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PubMed1985

Effects of L-dopa supplementation on concentrations of brain catechols, dopamine receptor binding and the incidence of pale, soft and exudative meat in stress-susceptible pigs.

The purpose of this research was to determine if chronic dietary L-DOPA supplementation will alter differentially the brain catechol concentrations, dopamine receptor binding (KD and Bmax) and the incidence of pale, soft and exudative (PSE) meat in stress-susceptible (SS) and stress-resistant (SR) pigs. Stress-susceptible and SR pigs were assigned randomly to these four groups: SS pigs as controls, SR pigs as controls, SS pigs with L-DOPA supplementation and SR pigs with L-DOPA supplementation. The experiment began when pigs weighed 23 kg and terminated when pigs weighed 95 kg. Anatomical brain structures removed at slaughter included hypothalamus, thalamus, cortex, cerebellum, olfactory bulb, caudate nucleus, putamen and substantia nigra. Concentrations of norepinephrine and dopamine were greater in the hypothalami of SS than of SR control pigs. The L-DOPA supplementation eliminated the strain differences of brain catecholamine concentrations. Pigs fed L-DOPA had greater concentrations of dihydroxyphenylacetic acid in six of the eight brain regions analyzed than the controls. Dopamine receptor binding (Bmax and KD) of spiroperidol was similar in all four groups of pigs. Pale, soft and exudative pork developed to the same extent in SS pigs with or without L-DOPA treatment. The results suggest that L-DOPA supplementation eliminates strain differences in brain catecholamine concentrations but does not alter PSE meat development or striatal dopamine receptor binding.

3,4-Dihydroxyphenylacetic Acid↗

PubMed2000

Outward transfer of dopamine precursor L-3,4-dihydroxyphenylalanine (L-dopa) by native and human P-glycoprotein in LLC-PK(1) and LLC-GA5 col300 renal cells.

The role of P-glycoprotein (P-gp) in the basal-to-apical uptake and flux of L-3,4-dihydroxyphenylalanine (L-dopa) was studied in LLC-PK(1) and LLC-GA5 Col300 cells, a renal cell line expressing the human P-gp in the apical membrane. In the absence of verapamil, LLC-GA5 Col300 cells accumulate less calcein (0.5 microM) than do LLC-PK(1) cells. In LLC-PK(1) cells, pretreatment with verapamil (25 microM) for 30 min increased the rate of accumulation of calcein by 5-fold, whereas in LLC-GA5 Col300 cells, no significant change in the rate of accumulation of calcein was observed. Exposure for 3 h to verapamil (25 microM) was found to increase the rate of accumulation of calcein by 2.5-fold in LLC-PK(1) cells and by 3. 7-fold in LLC-GA5 Col300 cells. A 30-min exposure to UIC2 (3 microg/ml) or verapamil (25 microM) increased L-dopa accumulation in LLC-PK(1) cells by 27 +/- 4 and 88 +/- 14% and reduced L-dopa apical extrusion by 29 +/- 4 and 23 +/- 1%, respectively. The exposure of LLC-GA5 Col300 cells to UIC2 (3 microg/ml) or verapamil (25 microM) for 30 min produced no significant changes in cell accumulation and apical extrusion of L-dopa. A more prolonged exposure (3 h) to UIC2 or verapamil resulted in a marked increase in L-dopa accumulation in the cell (105 +/- 13 and 146 +/- 24% increase) and a pronounced decrease (91 +/- 1 and 92 +/- 1% reduction) in the apical extrusion of L-dopa. It is concluded that LLC-PK(1) cells are endowed with P-gp and that the outward transfer of L-dopa at the apical cell border in both LLC-PK(1) and LLC-GA5 Col300 cells is in part promoted through this transporter.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed1976

The action of psychotropic drugs on DOPA induced behavioural responses in mice.

