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PubMed1994

The renal handling of dopamine originating from L-dopa and gamma-glutamyl-L-dopa.

1. The formation and outflow of dopamine and its deaminated metabolite 3,4-dihydroxyphenylacetic acid (DOPAC) was studied in cortical fragments of the rat kidney loaded with L-beta-3,4-dihydroxyphenylalanine (L-dopa) or gamma-glutamyl-L-dopa (GluDOPA). Dopamine and DOPAC in the tissues and in the effluent were assayed by means of h.p.l.c. with electrochemical detection. 2. In rats given 30 mg kg-1 L-dopa, tissue and outflow levels of both dopamine and DOPAC were 3 fold those observed with a lower dose of L-dopa (10 mg kg-1). In rats given GluDOPA (16.7 mg kg-1) levels of dopamine in renal tissues and in perifusate samples were found to be higher than those obtained with an equimolar dose of L-dopa (10 mg kg-1); however, no significant difference was observed for DOPAC. The outflow of both dopamine and DOPAC in kidney slices of rats injected with L-dopa (10 and 30 mg kg-1) or GluDOPA (16.7 mg kg-1) was found to decline monophasically with similar slopes of decline. The rate constants of loss (k, min-1) of DOPAC (10 mg kg-1 L-DOPA, k = 0.0070; 30 mg kg-1 L-DOPA, k = 0.0087; 16.7 mg kg-1 GluDOPA, k = 0.0080) were 2 to 3 fold those of dopamine (10 mg kg-1 L-dopa, k = 0.0027; 30 mg kg-1 L-DOPA, k = 0.0034; 16.7 mg kg-1 GluDOPA, k = 0.0030). With both precursors the DOPAC/dopamine ratio in perifusate samples were 2.0 fold those in the tissues. 3. Tissue and outflow levels of dopamine after incubation of renal tissues with L-DOPA, 50 and 100 MicroM were found to be lower than those observed with GluDOPA (50 and 100 MicroM). DOPAC/dopamine ratios in tissues and perifusate samples of experiments performed with L-DOPA were significantly higher(P<0.01) than those observed with GluDOPA. The outflow of both dopamine and DOPAC in renal slices incubated with L-DOPA (50 and 100 MicroM) were found to decline with time, but presented a biphasic shape. DOPAC/dopamine ratios in perifusate samples were 3 fold that in the tissues with both precursors.4. In conclusion, the present results show that both L-DOPA and GluDOPA give origin to substantial amounts of dopamine and the newly-formed amine undergoes considerable deamination to DOPAC.However, dopamine originating from GluDOPA was less deaminated than that resulting from L-DOPA;it appears that this different behaviour may concern aspects related to the formation of the amine and also those related to its deamination and disposition, namely the processes involved in the access of newly-formed dopamine to MAO.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1994

Cell inward transport of L-DOPA and 3-O-methyl-L-DOPA in rat renal tubules.

1. The present study has determined the kinetics of the uptake of L-3,4-dihydroxyphenylalanine (L-DOPA) and 3-O-methyl-L-DOPA (3-OMDOPA) in rat renal tubules and examined the effect of 3-OMDOPA on the inward transport of L-DOPA and on its conversion into dopamine in kidney homogenates. 2. The accumulation of both L-DOPA and 3-OMDOPA in renal tubules was found to occur through non-saturable and saturable mechanisms. The kinetics of the saturable component of L-DOPA and 3-OMDOPA uptake in renal tubules were as follows: L-DOPA, Vmax = 11.1 nmol mg-1 protein h-1 and Km = 216 microM (n = 6); 3-OMDOPA, Vmax = 8.1 nmol mg-1 protein h-1 and Km = 231 microM (n = 5). The diffusion constant of the non-saturable component for the accumulation of L-DOPA and 3-OMDOPA was 0.0010 and 0.0014 mumol-1, respectively. 3. 3-OMDOPA (100 to 2000 microM) was found to produce a concentration-dependent decrease (29% to 81% reduction) of the saturable component of the tubular uptake of L-DOPA; the Ki value of 3-OMDOPA for inhibition of L-DOPA uptake was found to be 181 microM (n = 5). The accumulation of L-DOPA obtained in experiments conducted at 4 degrees C was not affected by 3-OMDOPA. 4. In experiments conducted in kidney homogenates only L-DOPA (10 to 5000 microM) was found to be decarboxylated. The Vmax and Km values for aromatic L-amino acid decarboxylase determined in the absence of 3-OMDOPA (Vmax = 14.1 nmol mg-1 protein h-1; Km =62 MicroM) were not significantly different from those observed when the decarboxylation of L-DOPA was carried out in the presence of 1000 MicroM 3-OMDOPA (Vmax = 15.7 nmol mg-1 protein h-1; Km = 68 MicroM).5. It is concluded that the tubular uptake of both L-DOPA and 3-OMDOPA occur through nonsaturable and saturable mechanisms; only the saturable tubular uptake of L-DOPA was found to be inhibited by 3-OMDOPA. It is further shown that 3-OMDOPA neither undergoes decarboxylation into 3-MT nor affects the decarboxylation of L-DOPA.

