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L-Dopa and piribedil alter different components of attentional behavior dependent on dose.

L-Dopa (3, 10, 30, 100 mg/kg) given SC after carbidopa, and piribedil (10, 30, 100, 300 mg/kg) had biphasic effects on investigation of a novel cup. Gerbils given a low dose of L-Dopa (10 mg/kg) or piribedil (10 or 30 mg/kg) investigated the cup more than did vehicle-injected gerbils, whereas those gerbils given a high dose of L-Dopa (100 mg/kg) or piribedil (300 mg/kg) investigated it less. L-Dopa, but not piribedil, also had biphasic effects on investigation of conspecific odors. The increase in duration with no increase in frequency of investigation suggested an inability to shift attention normally. High-dose attenuation of investigation is considered nonspecific, as many other drugs have the same effect. Locomotor activity scores showed no concomitant increase following low doses, but only a dose-dependent decrease. In addition, L-Dopa (100 mg/kg), but not piribedil at any dose tested, prevented the normal decrement in response to the cup 24 h after injection. As a high response is normally only shown when the stimulus is novel, the data suggest that L-Dopa at the high dose, but not piribedil, interfered with selective attention. Thus, the different dopamine agonists affected different aspects of attention. The data are discussed in relation to neural effects of the drugs as reported in the literature.

Animals↗

L-Dopa feeding suppression: effect on catecholamine neurons of the perifornical lateral hypothalamus.

Injection of L-Dopa (0.8--200 nmoles) into the perifornical hypothalamus produced a dose-dependent suppression of feeding in hungry rats. This effect was positively correlated in magnitude with the same effect produced by the catecholamine agonists dopamine and epinephrine, and by the catecholamine-releasing drug amphetamine. L-Dopa's action was partially antagonized by separate injections of the dopaminergic blocker haloperidol (58% blockade) and the beta-adrenergic blocker propranolol (38% blockade). Combined injections of these two antagonists produced a 90% blockade of L-Dopa's effect. Perifornical administration of the dopa decarboxylase inhibitors Ro 4-4602 and MK-486 was also shown to reverse L-Dopas feeding suppression, at doses that enhanced the effect of injected dopamine and epinephrine. On the basis of these findings, L-Dopa appears to suppress food consumption in part through increased catecholamine synthesis, specifically within dopaminergic and adrenergic neurons of the perifornical hypothalamic region.

Animals↗

Alpha-methyl-DOPA induced mydriasis in the cat. Relationship between pupillary response and the oculomotor perfusate concentration of methyldopa and its metabolites.

In pentobarbital anaesthetized cats, intravenous administration of 30 mg/kg, alpha-methyl-DOPA produced mydriasis that reached a maximum plateau in 2--2.5 h. The oculomotor nucleus was perfused with saline using a push-pull cannula system chronically implanted over the nucleus. Perfusate samples were collected and subsequently analyzed by liquid chromatography with electrochemical detection (LC-EC). Alpha-methyl-DOPA administration resulted in a gradual build up of alpha-methyl-noradrenaline to approximately 32 mumoles over the 3 h sampling period. In contrast, the concentration of alpha-methyl-dopamine was below the detection level for the first 90 min with peak levels of less than 6 mumoles after 3 h. A linear regression analysis demonstrated a negative correlation (R = 0.90) between the pupil size and the perfusate concentration of alpha-methyl-DOPA and a positive correlation for both alpha-methyl-dopamine and alpha-methyl-noradrenaline (R = 0.88 and 0.94 respectively). Pretreatment with the DOPA-decarboxylate inhibitor, 3-hydroxy-benzyl-hydrazine (NSD-1015; 25 mg/kg, i.p.) completely blocked the mydriatic response to alpha-methyl-DOPA, with neither alpha-methyl-dopamine nor alpha-methyl-noradrenaline reaching detectable levels in the oculomotor perfusate. After treatment with the dopamine-beta-hydroxylase inhibitor, bis (4-methyl-homopiperazinyl thiocarbonyl) disulfide (FLA-63; 2.5 mg/kg, i.p.) there was a significant accumulation of alpha-methyl-dopamine when compared to that obtained in the alpha-methyl-DOPA controls but with no apparent alpha-methyl-dopamine related pupillary dilation. However, the correlation between alpha-methyl-noradrenaline concentration and the increase in the diameter of the pupil was maintained.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

Positron emission tomographic studies on aromatic L-amino acid decarboxylase activity in vivo for L-dopa and 5-hydroxy-L-tryptophan in the monkey brain.