The "DOPA potentiation" test in mice was investigated for its usefulness in the detection of compounds with antidepressant properties. It was found that the anti-depressant drugs imipramine, amitriptyline, 5-methylamino-acetyl-6-methyl-5,6-dihydro-phenanthridine-HCl (Org OI77) and 1,2,3,4,10,14b-hexahydro-2-methyl-dibenzo[c,f]pyrazino[1,2-a]azepine-HCl (mianserin, Org GB 94) potentiated the behavioural effect of DOPA in groups of mice which had been treated 17 h previously with the monoamine oxidase inhibitor (MAOI) iproniazid. However, the DOPA response was also potentiated by a variety of centrally acting drugs which do not have antidepressant properties (atropine, methysergide, chlordiazepoxide, apomorphine). The peptide hormones ACTH4-10 and desglycinamide lysine vasopressin had equivocal effects while melanocyte stimulating hormone release-inhibiting factor (MIF) had no effect on the DOPA response. The DOPA response was inhibited by the neuroleptics chlorpromazine and haloperidol. There appeared to be no correlation between the effects of the drugs on the behavioural responses elicited by DOPA and the changes found in the brain concentration of noradrenaline, dopamine, serotonin, gamma-aminobutyric acid, tryptophan and tyrosine. It is concluded that the "DOPA potentiation" test cannot be considered as a reliable test in the detection of anti-depressant compounds.

Animals↗

PubMed2002

Persistent behavioral sensitization to chronic L-DOPA requires A2A adenosine receptors.

To investigate the role of A(2A) adenosine receptors in adaptive responses to chronic intermittent dopamine receptor stimulation, we compared the behavioral sensitization elicited by repeated l-DOPA treatment in hemiparkinsonian wild-type (WT) and A(2A) adenosine receptor knock-out (A(2A) KO) mice. Although the unilateral nigrostriatal lesion produced by intrastriatal injection of 6-hydroxydopamine was indistinguishable between WT and A(2A) KO mice, they developed strikingly different patterns of behavioral sensitization after daily treatment with low doses of l-DOPA for 3 weeks. WT mice initially displayed modest contralateral rotational responses and then developed progressively greater responses that reached a maximum within 1 week and persisted for the duration of the treatment. In contrast, any rotational behavioral sensitization in A(2A) KO mice was transient and completely reversed within 2 weeks. Similarly, the time to reach the peak rotation was progressively shortened in WT mice but remained unchanged in A(2A) KO mice. Furthermore, daily l-DOPA treatment produced gradually sensitized grooming in WT mice but failed to induce any sensitized grooming in A(2A) KO mice. Finally, repeated l-DOPA treatment reversed the 6-OHDA-induced reduction of striatal dynorphin mRNA in WT but not A(2A) KO mice, raising the possibility that the A(2A) receptor may contribute to l-DOPA-induced behavioral sensitization by facilitating adaptations within the dynorphin-expressing striatonigral pathway. Together these results demonstrate that the A(2A) receptor plays a critical role in the development and particularly the persistence of behavioral sensitization to repeated l-DOPA treatment. Furthermore, they raise the possibility that the maladaptive dyskinetic responses to chronic l-DOPA treatment in Parkinson's disease may be attenuated by A(2A) receptor inactivation.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1975

Enteric coated levo-dopa in clinical practice.

The results of a clinical trial of enteric coated Levo-dopa are described for nineteen patients with Parkinsonism. Twelve cases comprise the nuclear group and all were intolerant to therapeutic doses of standard Levo-dopa. Seven cases were receiving Levo-dopa for the first time. Treatment periods ranged from three to twelve months. Of the whole group, 84% have improved. Of the poor responders to standard Levo-dopa 58% have improved markedly and the remaining 42% have improved to a moderate degree using clinical criteria. The mean stabilization dose was 1.5 grams daily and using the Mann-Whitney U test the difference is highly significant when comparison is made with the stabilization dose of 3.0 grams for standard Levo-dopa (P less than .001). The method of stabilization is described; the commonest initial stabilization period is three weeks. Side-effects are dose-related. No side-effects have appeared in 60% of the patients and only mild or transient side-effects have appeared in 20%. A characteristic toxic reaction is described. This enteric-coated preparation of the drug appears to control the "on-off" phenomenon in at least 50% of cases with this problem. The preparation is suitable for routine use in outpatients but added care is required to ensure that vitamin tonics are rigorously avoided. Two deaths are recorded during the trial, but analysis shows them to be unrelated causally to the therapy. Enteric coated Levo-dopa is recommended as the primary treatment in all new cases where Levo-dopa therapy is indicated. No adverse interactions have occurred with other commonly used anti-Parkinsonian drugs.