Animals↗
PubMed1992

Metabolism of 5-fluoro-dopa and 6-fluoro-dopa enantiomers in aggregating cell cultures of fetal rat brain.

The cerebral metabolism of enantiomers of 5-fluoro-DOPA (5F-DOPA) and 6-fluoro-DOPA (6F-DOPA) was characterized in organotypic cell cultures of fetal rat brain. This system permits the investigation of metabolic processes in brain tissue exclusively, without the effects of peripheral metabolism and transport. Metabolic profiles for each substrate were determined in comparison with those of L-DOPA and D-DOPA. The uptake of DOPA and fluoro-DOPA in aggregating brain cell cultures is strongly preferential for L-enantiomers. Decarboxylation by aromatic L-amino acid decarboxylase is an active step: the major products are dopamine (DA) or 6F-DA and their corresponding products of oxidative deamination, i.e. dihydroxyphenylacetic acid (DOPAC) or 6F-DOPAC, respectively. Decarboxylation products of D-enantiomers occur in lower amounts, and 5F-D-DOPA is not decarboxylated. However, 5F-DOPA is O-methylated to a great extent, and levels of 3-O-methyl-5F-DOPA are higher after incubation with 5F-D-DOPA than with 5F-L-DOPA. These data may serve as a support for more detailed modeling of [18F]F-DOPA metabolism than can be applied to the evaluation of the cerebral biochemistry of the DA system with positron emission tomography in vivo.

Animals↗
PubMed2000

Evaluation of L-DOPA biotransformation during repeated L-DOPA infusion into the striatum in freely-moving young and old rats.

The aim of this study was to assess changes in L-3, 4-dihydroxyphenylalanine (L-DOPA) biotransformation in response to two-pulse infusion of L-DOPA into the striatum of freely-moving young (3-4 month) and old (21-26 month) male Wistar rats. In addition, the effects of L-DOPA infusion on the vesicular dopamine (DA) store in young rats were also studied. Both L-DOPA-induced DA overflow and uptake of the perfused L-DOPA by the striatum were used to study L-DOPA biotransformation during microdialysis. High potassium-induced DA depletion was performed to assess the dynamics of the vesicular DA store following L-DOPA infusion. Concentric microdialysis probes were stereotaxically implanted in the lateral striatum of rats of both age groups and microdialysis was begun 24 h later. All rats received 2x20 min infusions of 3 mgr L-DOPA separated by an interval of 60 min. In the striatum of both groups, L-DOPA-induced DA overflow and uptake of exogenous L-DOPA were both significantly enhanced during the second infusion compared to the first. In young rats, when a 20-min infusion of 3 mgr L-DOPA was given between 2x20 min infusions of 100 mM potassium, no increased DA release was seen at the second high potassium challenge compared with the first. Our results suggest that the enhancement of DA overflow induced by the second L-DOPA infusion is, at least partially, due to an increase in L-DOPA biotransformation, and not simply to an enlarged DA pool. In contrast to the in vitro results, our own in vivo results show that L-DOPA utilization in the aging striatum does not deteriorate with age.

3,4-Dihydroxyphenylacetic Acid↗
PubMed2000

Transdermal absorption of L-dopa from a new system composed of two separate layers of L-dopa and hydrogel in rats.

