the lapse of only a few hours, proteins with rapid turnover rates must be critical in the activation of several kinds of cerebral receptors.

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Section: Observationsmentioning

confidence: 77%

mentioning

confidence: 99%

Changing the Actions of Neuroactive Drugs by Changing Brain Protein Synthesis

Tang¹,

Cotzias²,

Dunn³

1974

Proc. Natl. Acad. Sci. U.S.A.

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“…Representative mice were examined: (i) for spontaneous motor activity, by placing groups of three within the cage of an Animex® motor activity meter once a month (9,10); (ii) for capacity to mate, as detailed below; and (iii) for motor hyperactivity, muscle jerks, stereotyped movements, jumping, gnawing, corkscrew tails, ataxia, salivation, piloerection, red muzzle, and convulsions, which had been exhibited by mice receiving fixed doses of -dopa (11)(12)(13)(14).…”

Section: Methodsmentioning

confidence: 99%

“…No death could be attributed solely to starvation, since all mice given only water died prior to any of those receiving -dopa. Yet, not a single mouse developed any of the behavioral signs listed under Methods as being induced by fixed doses (11)(12)(13)(14). Histological studies on tissues of surviving animals killed on the 22nd day revealed no significant changes; such studies were not done on animals found dead.…”

Section: Observationsmentioning

confidence: 99%

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Prolongation of the Life-Span in Mice Adapted to Large Amounts of L-Dopa

Cotzias¹,

Miller²,

Nicholson³

et al. 1974

Proc. Natl. Acad. Sci. U.S.A.

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Various concentrations of L-dopa (levodopa, L-3,4-dihydroxyphenylalanine) were incorporated in the diets of young male Swisg albino mice, and the highest coneentrations to which these mice became adapted within 3 weeks were determined. One such concentration administered indefinitely eventually indticed a youthful appearance, a signifilantly prolonged life-span, but also corneal opaeities compatible with traumatic or chemical keratitis.The use of idopa (L-3,4-dihydroxyphenylalanine, levodopa) in the long-term treatment of Parkinson's disease, a chronic affliction, necessitates initial adaptation to high doses followed by sustained consumption of this amino acid (1, 2). Like other long-term regimens, treatment with t-dopa requires the physician's skill and care and the patient's cooperation, and even so, certain side effects can emerge (3). Shortly after the publication of papers describing the therapeutic effects of L-dopa (1, 2), many kinds of illness in patients with Parkinsonism wete being ascribed by others to idopa as its side effects, whether or not the recommended regimen was followed. The accruing literature, too voluminous even for references here, gave rise to fears about the long-term influence of idopa on patients' general health. These fears have been slow to recede despite (i) subsequent reports that iLdopa is the most effective drug for treating Parkinson's disease (see ref. 4) and (ii) the fact that no deaths of treated patients have been ascribed to idopa, in sharp contrast to findings with all other major drugs.In our investigations on the effects of L dopa on general health, we initiated animal experiments to supplement our long-term observations on human patients. Since life-span can be considered as an indicator of health, we determined the maximal concentrations of -dopa incorporated in the chow to which mice could become adapted so that we could then study the effects of a very high concentration on longevity. The results show that this amino acid could either kill the mice or significantly extend their life-span and apparent prime of life, depending on the way it was given. Some of the longevity data, although preliminary, are being presented here to expedite studies of the relevance of these long-lasting experiments to human patients. MATERIALS AND METHODSAnimals. Most of the animals were 4-5 week-old, male Swiss albino mice of the Hale-Stoner strain. In some experiments females of the same strain and age, and aging males, were also used. Cages containing six mice (or two, in the case of aging males) were kept in air-conditioned rooms with controlled humidity, lighted 12 hr each day.Diets. Ground Purina chow was given freely, plain for the controls and with certain concentrations of idopa (levodopa, i-3,4-dihydroxyphenylalanine, Nutritional Biochem. Corp.) added for the test mice. The Purina chow itself, in contrast to some other rodent diets (5, 6), did not contain a measurable amount of idopa. The different -dopa concentrations in the chow mixtures, as determined spectrofl...

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Levodopa in the Treatment of Parkinsonism

Cotzias¹

1971

JAMA

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Block of Cerebral Actions of L-Dopa with Methyl Receptor Substances

Cited by 23 publications

References 11 publications

Changing the Actions of Neuroactive Drugs by Changing Brain Protein Synthesis

Changing the Actions of Neuroactive Drugs by Changing Brain Protein Synthesis

Prolongation of the Life-Span in Mice Adapted to Large Amounts of L-Dopa

Levodopa in the Treatment of Parkinsonism

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