Adult↗

PubMed2002

Acoustic analysis of parkinsonian speech II: L-Dopa related fluctuations and methodological issues.

The drug L-Dopa is used in the treatment of Parkinson's disease (PD), and patients often experience fluctuations in performance after a period of time taking L-Dopa. This paper reviews the literature pertaining to these fluctuations. While a number of researchers have examined L-Dopa related fluctuations in general, these fluctuations have rarely been addressed in speech research. To examine the effect of L-Dopa related fluctuations a number of methodological issues need to be addressed including time of day, anxiety level, disease stage, and drug regimen differences. Strategies are proposed for addressing these methodological issues in studying the effects of L-Dopa fluctuations on PD speech. This paper is part two of a two part series; Part one examined PD and PD speech in general, along with L-Dopa treatment, and the effects of L-Dopa treatment on speech.

Articulation Disorders↗

PubMed1992

[The effects of l-dopa administration on the prolactin levels in short-stature subjects].

In this study, on the basis of the inhibiting action of l-dopa administration on prolactin (PRL) secretion, we evaluated in a number of short children the levels of PRL during the provocative stimuli test with l-dopa in order to identify an index able to give reliability to the test and to investigate whether some differences may exist among the subjects showing a different response in growth hormone (GH) secretion to l-dopa. We examined 76 subjects (44 boys and 32 girls) with chronological age from 4.5-15.17 years. The subjects, on the basis of the GH peaks during two provocative stimuli tests [l-dopa and insulin-induced hypoglycemia (IIH)], were subdivided into 3 groups: group 1 (n = 24) with both deficient responses (peak less than 10 ng/ml); group 2 (n = 28) with discordant responses and further subdivided into group 2a (n = 14) with normal responses to IIH and 2b (n = 14) with a normal response to l-dopa; group 3 (n = 24) with both normal responses. PRL levels peaked between times -20' (58 cases) and +20' (2 cases) whereas nadir occurred between +80' (4 cases) and +120 (48 cases) without any significant difference (p = ns) among the groups. PRL levels significantly decreased in all groups, also in those with a deficient response to l-dopa (1 and 2a); furthermore no significant correlation between PRL and GH levels was demonstrated. In conclusion, this study showed the importance of PRL evaluation during l-dopa test in order to give reliability to the test and did not demonstrate any difference in PRL levels among the examined groups of short children.

Adolescent↗

PubMed1991

[The action of L-DOPA on the spontaneous activity generated by the isolated spinal cord of 16- to 20-day-old chick embryos].

Effect of bath application of L-DOPA, dopamine (DA), noradrenaline (NA) on the spontaneous activity--cyclical oscillations of electrotonic potentials in dorsal and ventral roots (DR and VR, respectively) generated by isolated spinal cord of 16-20-day-old chick embryo was studied. L-DOPA in low concentration (30-150 mumol/l) activated spinal generator: suprathreshold rhythms appeared (i.e., spike activity in DR and VR). High concentration (200-1000 mumol/l) of L-DOPA depressed generator activity, but in the course of washing of the spinal cord spontaneous activity was enhanced and suprathreshold rhythms appeared. DA and NA (50 mumol/l) did not influence the activity but in concentration 100 mumol/l they depressed spontaneous activity in DR and VR. Bath application of 2-amino-5-phosphonovaleric acid (20 mumol/l) blocked activity induced by small concentration of L-DOPA. Activity generated by the neuronal network of the isolated dorsal horn was intensified after bath-application of L-DOPA in small concentration. Rhythmic activity in the isolated ventral horn did not appear after bath-application of L-DOPA. It is concluded that excitatory action of L-DOPA on the neuronal network of dorsal horn chick embryo was direct (i.e., did not depend on catecholamines).