To maintain the stability of L-dopa in hydrogel, a new system composed of two separate layers of L-dopa and hydrogel was developed. L-Dopa sheets were made by immersing L-dopa solution into wiper sheets and by lyophilizing them. Examination for stability of L-dopa in the L-dopa sheet revealed that its stability was maintained for at least 12 weeks, providing the sheet was kept at room temperature in a dark box. In a cutaneous absorption study of L-dopa in rats, an L-dopa sheet was attached to the shaved abdominal skin. A hydrogel composed of cutaneous absorption enhancers, water and ethanol, was spread on vinyl tape (hydrogel sheet), and this sheet was placed over the L-dopa sheet. L-Dopa that was administered transdermally effectively penetrated through the skin: The plasma level of L-dopa peaked at 30 min and remained high between 60 and 180 min after the cutaneous application. Our system, composed of two separated layers of L-dopa and hydrogel, enabled the stability of L-dopa to be maintained without losing transdermal absorption of L-dopa.

Administration, Cutaneous↗
PubMed2002

Elevation of plasma levels of L-dopa in transdermal administration of L-dopa-butylester in rats.

To increase delivery of L-dopa in its transdermal absorption, a new lipophilic derivative of L-dopa, L-dopa-butylester, was synthesized. An in-vitro study employing two-chamber diffusion cells, in which the excised rat abdominal skin was mounted, revealed that, in the presence of L-menthol and ethanol, L-dopa-butylester penetrated in its original form more effectively than L-dopa. L-Dopa-butylester sheets were made by immersing wiper sheets in methanol containing the compound, and then evaporating the methanol. An extraction study of the compound from the sheets revealed that its stability was maintained for at least 12 weeks. In an in-vivo cutaneous absorption study, an L-dopa-butylester sheet was attached to the shaved rat abdominal skin. A hydrogel containing L-menthol and ethanol was spread on vinyl tape, and this sheet was placed over it. In plasma, the L-dopa level rose linearly between 30 and 180 min after the cutaneous application; L-dopa-butylester was not detected. The L-dopa level was higher than that in which L-dopa was applied. These findings indicated that the lipophilic nature of L-dopa-butylester further increased its penetration through the skin, and that L-dopa-butylester that was taken up into the general circulation system was rapidly converted to L-dopa by hydrolysis in the body.

Administration, Cutaneous↗
PubMed2001

The central aromatic amino acid DOPA decarboxylase inhibitor, NSD-1015, does not inhibit L-DOPA-induced circling in unilateral 6-OHDA-lesioned-rats.

The centrally acting aromatic amino acid dopa decarboxylase (AADC) inhibitor, 3-hydroxybenzyl hydrazine (NSD-1015), is widely used to study the neurotransmitter-like actions of L-DOPA. However, the effects of NSD-1015 on L-DOPA-induced motor activity are unclear as both increases and decreases have been reported. We now investigate the effects of NSD-1015 on L-DOPA-induced contralateral circling behaviour in 6-OHDA-lesioned rats and on striatal levels of L-DOPA, 3-O-methyl-DOPA (3-OMD), dopamine, dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) using microdialysis techniques. NSD-1015 (50-200 mg/kg i.p.) inhibited AADC activity both in the liver and striatum of normal rats. Administration of NSD-1015 (50-200 mg/kg i.p.), delayed the onset of circling produced by administration of L-DOPA (25 mg/kg i.p.) and carbidopa (12.5 mg/kg i. p.), suggesting blockade of central AADC activity. However, the duration of the L-DOPA-induced circling was prolonged and overall no inhibition of circling behaviour occurred. L-DOPA (25 mg/kg i.p.) plus carbidopa (12.5 mg/kg i.p.) increased extracellular levels of L-DOPA, 3-OMD, dopamine, DOPAC and HVA in the 6-OHDA-lesioned striatum. Pretreatment of rats with the central AADC inhibitor, NSD-1015 (100 mg/kg i.p.), potentiated the increase in dialysate levels of L-DOPA and 3-OMD. However, it did not reduce striatal dopamine levels in the 6-OHDA-lesioned hemisphere, which were elevated following L-DOPA administration. The increases in DOPAC and HVA levels were abolished by NSD-1015 pretreatment. These results suggest that, while NSD-1015 blocks central AADC activity, it also acts as a monoamine oxidase inhibitor so maintaining striatal dopamine concentration by reducing dopamine metabolism. NSD-1015, therefore, may not be an appropriate tool for the study of brain AADC activity and for assessing the neuromodulatory role of L-DOPA.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1994

Pharmacokinetic and pharmacodynamic studies of L-dopa in rats. I. Pharmacokinetic analysis of L-dopa in rat plasma and striatum.