The regional brain kinetics following 5-hydroxy-L-(beta-11 C)tryptophan and L-(beta-11 C)DOPA intravenous injection was measured in twelve Rhesus monkeys using positron emission tomography (PET). The radiolabelled compounds were also injected together with various doses of unlabelled 5-hydroxy-L-tryptophan or D-DOPA. The radioactivity accumulated in the striatal region and the rate of increased utilization with time was calculated using a graphical method with back of the brain as a reference region. The rate constants for decarboxylation were 0.0070 +/- 0.0007 (S. D) and 0.0121 +/- 0.0010 min-1 for 5-hydroxy-L-(beta-11 C)tryptophan and L-(beta-11 C)DOPA, respectively. After concomitant injection with unlabelled 5-hydroxy-L-tryptophan, the rate constant of 5-hydroxy-L-(beta-11 C)tryptophan decreased dose-dependently and a 50 percent reduction was seen with a dose of about 4 mg/kg of unlabelled compound. A decreased utilization rate of L-(beta-11 C)DOPA was seen only after simultaneous injection of 30 mg/kg of either L-DOPA or 5-hydroxy-L-tryptophan. This capacity limitation was most likely interpreted as different affinity of the striatal aromatic amino acid decarboxylase for L-DOPA and 5-hydroxy-L-tryptophan, respectively.

5-Hydroxytryptophan↗

L-dopa infusion mode differentially affects corpus striatal dopamine efflux in the presence of reserpine.

In the present experiment we tested the effects of L-DOPA upon dopamine (DA) efflux in vitro from superfused corpus striatal tissue fragments in medium containing reserpine. The purposes of this experiment were first, to evaluate the effects of differing infusion modes of L-DOPA upon DA efflux under conditions in which DA storage capacity has been diminished, and second, to compare this L-DOPA stimulated DA efflux with that of other putative DA secretagogues such as amphetamine and potassium. No differences were obtained in stimulated DA efflux between superfusions performed in the presence or absence of reserpine (10 microM) in the medium when L-DOPA (5 microM) was infused in a continuous (70 minute) mode during the superfusion. In contrast, a continuous infusion of either amphetamine (10 microM) or high potassium (30 mM) resulted in significantly greater stimulated DA efflux in superfusions performed with reserpine in the medium. In addition, when L-DOPA (5 microM) was administered for a brief 10-minute infusion period, a significantly greater stimulated DA efflux was obtained with superfusions containing reserpine in the medium. These results suggest that the mode of L-DOPA infusion may be an important factor in regulating DA release under conditions of diminished DA storage capacity.

Amphetamine↗

Potentiation of central effects of L-dopa by an inhibitor of catechol-O-methyltransferase.

The effects of a COMT-inhibitor, U-0521, and a MAO-B-inhibitor, 1-deprenyl, on L-dopa-induced circling behaviour were compared in 6-OHDA-lesioned rats. The actions of U-0521 and 1-deprenyl on the anti-cataleptic effect of L-dopa were also studied. Both U-0521 and 1-deprenyl were found to potentiate L-dopa-induced circling behaviour and anti-cataleptic effect of L-dopa. In both test systems the L-dopa potentiation of 1-deprenyl was longer-lasting than that caused by U-0521. Thus inhibition of COMT, like inhibition of MAO, is able to enhance the central effects of L-dopa. This principle might be beneficial in the treatment of Parkinson's disease especially if COMT-inhibitors with greater performance can be developed.

Animals↗

An in vivo comparison of the capacity of striatal versus extrastriatal brain regions to form dopamine from exogenously administered L-dopa.