2-Amino-5-phosphonovalerate↗

PubMed1975

Uptake of radioactive DOPA by Mycobacterium leprae in vitro.

Our previous studies demonstrated that Mycobacterium leprae contains a characteristic o-diphenoloxidase which converts a variety of phenolic compounds to quinones in vitro. This enzyme was not present in any other mycobacteria tested. The results reported here deal with the uptake and binding of radioactive DOPA by M. leprae. The leprosy bacilli incubated with tritium-labelled DOPA, readily took up the substrate. The binding of DOPA by the bacilli was markedly inhibited by diethyldithiocarbamate. The organisms also bound tritiated norepinephrine. Mycobacterium phlei which does not oxidize phenolic substrates failed to bind DOPA. Cultures of melanocytes which contain o-diphenoloxidase took up tritiated DOPA. Catecholamine metabolism is known to be important in myocardial cells. Cultures of turtle-heart cells did not oxidize DOPA to quinone; however, these cells bound the labelled substrate. A cell line of fibroblasts derived from armadillo skin neither oxidized nor took up DOPA. The results indicate that, like melanocytes and turtle-heart cells, M. leprae probably possesses specific receptor sites for the binding and subsequent metabolism of phenolic substrates.

Animals↗

PubMedDate not supplied

L-DOPA treatment of comatose states due to cerebral lesions. Preliminary findings.

The results of a study on the effects of L-Dopa in brain-injured patients showing impairment of consciousness are reported. Fifteen patients were selected for this study. The degree of consciousness impairment, or level of coma, varied in the different patients. In all of them, however, the comatose state persisted unchanged for at least 6 days before the beginning of L-Dopa treatment. A gradual and progressive improvement of the level of consciousness, as well as of the EEG patterns, followed the administration of L-Dopa in patients whose treatment commenced while they were in comas III, II and I (classification of Fishgold and Mathis, 1959, and Rossi, 1962). On the other hand, the results of the treatment were questionable in the sequelae of coma (apallic syndrome, coma vigil, akinetic mutism). A direct relation between L-Dopa and consciousness improvement appears to be supported by: 1) the fact that the level of coma was stabilized for several days prior to L-Dopa treatment (see above); 2) the fact that consciousness improvement occurred abreast of L-Dopa dosage; 3) the observation in some patients that worsening followed the temporary withdrawal of L-Dopa treatment and, vice-versa, improvement followed its resumption. The hypothesis of neurochemical components in the processes responsible for the decrease of vigilance following cerebral injury would appear supported by the findings reported.

Brain Injuries↗

PubMed1979

Role of peripheral adrenoreceptors and vasopressin in the suppression of plasma renin activity by L-dopa in carbidopa-treated dogs.

When extracerebral dopa decarboxylase is inhibited by carbidopa, L-dopa lowers plasma renin activity (PRA). The present study was designed to determine whether this suppression of PRA is mediated by the sympathetic nerves, and to identify the peripheral adrenergic receptor types involved. All experiments were performed in pentobarbital-anesthetized dogs in which changes in renal perfusion pressure were minimized by means of a suprarenal aortic clamp. Neither alpha adrenoreceptor blockage with phenoxybenzamine nor beta adrenoreceptor blockade with propranolol was by itself sufficient to block the suppression of PRA by L-dopa with carbidopa. However, combined alpha and beta adrenoreceptor blockade lowered PRA and completely prevented any further suppression of PRA by L-dopa with carbidopa. It was also observed that phenoxybenzamine decreased PRA by 48% when administered to propranolol-treated animals. Taken together, these data indicate that L-dopa with carbidopa suppresses PRA by decreasing sympathetic nerve stimulation of both alpha and beta adrenoreceptors. Plasma vasopressin concnetration was significantly decreased by L-dopa with carbidopa both in the control group and in animals with combined alpha and beta adrenoreceptor blockade. Because plasma vasopressin levels decreased after L-dopa, vasopressin is unlikely to play a causative role in the suppression of PRA.