The purpose of this investigation was to quantitatively describe the pharmacokinetics of exogenous and endogenous L-dopa in plasma and the striatum using a basic physiological model, and to determine the apparent metabolism clearance from L-dopa to dopamine in the striatum. Male Wistar rats were used in this study. The time courses of L-dopa concentrations in plasma and the striatum were determined before and after the rapid i.v. injection of 10, 50 and 100 mg/kg. Plasma and striatum samples were obtained over 480 min (17 time points) from different group of animals and then assayed by HPLC-ECD. The endogenous L-dopa concentration in plasma before drug administration was 2.1 +/- 0.6 mg/l. The exogenous L-dopa concentration declined biexponentially with time after drug injection. The total clearance of exogenous L-dopa in plasma was 3.13(l/h)/kg. The production rate constant of endogenous L-dopa in plasma was 6.59(mg/h)/kg. The value of the production rate constant of endogenous L-dopa in plasma could be calculated by the multiplication of the total clearance of L-dopa and the endogenous L-dopa concentration in plasma before drug injection. The pharmacokinetics of endogenous and exogenous L-dopa in plasma could be described quantitatively by a two compartment model which included the production rate constant of endogenous L-dopa. The time course of L-dopa concentrations in the striatum was analyzed on a hybrid model in which the striatum compartment is independently connected with the plasma compartment by the apparent diffusion clearance.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Effect of dopamine, L-dopa, carbidopa and L-dopa/carbidopa on arthus and delayed hypersensitivity skin reactions in the rat.

This study deals with the effects of dopamine (DA), L-dopa, carbidopa and L-dopa/carbidopa on immuno-inflammatory skin reactions in the rat. For this purpose, male Wistar rats immunized with bovine serum albumin in Freund's adjuvant were treated subcutaneously with different doses of DA, L-dopa, carbidopa and L-dopa/carbidopa, for a period of 14 consecutive days or 3 days before skin-testing with BSA. An additional group of rats received 1 injection of a dopamine-related drug 4 hours before and 1 injection 4 hours after skin-testing. Corresponding controls were treated with saline. Arthus and delayed hypersensitivity skin reactions were read at 4 and 24 hours respectively. The results showed that repeated injections of DA, L-dopa and L-dopa/carbidopa significantly suppressed Arthus and delayed reactions. The highest suppression was recorded in rats treated with L-dopa plus carbidopa. Concerning the dose required for immunosuppression it appears that DA was the most effective. Carbidopa did not affect hypersensitivity skin reactions. These results suggest the in vivo relationship between dopamine-related compounds (L-dopa and DA) and immuno-inflammatory reactions. Most probably, L-dopa when is given alone converts into DA and this increase of DA content in periphery depresses immune reactions. However, L-dopa given together with carbidopa (an enzyme which prevents decarboxylation of L-dopa into DA, and enables the penetration of L-dopa into CNS) augments the content of DA in the brain and thus affects immune responses. It appears, therefore, that L-dopa and DA act both peripherally and centrally on immune responsiveness.

Animals↗
PubMed1995

Activation of dopamine cell firing by repeated L-DOPA administration to dopamine-depleted rats: its potential role in mediating the therapeutic response to L-DOPA treatment.

The administration of L-dihydroxyphenylalanine (L-DOPA) to patients with Parkinson's disease is known to produce acute effects that include the reduction of rigidity as well as delayed therapeutic actions involving the resumption of complex motor behavior. In order to examine the potential role of dopamine (DA) cell activity in mediating these responses, the effects of acute and repeated L-DOPA administration on the electrophysiological activity of the residual dopamine (DA) neurons were examined in rats that had received partial 6-hydroxydopamine (6-OHDA)-induced DA lesions. DA cell activity was assessed along three dimensions: (1) the relative proportion of DA neurons exhibiting spontaneous spike firing, (2) their basal firing rate, and (3) their firing pattern. Following 6-OHDA-induced DA depletion, rats were treated for 1 month with saline or L-DOPA. In addition, rats from each group received either an acute injection of L-DOPA or saline on the day of recording. In rats receiving repeated saline treatment, the DA neurons recorded following acute L-DOPA administration were firing at significantly slower basal firing rates and exhibited less burst firing when compared to saline-pretreated rats given acute saline. In contrast, DA cells recorded from rats that had received repeated L-DOPA administration for 4 weeks followed by an acute saline injection did not exhibit any significant differences from DA cells of intact control rats with respect to basal firing rate or firing pattern; however, there was a substantial increase in the proportion of DA neurons exhibiting spontaneous spike firing after correcting for 6-OHDA-induced cell loss. In addition, in rats receiving repeated L-DOPA treatment, the DA cells recorded following acute administration of L-DOPA showed significantly less of a reduction in firing rate when compared to the cells recorded following acute L-DOPA in the saline treatment group. These results show that: (1) acute L-DOPA administration appears to exert its actions by DA autoreceptor stimulation, whereas (2) repeated L-DOPA administration increases the proportion of spontaneously active DA neurons in partially lesioned rats. As a result, repeated L-DOPA administration would be expected to cause an increase in spike-dependent DA release as a consequence of the greater proportion of DA cells showing spontaneous activity. This may be the major factor underlying the delayed therapeutic benefits of L-DOPA therapy in the treatment of Parkinson's disease.