We used the technique of cerebral microdialysis to monitor the metabolism of exogenously administered L-dopa and compared dopamine and dopamine metabolite formation in the striatum (a site containing abundant dopamine nerve terminals and dopa-decarboxylase (DDC) activity) versus the cerebellum and occipital cortex (sites with limited dopaminergic innervation and DDC activity). The concentrations of dopamine and the major dopamine metabolites dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) increased in each brain region following L-dopa perfusion; however, dopamine formation was 90% less in the occipital cortex as compared to the striatum and 95% less in the cerebellum. DOPAC formation was 57% less in the occipital cortex and 74% less in the cerebellum. HVA formation was 42% less in the occipital cortex and 70% less in the cerebellum. The levels of the L-dopa metabolite 3-O-methyldopa and the serotonin metabolite 5-hydroxyindoleacetic acid (5HIAA) were identical in the striatum, occipital cortex, and cerebellum both before and after L-dopa administration. We conclude that brain areas with marked reductions in dopamine nerve terminals and DDC activity have a diminished capacity to synthesize dopamine and also lack storage mechanisms to protect the newly synthesized dopamine from degradative metabolism. The relevance of these findings to the use of L-dopa in treating Parkinson's disease is discussed.

3,4-Dihydroxyphenylacetic Acid↗

Combined effects of cabergoline and L-dopa on parkinsonism in MPTP-treated cynomolgus monkeys.

The behavioral effects of L-dopa or cabergoline alone were compared with those of the joint administration of the two drugs in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned parkinsonian cynomolgus monkeys with attention to the induction of hyperactivity and dyskinesia. Cabergoline alone at 0.2 mg/kg or less improved in a dose-dependent fashion the parkinsonism without inducing hyperactivity and dyskinesia following a single subcutaneous injection. L-dopa alone improved the parkinsonism, but induced hyperactivity and dyskinesia, depending on the dose applied. Doses required for 50% amelioration by L-dopa and cabergoline were 10 and 0.038 mg/kg, s.c., respectively. With low doses (50%-amelioration doses), cabergoline or L-dopa alone improved the parkinsonism without induction of hyperactivity and dyskinesia, but the duration of action was brief. Cabergoline in combination with L-dopa was highly effective in improving motor disability without induction of hyperactivity and dyskinesia. Moreover, the duration of action was more prolonged with the coadministration than with the single administration of each drug. These findings suggest that the combined therapy with low doses of L-dopa and cabergoline is beneficial for treating patients with advanced Parkinson's disease.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗

Pavlovian conditioning of L-dopa induced movement.

Using the unilateral 6-hydroxydopamine (6-OHDA) substantia nigra pars compacta (SNC) lesion rat model and a Pavlovian conditioning protocol, the present investigation determined that the contralateral rotation response induced by the antiparkinsonian dopaminergic drug L-dopa can become conditioned to exteroceptive test environment stimuli. Two non-drug conditioning tests indicated that contralateral rotation was elicited by the test environment without the presence of L-dopa. This conditioned response had a rotation diameter profile that was qualitatively the same as the L-dopa induced contralateral rotation response. Additionally, drug tests with the combined dopaminergic receptor antagonists, SCH 23390 (0.1 mg/kg) and haloperidol (0.5 mg/kg), at doses sufficient to block spontaneous behavior and L-dopa (20 mg/kg)-induced rotation, revealed that the conditioned contralateral rotation response, unlike L-dopa-induced contralateral rotation, is not affected by D1/D2 receptor blockade. Thus, the conditioned stimuli of the test environment can elicit the contralateral rotation response even in animals rendered akinetic by D1/D2 antagonists. This activation of a conditioned dopaminergic drug response by the situational stimuli, independent of dopaminergic mechanisms, may, therefore, contribute to the untoward overstimulation clinical effects of L-dopa through summation of conditioned and drug-induced effects. Furthermore, the use of conditioning procedures to elicit movement in akinetic animals may provide a new research methodology to investigate the phenomenon of paradoxical kinesia.

Animals↗

A meta-analysis of the response to chronic L-dopa in patients with schizophrenia: therapeutic and heuristic implications.