Animals↗

PubMed1977

[Long-term l-DOPA therapy for parkinsonism and its pathochemical aspect].

The conducted study of the effectiveness of L-DOPA in its long-term (up to 7 years) continuous administration to parkinsonic patients depicted a high therapeutical action of the drug for the first 6 months of the treatment. L-DOPA administration up to 3 years had an antiparkinsonic action approximately in half of the patients. A further prolongation of treatment period decreased L-DOPA effectiveness even more. The increase of the doses in order to raise a therapeutical effect was impossible due to the appearance of side-effects characteristic of L-DOPA. The longitudinal biochemical studies on biogenic amines in those patients' urine established a correlation with the clinical state. The obtained biochemical data permitted to assume an acceleration of extracerebral metabolism of monoamines in L-DOPA treatment for 1--3 years and further on the decrease of sensitivity of CNS dophaminergic neurons to administered L-DOPA. The methods of increasing the effectivity of L-DOPA use in parkinsonism are given.

Dihydroxyphenylalanine↗

PubMed1978

gamma-Glutamyl dopa: a kidney-specific dopamine precursor.

gamma-Glutamyl derivatives of amino acids and peptides are selectively accumulated in the kidney and introduced into the metabolism of kidney cells. gamma-Glutamyl L-3,4-dihydroxyphenylalanine (gamma-glutamyl dopa) was synthesized both chemically and enzymatically. Injection of this derivative into mice led to a selective generation of dopamine in the kidney as a consequence of the sequential action of gamma-glutamyl transpeptidase and aromatic L-amino acid decarboxylase, two enzymes which are highly concentrated in the kidney. The concentration of dopamine in the kidney after gamma-glutamyl dopa was almost 5 times higher than that after an equivalent dose of L-dopa. Infusion of 10 nmol/g/30 min of gamma-glutamyl dopa to rats produced a 60% increase in renal plasma flow. By contrast the same dose of L-dopa had no effect on renal plasma flow. Only a small pressor effect was observed after the infusion dose of gamma-glutamyl dopa was increased 20-fold indicating that the systemic effects of this pro-drug slight. The results suggest that the pro-drug gamma-glutamyl dopa can be used as a specific renal vasodilator.

Animals↗

PubMed1981

Melanoma detection by enzyme-radioimmunoassay of L-dopa, dopamine, and 3-O-methyldopamine in urine.

This enzyme-radioimmunoassay for the measurement of L-dopa, dopamine, and 3-O-methyldopamine is based on the incubation of urine in the presence of catechol-O-methyltransferase, aromatic-L-amino-acid decarboxylase, and S-adenosylmethionine. The O-methylated dopamine metabolite formed, 3-O-methyldopamine, was characterized by radioimmunoassay. To evaluate the role of L-dopa metabolism in melanoma, we used the enzyme-radioimmunoassay to assess concentrations of L-dopa, dopamine, and 3-O-methyldopamine in urine from 10 healthy subjects, 10 hospitalized patients without melanoma and 28 patients with different degrees of melanoma. The effect of surgery for melanoma on urinary output of these catechols of melanoma patients was also evaluated. No significant difference in urinary L-dopa, dopamine, and 3-O-methyldopamine excretion rates was seen between normal subjects (L-dopa 1.3 +/- 0.3, dopamine 147 +/- 38, and 3-O-methyldopamine 31.4 +/- 13.6 microgram/24 h), hospitalized patients without melanoma, and amelanotic melanoma patients. However, the excretion rates for these metabolites in melanotic melanoma (L-dopa 5.6 +/- 1.2, dopamine 555 +/- 121, and 3-O-methyldopamine 178 +/- 40.3 microgram/24 h) were significantly (p < 0.005) higher than in control or amelanotic melanoma subjects. After surgery, there was a substantial decrease in urinary output of L-dopa and its metabolites by these patients.

