L-3,4-dihydroxyphenylalanine-induced hypersensitivity simulating features of denervation.

Abstract

The manner in which dyskinesia and intermittency of neurological control had emerged late in the therapy of Parkinsonism with L-3,4-dihydroxyphenylalanine (levodopa) had suggested to us that this drug can imprint on the brain a chemical memory of its passage. The majority of authors ascribed these events to denervation hypersensitivity caused by the nigral and other lesions of the disease. By feeding levodopa to mice, however, we induced a state that simulated denervation hypersensitivity, including hyperreaction to single injections of levodopa and increased dopamine-stimulated adenylate cyclase [ATP pyrophosphate-lyase (cyclizing), EC 4.6.1.11 activity in homogenates of caudate nuclei. These phenomena were not caused by actual denervation, because the hypersensitivity declined and disappeared some weeks after the dietary levodopa was stopped.Long-term therapy of Parkinson's disease with L-3,4-dihydroxyphenylalanine (levodopa) can be marred by the gradual, late emergence of adventitious movements (dyskinesia) (1). Diminishing the drug diminishes the dyskinesia but can induce episodic re-emergence of the original symptoms ("on-off" phenomenon) (2). Most authors ascribed these events to "denervation hypersensitivity," presumably caused by irreversible nigral and other lesions of the brain (3-9). We, in contrast, interpreted the manner in which these events manifested themselves as suggesting that these ". . . patients have shown evidence of having stored a chemical memory of the drug's passage" (10). Circumstantial evidence, including the potentiation of the actions of levodopa by the growth hormone that it releases (11-13), was compatible with our suggestion. It Main Experiments. The mice, receiving water ad libitum, were divided into groups on the basis of their diets. One or more of these groups received levodopa in their Purina Laboratory Chow while one consumed Purina without the drug. The HS mice received the amounts of dietary levodopa that had increased their lifespan (40 mg of drug per g of chow) (16, 17). The concentration given to the C3H/HeJ mice (100 mg/g of body weight) was approximating the maximal tolerated one.Each group was subdivided into two subgroups. The first consisted of 18 animals. Six of these were used for scoring the dyskinesia, the adventitious movements, the stereotypy, and some other reactions evoked by the single standardized intraperitoneal injections of levodopa (15). Twelve mice were used for the determinations of adenylate cyclase [ATP pyrophosphate-lyase (cyclizing), EC 4.6.1.1] in homogenates of their caudates. Six were used for measuring the basal activity, the other six for measuring the total activity, which consisted of the basal activity plus the dopamine-stimulated one (18). Thus, the data were also checked for possible increase of the total activity by the endogenous dopamine produced from the levodopa.The dopamine concentrations added to activate the cyclase in the homogenates of the caudate nuclei were chosen on the basis of the experiments detailed under ...

Chronic treatment with I‐dopa plus carbidopa in hemitransected rats: Preferential effects at intact dopamine synapses leading to behavioural signs of dopamine receptor supersensitivity

“…In agreement with previous papers (Tang & Cotzias 1977, Wilner et al 1980) the present results mainly show that chronic 1-dopa plus carbi-dopa treatment in rats can induce behavioural signs of DA receptor supersensitivity (see also . In the present analysis behavioural supersensitivity to apomorphine was shown and reveals itself as an increase in the maximal amount of ipsilateral turning behaviour induced by apomorphine in hemitransected rats.…”

“…In the present paper we have investigated the effects of chronic 1-dopa plus carbi-dopa treatment in hemitransected rats in order to better understand the adaptive changes produced by such treatment at intact and supersensitive DA receptors using the DA receptor antagonist 3H-spiperone, which labels regulatory sites of DA receptors of the D2 type (Seeman 1980), as well as a behavioural analysis. Previous results have indicated that chronic 1-dopa therapy may induce both DA receptor supersensitivity (Tang & Cotzias 1977, Wilner et al 1980) and…”

Alterations in preproenkephalin and adenosine‐2a receptor mRNA, but not preprotachykinin mRNA correlate with occurrence of dyskinesia in normal monkeys chronically treated with l‐DOPA

“…Chronic treatment of normal mice and rats with L-DOPA plus carbidopa (fed powdered Purina rat/mice chow containing approximately 0.94 g/kg/day L-DOPA + 0.25 g/kg/day carbidopa for up to 18 months) did not induce abnormal behaviours and did not alter striatal DA levels or the number of nigral DAergic neurons (Hefti et al, 1981;Reches & Fahn, 1982;Perry et al, 1984). However, when L-DOPA was given to normal rodents for up to 8 weeks, an increase in caudate adenylate cyclase activity was observed, accompanied by behavioural supersensitivity to subsequent L-DOPA challenge (Tang & Cotzias, 1977;. Juncos et al (1989) found a signi®cant increase in glutamic acid decarboxylase (GAD) activity, in the intact as well as DA denervated striatum of rats with a unilateral 6-OHDA lesion given chronic intermittent high dose L-DOPA which was accompanied by behavioural sensitization.…”

“…1984). However, when l ‐DOPA was given to normal rodents for up to 8 weeks, an increase in caudate adenylate cyclase activity was observed, accompanied by behavioural supersensitivity to subsequent l ‐DOPA challenge (Tang & Cotzias 1977; Jenner & Marsden 1987). Juncos et al .…”

Cyproheptadine in levodopa‐induced dyskinesia in parkinsonism

“…Some workers!' 3 have ascribed dyskinesia to de nervation hypersensitivity, while we 16 have suggested that this might be due to simulated rather than actual denervation hypersensitivity. It was reported earlier 5 that injections of apomorphine, a direct dopamine receptor agonist, had ameliorated levodopa-induced dyskinesia, possibly because of antidopa-minergic or even cholinergic properties 1B associated with the piperidine portion of the molecule.…”