RATIONALE: While it is generally believed that administration of the dopamine precursor levodopa ( L-dopa) exacerbates symptoms of schizophrenia, numerous reports suggest that adjunctive L-dopa may be beneficial. This body of literature has not been critically reviewed. OBJECTIVES: On the basis of published studies, to determine whether L-dopa administered concomitantly with antipsychotic drugs provides a beneficial response in patients with schizophrenia. METHODS: This review examined 30 studies involving 716 patients. Due to wide methodological variability and limited statistical information, only five studies encompassing 160 patients could be included in a meta-analysis. The others were evaluated qualitatively. RESULTS: When L-dopa was added to antipsychotic drugs, the overall improvement was moderate ( d=0.71) and highly significant ( P<0.0001). There were 16 other studies in which L-dopa was added to antipsychotic drugs, but which did not meet criteria for inclusion in the meta-analysis. In these, worsening occurred in less than 20% of patients; the percentage of improved patients varied widely but had a central tendency around 50%. CONCLUSIONS: . In patients already on antipsychotic drugs, the addition of L-dopa can be beneficial. Dopamine agonists merit further consideration as adjuncts to antipsychotic drugs in the treatment of schizophrenia.

Adolescent↗

L-DOPA biotransformation: correlations of dosage, erythrocyte catechol O-methyltransferase and platelet SULT1A3 activities with metabolic pathways in Parkinsonian patients.

The objectives of this study were to determine (1) the effects of dose and drug absorption on pathways of biotransformation of L-DOPA in Parkinsonian patients treated with Sinemet, and (2) the extent to which genetically-determined variations in the activities of erythrocyte catechol O-methyltransferase and/or platelet phenol sulfotransferase might be reflected in individual differences in L-DOPA metabolism. In the 19 patients studied, there were negative correlations between dosage or absorption and extent of O-methylation and of sulfation of L-DOPA or its metabolites. Levels of activity for erythrocyte COMT were also reflected in individual variation in the metabolism of L-DOPA. In contrast, differences in platelet phenol sulfotransferase were not reflected in differences in sulfation of L-DOPA or of its metabolites. If such a relationship did exist, it might have been obscured by the effects of high dosage of L-DOPA, effects which might have resulted from a deficiency of the sulfation cosubstrate 3'-phosphoadenosine 5'-phosphosulfate in patients taking higher doses of drug.

Adenosine Diphosphate↗

Alteration in L-DOPA evoked dopamine and DOPAC output under conditions of impaired vesicular dopamine storage.

We examined the effect of L-dihydroxyphenylalanine (L-DOPA) infusion in vitro upon dopamine (DA) and dihydroxyphenylacetic acid (DOPAC) output from superfused corpus striatum of vehicle and reserpine or tetrabenazine (TBZ) treated male rats. Specifically, we tested the effects of two 20-min infusions of L-DOPA (5 uM) upon DA and DOPAC output (pg/mg/min) in reserpine (5 mg/kg, i.p., 24 hours before sacrifice; n=11), TBZ (30 mg/kg, i.p. 1 hour before sacrifice; n=8) or vehicle (n=21) treated rats. There was an overall significantly higher L-DOPA evoked DA output from the vehicle (12.22+/-1.74) versus reserpine (4.39+/-2.40) (p < 0.05), but not TBZ (9.16+/-2.81) treated rats. In addition, the DA response to the second L-DOPA infusion was significantly increased over that of the first response in the vehicle (9.40+/-2.11 vs. 15.04+/-2.78) (p < 0.05), but not reserpine or TBZ treated rats. The overall DOPAC outputs did not achieve a statistically significant difference among all treatment groups. However, the DOPAC outputs following the second L-DOPA infusion were significantly reduced in reserpine (41.15+/-6.10 vs. 20.27+/-4.54) and TBZ (21.38+/-4.41 vs. 10.87+/-2.36) (both p < 0.05), but not vehicle (28.99+/-4.00 vs. 24.91+/-4.78) treated rats. We conclude that: 1) the storage capacity of DA neurons is one of the important elements involved in affecting L-DOPA's effects upon DA and DOPAC output, 2) the shunting of storage to metabolism may represent a common characteristic in impaired nigrostriatal dopaminergic system, and 3) TBZ may operate differently from reserpine in the nigrostriatal dopaminergic system.