Adolescent↗

PubMed1991

[A new levodopa benserazide preparation for Parkinson's disease with motor fluctuations refractory to standard L-dopa].

As Parkinson's disease worsens, many patients develop motor fluctuations which usually correlate directly or indirectly with L-dopa plasma levels. A new L-dopa-benserazide HBS preparation (Madopar) a control release pharmaceutical formulation which is activated when it contacts gastric fluid thus providing more stable L-dopa plasma levels, was assayed. Ten patients with a diagnosis of idiopathic Parkinson's disease and motor fluctuations otherwise unresponsive to conventional therapy were selected. The average age was 62 years and the duration of the disease 9 years. The motor status was evaluated on an hourly basis with the King's College Parkinson's disease rating scale; in addition, a nocturnal disability scale (Lees) was used. Out of the 10 patients, 2 dropped out within the first month due to worsening of parkinsonian signs, while 7 of the remainders preferred HBS preparation to the previous treatment. The number of off hours in this group was reduced by 58% and motor fluctuation became less severe. In only 3 cases was it possible to use HBS as monotherapy while in the rest standard L-dopa had to be added, specially as morning doses. The average L-dopa daily dose was increased by 36%. Unwanted effects included psychiatric disturbances in two (in one L-dopa dose had to be reduced) and epigastralgia in one. Our findings suggest that this L-dopa-benserazide control release may be considered an able therapeutic formulation in the control of motor fluctuations in Parkinson's disease.

Adult↗

PubMed1994

[Evidence for the existence of L-dopa-immunoreactive neurons in the human mesencephalic region].

The existence of L-3,4-dihydroxyphenylalanine (L-DOPA) immunoreactivity is demonstrated for the first time in some neurons in the human mesencephalic region, using an immunohistochemical method with a newly raised, highly specific anti-L-DOPA antiserum. In this study, we have found many L-DOPA-positive/dopamine (DA)-positive neurons. On the other hand, we observed a few L-DOPA-positive/DA-negative cell bodies in the dopaminergic regions in the midbrain. The present results suggest the possibility of the existence of more than one neuronal group in the human mesencephalic ventral tegmental area region. L-DOPA in one group is an intermediate metabolite for decarboxylation to DA and in another group may exist as an end-product. L-DOPA in the latter group could be a neuromodulator and/or neurotransmitter. Thus, we suggest that L-DOPA plays an important role besides being an intermediate of DA in the human mesencephalon.

Antibody Specificity↗

PubMed1980

Decarboxylation of exogenous L-DOPA in rat striatum after lesions of the dopaminergic nigrostriatal neurons: the role of striatal capillaries.

In rats with unilateral nigrostriatal lesions, L-DOPA-induced dopamine increases in ipsilateral striata were further enhanced after inhibition of DOPA decarboxylase in cerebral microvessels by carbidopa. DOPA levels were similar, but dopamine increases in lesioned striata were smaller, after carbidopa and DOPA (100 mg/kg) than after DOPA alone (500 mg/kg). These findings suggest that after degeneration of dopaminergic terminals, striatal decarboxylation of exogenous DOPA occurs partly, but not exclusively, in tbe capillaries.

Animals↗

PubMed1991

Dopa decarboxylase activity of the living human brain.

Monoaminergic neurons use dopa decarboxylase (DDC; aromatic-L-amino-acid carboxy-lyase, EC 4.1.1.28) to form dopamine from L-3,4-dihydroxyphenylalanine (L-dopa). We measured regional dopa decarboxylase activity in brains of six healthy volunteers with 6-[18F]fluoro-L-dopa and positron emission tomography. We calculated the enzyme activity, relative to its Km, with a kinetic model that yielded the relative rate of conversion of 6-[18F]fluoro-L-dopa to [18F]fluorodopamine. Regional values of relative dopa decarboxylase activity ranged from nil in occipital cortex to 1.9 h-1 in caudate nucleus and putamen, in agreement with values obtained in vitro.

Brain↗