Animals↗
PubMed1988

D-dopa and L-dopa similarly elevate brain dopamine and produce turning behavior in rats.

In the intact rat, intragastric administration of D-dihydroxyphenylalanine (D-DOPA) together with carbidopa (alpha-methyldopa hydrazine, a peripheral dopadecarboxylase inhibitor) increased striatal dopamine concentration to the same extent as a similar treatment with L-DOPA plus carbidopa. In rats with unilateral 6-hydroxydopamine-induced lesions of their substantia nigra, both stereoisomers of DOPA produced significant increases in dopamine and its metabolites in the intact striata. Although dopamine concentrations in the lesioned striata did not change, a significant increase in dopamine metabolites was observed, indicating some extraneuronal formation of dopamine. These results suggest that D-DOPA can be converted to dopamine in the normal striatum as well as in the striatum devoid of dopamine nerve terminals. D- and L-DOPA produced turning behavior in unilaterally lesioned rats with a similar efficacy. The onset of turning after D-DOPA was delayed compared with L-DOPA. Turning behavior elicited by these amino acids was attributed to stimulation of supersensitive dopamine receptors in the lesioned striata by the extraneuronally formed dopamine. Preliminary results suggest that D-DOPA is converted to dopamine via transamination and/or D-amino acid oxidation to 3,4-dihydroxyphenylpyruvic acid which upon further transamination gives rise to L-DOPA and hence dopamine. The relatively fast and slow onset of stimulation of dopamine receptors L-DOPA and D-DOPA respectively suggests that the use of the racemic mixture of DOPA combined with a peripheral dopadecarboxylase inhibitor may prove useful in the treatment of parkinsonism.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1971

Failure of vitamin B6 to reverse the L-dopa effect in patients on a dopa decarboxylase inhibitor.

Seven patients with Parkinsonism previously on l-dopa were placed on a regimen of l-dopa and alpha methyl dopa hydrazine (a dopa decarboxylase inhibitor). Two of these patients had previously shown marked clinical deterioration of the l-dopa improvement when given pyridoxine. None of the seven patients receiving alpha methyl dopa hydrazine demonstrated any change in their condition when given pyridoxine. The failure of vitamin B(6) to reverse the clinical effect of l-dopa in patients receiving both l-dopa and a peripheral dopa decarboxylase inhibitor suggests that reversal of the l-dopa effect induced by vitamin B(6) is due to increasing the activity of the enzyme dopa decarboxylase outside the central nervous system.

Adult↗
PubMed2002

Differential regulation of GAD67, enkephalin and dynorphin mRNAs by chronic-intermittent L-dopa and A2A receptor blockade plus L-dopa in dopamine-denervated rats.