3,4-Dihydroxyphenylacetic Acid↗

SCH 23390 enhances exogenous L-DOPA decarboxylation in nigrostriatal neurons.

Exogenous L-DOPA enhances dopamine metabolism in the intact and denervated striatum, and is the treatment of choice for Parkinsonism. Aromatic L-amino acid decarboxylase (AAAD) converts L-DOPA to dopamine. Blockade of dopamine D1-like receptors increases the activity of AAAD in both intact and denervated striatum. A single dose of SCH 23390, a dopamine D1-like receptor antagonist, increases the activity of AAAD in the striatum and midbrain and induces small changes in dopamine metabolism. When L-DOPA is administered after SCH 23390, there is a significant increase in the formation of 3,4-dihydroxyphenylacetic acid and dopamine turnover in striatum and midbrain compared to L-DOPA alone, suggesting further enhancement of dopamine metabolism. When the studies are repeated in the MPTP mouse model of Parkinson's disease, there is significantly more dopamine metabolism in the striatum of lesioned mice pretreated with SCH 23390 than in a comparison group treated with L-DOPA alone. These studies suggest that it may be possible to enhance the conversion of L-DOPA to dopamine in Parkinson's disease patients by administering substances that augment brain AAAD.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗

Transcription factors involved in the pathogenesis of L-DOPA-induced dyskinesia in a rat model of Parkinson's disease.

L-DOPA-induced dyskinesia (abnormal involuntary movements) is one of the most debilitating complications of chronic L-DOPA pharmacotherapy in Parkinson's disease. It is generally agreed that dyskinesia arises as a consequence of pulsatile dopamine-receptor stimulation in the brain, causing downstream changes in genes and proteins. Advance in our understanding of such changes is critically dependent on the availability of suitable animal models. We have introduced a new method to classify and rate L-DOPA-induced abnormal involuntary movements (AIMs) in 6-hydroxydopamine (6-OHDA) lesioned rats. This method allows us to dissect the molecular correlates of a dyskinetic motor response to L-DOPA in this species. One of the most prominent molecular changes underlying the development of dyskinesia in the rat consists in the striatal induction of prodynorphin gene expression by L-DOPA. This effect is mediated by FosB-related transcription factors of 32-37 kDa, which are co-induced with prodynophin in striatal neurons of the "direct pathway". Both AIM development and the associated upregulation of prodynorphin mRNA by L-DOPA are significantly inhibited by the intrastriatal infusion of fosB antisense. Antisense-mediated knockdown of CREB (cyclic AMP response-element binding proteins) has however no effect. Our results identify fosB as a potential target for adjunctive antiparkinsonian therapies.

Animals↗

L-DOPA increases lignification associated with Glycine max root growth-inhibition.

L-3,4-dihydroxyphenylalanine (L: -DOPA), an allelochemical exuded from the roots of velvet bean [Mucuna pruriens (L.) DC. var. utilis], presents a highly inhibitory action to plant growth. The effects of L-DOPA on phenylalanine ammonia-lyase (PAL, EC 4.3.1.5) and peroxidase (POD, EC 1.11.1.7) activities, and phenolic compound and lignin content in soybean [Glycine max (L.) Merr.] roots were investigated to determine the possible phytotoxic mechanism. Three-day-old seedlings were cultivated in half-strength Hoagland nutrient solution (pH 6.0), without or with 0.1 to 1.0 mM L-DOPA in a growth chamber (25 degrees C, 12-hr light to 12-hr darkness photoperiod, irradiance of 280 micromol m-2 s-1) for 24 hr. In general, the length, fresh weight, and dry weight of the roots decreased, whereas PAL and POD activities and phenolic compound and lignin content increased after L-DOPA treatments. Results showed the susceptibility of soybean to L-DOPA and reinforce the role of this nonprotein amino acid as a strong allelochemical. The present findings also suggest that L-DOPA-induced inhibition in soybean roots may be because of a cell wall stiffening process related to the formation of cross-linking between cell wall polymers linked to lignin production.

Levodopa↗

Predominance of L-dopa in fetal plasma and the amniotic fluid during late gestation in the rat.

