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PubMed1978

The L-dopa on-off effect in Parkinson disease: treatment by transient drug withdrawal and dopamine receptor resensitization.

It has been suggested that patients with Parkinson disease partially compensate for neuron loss by developing denervation supersensitivity, and, if so, that prolonged levodopa (L-dopa) therapy might lead to desensitization. As a preliminary test of this hypothesis, and in order to study whether it was possible to "resensitize" a patient who had already presumably been desensitized by previous L-dopa therapy, a patient who had become unpredictably responsive to L-dopa was investigated. The patient had been taking L-dopa for eight years and had exhibited severe dyskinesia-akinesia oscillation ("on-off" phenomenon) before the study. There was no consistent response to his hourly doses of Prolopa (L-dopa and benserazide in a 4:1 ratio). He was first lowered, over 33 days, to 20% of his original Prolopa dose. The dosage was then increased until a consistent response was observed. The three main results achieved were, first, overall reduction by 64% of the daily requirement for L-dopa; second, conversion from a previously unpredictable to a predictable response to each dose of L-dopa; and, third, change in his movement fluctuations to a pattern more typical of "end-of-dose" akinesia than the "on-off" phenomenon. The results support the idea of dopamine receptor resensitization upon reduction of the L-dopa dosage.

Humans↗
PubMed1986

Long-term follow-up of early dopa treatment in Parkinson's disease.

A group of 19 patients with Parkinson's disease, who began dopa therapy 1 to 3 years after onset of symptoms, were followed for 12 years. They were evaluated every 3 to 4 months on the UCLA disability scale and the Hoehn and Yahr functional classification scale. This present group was compared to two other historical groups reported on earlier [8], one that began treatment with dopa 4 to 6 years after onset of symptoms and the other that began dopa treatment 7 to 9 years after onset of symptoms. Results on both scales showed that the mean disability scores of the three groups did not differ significantly when duration of disease was matched, even though duration of dopa therapy among the groups varied from 1 to 12 years. The highly significant differences between the groups prior to dopa treatment continued throughout the study. These longitudinal data support the conclusion that the worsening over time is the result of progression of Parkinson's disease and not a result of the duration of dopa treatment. Early treatment improves the beginning years of the disease and has no adverse effect on later years. Twelve years after beginning dopa therapy, 32% of the present group had died at a mean age of 76.0, in contrast to 50% (mean age, 74.7) and 57% (mean age, 71.5) in the groups who began dopa increasingly later in the course of their disease. Incidence of dementia increased with disease duration regardless of treatment duration.(ABSTRACT TRUNCATED AT 250 WORDS)

Dementia↗
PubMed1990

L-dopa pharmacokinetics in plasma and cisternal and lumbar cerebrospinal fluid of monkeys.

The pharmacokinetics of levodopa (L-dopa) in plasma and in cisternal and lumbar cerebrospinal fluid (CSF) were studied in Rhesus monkeys that were given 2- to 3-hour intravenous infusions of L-dopa. Steady-state L-dopa concentrations in cisternal CSF correlated well with plasma levels, and yielded a CSF:plasma ratio of 0.17. The disappearance of L-dopa from plasma and cisternal CSF compartments fits an open, two-compartment pharmacokinetic model. Although slower, the distribution and elimination half-lives for L-dopa from cisternal CSF (8.9 and 49.2 minutes, respectively) were of a similar magnitude to those from plasma (4.9 and 33.2 minutes, respectively). If cisternal CSF reflects brain extracellular fluid, then plasma pharmacokinetics of L-dopa are a reasonable approximation of those in the brain. In contrast to cisternal CSF, the disappearance of L-dopa from lumbar CSF fits an open, one-compartment model with an elimination half-life of 100 minutes. This indicates that the lumbar CSF compartment is unsuitable for investigation of the pharmacokinetics of L-dopa in the brain.

Animals↗
PubMed1990

Differing patterns of striatal 18F-dopa uptake in Parkinson's disease, multiple system atrophy, and progressive supranuclear palsy.

Using positron emission tomography (PET), we studied regional striatal 18F-dopa uptake in 16 patients with L-dopa-responsive Parkinson's disease (PD), 18 patients with multiple system atrophy, and 10 patients with progressive supranuclear palsy. Results were compared with those of 30 age-matched normal volunteers. The patients with PD showed significantly reduced mean uptake of 18F-dopa in the caudate and putamen compared to controls, but while function in the posterior part of the putamen was severely impaired (45% of normal), function in the anterior part of the putamen and in the caudate was relatively spared (62% and 84% of normal). Mean 18F-dopa uptake in the posterior putamen was depressed to similar levels in all patients. Unlike patients with PD, the patients with progressive supranuclear palsy showed equally severe impairment of mean 18F-dopa uptake in the anterior and posterior putamen. Caudate 18F-dopa uptake was also significantly lower in patients with progressive supranuclear palsy than in patients with PD, being depressed to the same level as that in the putamen. Mean 18F-dopa uptake values in the anterior putamen and caudate in patients with multiple system atrophy lay between PD and progressive supranuclear palsy levels. Locomotor disability of individual patients with PD or multiple system atrophy correlated with decline in striatal 18F-dopa uptake, but this was not the case for the patients with progressive supranuclear palsy. We conclude that patients with PD have selective nigral pathological features with relative preservation of the dopaminergic function in the anterior putamen and caudate, whereas there is progressively more extensive nigral involvement in multiple system atrophy and progressive supranuclear palsy.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed2001

Antiparkinsonian activity and dyskinesia risk of ropinirole and L-DOPA combination therapy in drug naïve MPTP-lesioned common marmosets (Callithrix jacchus).