Adenosine A2A receptor antagonists have been proposed as an effective therapy in the treatment of Parkinson's disease. In the present study, we compared the modifications on striatal glutamate decarboxylase (GAD67), enkephalin, and dynorphin mRNA levels produced by a chronic-intermittent administration of L-3,4-dihydroxyphenyl-alanine (L-dopa) (6 mg/kg) with those produced by the adenosine A2A receptor antagonist SCH 58261 (5 mg/kg) plus L-dopa (3 mg/kg) in unilaterally 6-hydroxydopamine (6-OHDA)-lesioned rats. As previously reported, L-dopa (6 mg/kg) and SCH 58261 (5 mg/kg) plus L-dopa (3 mg/kg) produced the same degree of turning behavior after the first administration. However, while L-dopa (6 mg/kg) induced a sensitized turning behavior response during the course of the treatment, which indicated a dyskinetic potential, SCH 58261 (5 mg/kg) plus L-dopa (3 mg/kg) produced a stable turning behavior response, which was predictive of absence of dyskinetic side effects. Unilateral 6-OHDA lesion produced an elevation in striatal GAD67 and enkephalin mRNA levels and to a decrease in dynorphin mRNA levels. Chronic-intermittent L-dopa (6 mg/kg) treatment increased the striatal levels of GAD67, dynorphin, and enkephalin mRNA in the lesioned side as compared to the vehicle treatment. Chronic-intermittent SCH 58261 (5 mg/kg) plus L-dopa (3 mg/kg) as well as L-dopa (3 mg/kg) or SCH 58261 (5 mg/kg) alone did not produce any significant modification in GAD67, dynorphin, or enkephalin mRNA levels in the lesioned striatum as compared to the striatum of vehicle-treated rats. The results show that combined SCH 58261 plus L-dopa did not produce long-term changes in markers of striatal efferent neurons activity and suggest that the lack of modifications in GAD67 and dynorphin mRNA after SCH 58261 plus L-dopa might correlate with the lack of turning behavior sensitization which predicts drug dyskinetic potential.

Animals↗
PubMed1989

Identification of L-dopa-dopamine and L-dopa cell bodies in the rat mesencephalic dopaminergic cell systems.

An immunocytochemical technique for simultaneously visualizing two different antigens, dihydroxyphenylalanine (L-DOPA) and dopamine (DA), has been used to investigate the presence of cell bodies containing both compounds L-DOPA and DA and those having only L-DOPA in rat mesencephalon areas. The brain slices were processed with a double peroxidase-antiperoxidase method using simultaneously an incubation of a rabbit anti-L-DOPA serum and a monoclonal anti-DA antibody raised in mouse. Both antigens were revealed by the peroxidase reaction but with different chromogens that are easily distinguishable. In this staining procedure, the first antigen, conjugated DA was stained using the 3,3'-diaminobenzidine (DAB)-Nickel complex; while the second antigen, conjugated L-DOPA, was localized using DAB. The yellow-brown color due to DAB was masked by that of DAB-nickel. The possible existence of both single and double labelings could be worked. We have found many L-DOPA-positive/DA-positive and a few L-DOPA-positive/DA-negative cell bodies in dopaminergic regions in the rat midbrain: substantia nigra, ventral tegmental area, and raphe nuclei. In the locus coeruleus, we noted only L-DOPA-positive/DA-positive cell bodies. These results confirm those previously described for rat and cat hypothalamus, where both immunoreactive-cell body types have been detected: L-DOPA positive/DA positive and L-DOPA positive/DA negative. The existence of neuronal cells containing only L-DOPA is a new neuroanatomic finding, accounting better for the heterogeneity of dopamine systems with respect to physiologic, pharmacologic, and molecular data.

Animals↗
PubMed2005

Different responsiveness of striatonigral and striatopallidal neurons to L-DOPA after a subchronic intermittent L-DOPA treatment.

Early gene induction by L-DOPA in the striatum of dopamine denervated rats represents a useful way to study long-term modifications produced by this drug. The effects of acute and subchronic L-DOPA administration on zif-268 mRNA expression were compared in 6-hydroxydopamine-lesioned rats. Rats received a subchronic intermittent L-DOPA (6 mg/kg) treatment, which produces behavioural sensitization, a correlate of dyskinetic movements. Three days after interruption of subchronic treatment, zif-268 mRNA was evaluated after an L-DOPA challenge. Zif-268 mRNA levels increased in the lesioned dorsolateral striatum after either acute or subchronic L-DOPA administration. Double labelling of striatal cells with zif-268 and enkephalin or dynorphin mRNA probes was performed to assess neuronal activation in the indirect and direct output pathway. Single acute L-DOPA significantly increased zif-268 in all striatal neurons reflecting a hyperresponsiveness of dopamine-depleted striatum. After subchronic L-DOPA, zif-268 mRNA labelling was still increased in the striatonigral pathway, limited to dynorphin(+) neurons, whereas in all other neurons it was similar to the control value. Results suggest that striatal neurons responding to acute L-DOPA differ from those responding to subchronic L-DOPA. L-DOPA-induced behavioural sensitization was associated to a down-regulation in the responsiveness of striatopallidal and striatonigral dynorphin(-) neurons, whereas in striatonigral neurons containing dynorphin a hyperresponsiveness to L-DOPA was observed. High levels of zif-268, together with a persistent hyperresponsiveness of striatonigral dymorphinergic neurons and hyporesponsiveness of striatopallidal neurons, by creating an unbalanced state of striatal efferent neurons, may be implicated in dyskinetic movements observed in Parkinson's disease (PD).