The purpose of this study was to reevaluate catecholamine distribution in fetal and maternal compartments during late gestation in the rat. Fetal and maternal plasma and amniotic fluid were collected from anesthetized rats on consecutive days from day 17 to day 22, the day of parturition. The fluid was analyzed for dihydroxyphenylalanine (L-dopa), dopamine, norepinephrine, and epinephrine by radioenzymatic assays. Amniotic fluid volume was determined by a direct weighing method. L-Dopa concentrations constituted approximately 50% of total fetal plasma catecholamines and were significantly higher in fetal than in maternal circulation. Dopamine concentrations in fetal plasma were tenfold lower than those of L-dopa but were also significantly higher in fetal than in maternal plasma; norepinephrine levels were similar in both. Maternal plasma epinephrine levels remained relatively constant, whereas fetal epinephrine levels increased fiftyfold from day 17 to day 22. L-Dopa concentrations in the amniotic fluid were tenfold higher than those of dopamine, and the concentrations of both increased markedly during the last 2 days of gestation. However, this apparent rise could be attributed to the concomitant fivefold reduction in the amniotic fluid volume observed at this time. It is concluded that L-dopa is the predominant catecholamine in both the fetal plasma and the amniotic fluid during late gestation in the rat. At the present time, neither the source nor the possible physiologic functions of L-dopa during fetal life are known.

Amniotic Fluid↗

Growth enhancement induced by prolonged L-dopa administration in rats.

To follow growth of rats, in which growth hormone secretion has been chronically stimulated, L-Dopa (5 mg/kg) was injected subcutaneously twice daily for 70 days to growing rats. A control group, matched for sex and sibship, pair fed with the treatment group was given saline injections. At 10-day intervals, the rats were weighed and measured. At 90 days of age the rats were ether anesthesized, bled for growth hormone determination, and internal viscera weighed. Weight gain and length in the L-Dopa-treated group was found to be significantly greater. A mean weight gain of 6% and 12% in the male and female rats, respectively, and a mean length gain of 5% in both male and female rats was observed at 90 days of age. The thymus, thyroid, adrenals, uterus, and gonads all tended to be heavier in the L-Dopa-treated group. Significantly heavier kidneys were found in the L-Dopa group. Serum growth hormone was found to be 8.44 +/- 1.4(SE) ng/ml in the L-Dopa group and 4.6 +/- 0.9 ng/ml in the control group. It is concluded that the continuous administration of L-Dopa produces an increase of circulating serum growth hormone levels, and this in turn enhances growth.

Animals↗

The effect of lysergic and diethylamide (LSD) and 2-bromolysergic acid diethylamide (BOL) on the striatal DOPA accumulation: influence of central 5-hydroxytryptaminergic pathways.

Selective chronic lesions of the dorsal raphe nucleus or combined lesions of the dorsal and median raphe nuclei did not significantly change the in vivo tyrosine hydroxylation in the striatum as measured by the DOPA accumulation after decarboxylase inhibition. Neither did acute combined lesions of the raphe nuclei, nor did electrical stimulation of the dorsal raphe nucleus have any significant effect. p-Chloroamphetamine (PCA, 20 mg/kg, i.p.) and p-chlorophenylalanine (PCPA, 400 mg/kg, i.p.), known inhibitors of the 5-hydroxytryptamine (5-HT) synthesis, significantly decreased the DOPA accumulation. The increase in DOPA accumulation observed after LSD (0.5 mg/kg, i.p.) or BOL (0.5 mg/kg, i.p.) was seemingly unaffected by pretreatment with PCA or PCPA and also after lesion of the dorsal raphe nucleus. The results suggest that the effect of LSD or BOL on the DOPA accumulation in the striatum is not mediated via a 5-hydroxytryptaminergic control mechanism originating in the dorsal raphe nucleus. A control mediated via the median raphe nucleus cannot be excluded, since LSD did not increase the DOPA accumulation after combined chronic raphe lesions. Such a control would also be in agreement with our previous results suggesting that hte DOPA generation after LSD is controlled by 5-HT receptors.

Animals↗