Analysis of Variance↗
PubMed1990

Long-term double masked trial of early treatment with L-dopa plus bromocriptine versus L-dopa alone in Parkinson's disease. Interim results.

The quality and duration of control in two groups of parkinsonian patients under treatment with an L-dopa-based drug alone or L-dopa-based drug which has been partially substituted with bromocriptine are being compared over a 5-year period using a double-blind placebo-controlled study design. The aim is to establish whether early addition of bromocriptine will minimise late L-dopa complications. Results are presented after 1 year. Of 31 patients randomised, 13 were treated with combined L-dopa/bromocriptine and 14 with L-dopa/placebo. 4 patients were withdrawn for various reasons. In both groups any dose adjustments were aimed at maintaining the pre-entry clinical condition. In the group receiving bromocriptine combination therapy, progressive reduction of L-dopa was possible without deterioration of the patients' condition. In patients receiving L-dopa alone, the dose of L-dopa at 12 months was almost similar to that recorded on entry to the study. The total number of patients reporting adverse events in the L-dopa/bromocriptine combination and L-dopa alone groups were 8 and 7, respectively. At the present interim stage of the study it is not possible to compare the incidence of L-dopa long-term complications in either group.

Bromocriptine↗
PubMed1999

A controlled study of additional sr-L-dopa in L-dopa-responsive restless legs syndrome with late-night symptoms.

OBJECTIVE: To investigate whether a combination treatment of regular-release levodopa (rr-L-dopa) and sustained-release levodopa (sr-L-dopa) compared with monotherapy of rr-L-dopa improves sleep quality and reduces periodic limb movements (PLM) in patients with restless legs syndrome (RLS) and problems with maintaining sleep. BACKGROUND: Reappearance of RLS symptoms during the second half of the night while being treated with rr-L-dopa is a common problem in the treatment of sleep disturbances caused by RLS. METHODS: A randomized, controlled, double-blind crossover trial was undertaken. Eligible patients fulfilled the diagnostic criteria of the International RLS Study Group, and met an actigraphically confirmed higher number of PLM per hour time in bed (PLM index) during the second half compared with the first half of the night under treatment with rr-L-dopa. During the crossover periods the patients received 100 to 200 mg rr-L-dopa plus either placebo or 100 to 200 mg sr-L-dopa at bedtime for 4 weeks each period. RESULTS: Thirty patients with RLS (11 men and 19 women) were assessed by actigraphy and subjective sleep quality, and showed a significant improvement in PLM index (p < 0.0001), in "time in bed without movements" (p < 0.0001), and in subjective sleep quality (p < 0.001). Eight of 30 patients reported an altered pattern of RLS symptoms, characterized by a time shift of RLS symptoms into the afternoon or evening, five of these during monotherapy with rr-L-dopa. CONCLUSIONS: A combination therapy of rr-L-dopa and sr-L-dopa is better than monotherapy with rr-L-dopa in reducing the frequency of PLM and problems maintaining sleep, even in patients who are severely affected.

Adult↗
PubMed1993

alpha-Amino-n-butyric acid methyl ester induces concentrative uptake of L-dopa in human Langerhans' cells normally not operative for L-dopa transport.

We recently reported the existence of two kinds of human epidermal Langerhans' cells (LC), one which can take up and accumulate L-dopa and one which cannot. The dopa(+) LC take up L-dopa by carrier-mediated exchange diffusion, that is, the influx of L-dopa and the outflow of an intracellular substance are linked via the same carrier. The nature of the fundamental difference between L-dopa(+) and L-dopa(-) cells has not been clarified. We have now found that alpha-amino-n-butyric acid methyl ester (ABA-OME) penetrates into intracellular compartments, perhaps endosomes or lysosomes, of all LC, where hydrolysis results in the accumulation of the free amino acid (ABA). This accumulation causes a considerable increase in osmotic pressure of the membrane-limited organelle, leading to influx of water and swelling. Co-incubation with L-dopa revealed an influx of L-dopa into LC which normally cannot take up this amino acid. It is suggested that these LC lack the capacity to synthesize and/or store the counterpart which allows L-dopa to enter the dopa(+) LC, but that ABA in the L-dopa(-) LC can function as an equivalent counterpart.

Adult↗