De novo administration of long-acting dopamine agonists, such as ropinirole, to patients with Parkinson's disease or to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated subhuman primates produces a lower incidence of dyskinesia than occurs with L-DOPA. This study compares the intensity of dyskinesia produced by combinations of L-DOPA and ropinirole and by these drugs alone, using the MPTP-treated common marmoset model of Parkinson's disease. The objective is to determine the optimum therapeutic strategy for the long-term control of Parkinson's disease with a minimal risk of dyskinesia. MPTP-treated marmosets received either L-DOPA alone, ropinirole alone, or one of two combinations of these drugs (either L-DOPA dominant or ropinirole dominant) daily for 28 days in doses titrated to produce a similar improvement in disability and increase in locomotion. In the group receiving L-DOPA alone, there was a trend for peak dose locomotor activity to increase and the duration of drug effect to decline over the period of the study. L-DOPA alone induced marked dyskinesia over the period of treatment, in contrast to ropinirole which produced a low intensity of involuntary movements. The L-DOPA dominant combination initially produced little dyskinesia, but this became increasingly intense as the study progressed. In contrast, the ropinirole dominant combination produced no greater intensity of dyskinesia than was produced by ropinirole alone. These data suggest that in early Parkinson's disease, the use of ropinirole alone or in combination with a low-dose L-DOPA might delay the induction of dyskinesias while improving motor performance.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1997

Simultaneous MAO-B and COMT inhibition in L-Dopa-treated patients with Parkinson's disease.

The effect of selegiline (L-deprenyl) on plasma catecholamines, clinical response, and drug tolerability was studied in 13 patients with Parkinson's disease (PD) treated with L-Dopa/benserazide and entacapone, a peripheral catechol-O-methyltransferase (COMT) inhibitor, in a placebo-controlled double-blind study. An L-Dopa test was performed on 3 study days. The first study day was with L-Dopa/benserazide only (control), the second after 14 days of treatment with 200 mg entacapone taken concomitantly with L-Dopa/benserazide in combination with either selegiline (10 mg daily) or placebo. After a 2-week washout period, selegiline and placebo treatments were switched, and the third study day was after 14 days of treatment. During the study days, clinical response was evaluated at 30-min intervals for 6 h, by using the motor score of the Unified Parkinson's Disease Rating Scale (UPDRS). In addition, repeated blood pressure measurements were made, and plasma samples were taken for analysis of L-Dopa, 3-O-methyldopa (3-OMD), dihydroxyphenyl acetic acid (DOPAC), homovanillic acid (HVA), dopamine, noradrenaline, and 3-methoxy-4-hydroxyphenylethylene glycol (MHPG). Monoamine oxidase B (MAO-B) and COMT enzyme activities were measured from platelets and erythrocytes, respectively. Entacapone improved the clinical response to L-Dopa during both selegiline and placebo (p < 0.001) treatments. The improvement was more marked during combined selegiline and entacapone treatment than with entacapone alone (p < 0.01). Entacapone significantly increased plasma L-Dopa and DOPAC levels and decreased plasma 3-OMD and MHPG levels both with selegiline and placebo. Selegiline partially inhibited the entacapone-induced increase of plasma DOPAC. Plasma dopamine and noradrenaline levels did not change. Entacapone decreased erythrocyte COMT activity by > 35% (p < 0.001), and platelet MAO-B activity was almost completely inhibited by selegiline (p < 0.001). One patient withdrew because of diarrhea, dizziness, and loss of sleep when receiving selegiline treatment. Otherwise no differences in adverse events, mean daily blood pressures, or other safety parameters were observed between selegiline and placebo treatments. Our results suggest that entacapone can be safely administered together with L-Dopa and selegiline in patients with PD, although further studies with larger number of patients and longer treatment periods are necessary to confirm this finding.

Aged↗
PubMed2002

MK-801 alters the effects of priming with L-DOPA on dopamine D1 receptor-induced changes in neuropeptide mRNA levels in the rat striatal output neurons.

In a previous study, we have shown in unilaterally dopamine-depleted rats that increased behavioral responsiveness to the dopamine D1-receptor agonist SKF-38393, which was induced by pretreatment with L-DOPA, is paralleled by specific alterations in striatal neuropeptide mRNA levels. The behavioral 'priming' effect of L-DOPA is prevented if L-DOPA is preceded by the NMDA-receptor antagonist MK-801. In the present study, the question is addressed whether blockade of the increased behavioral responsiveness with MK-801 also prevents the observed changes in striatal neuropeptide mRNA levels. After a challenge with SKF-38393 (3 mg/kg, s.c.), the striatal levels of preprodynorphin, preprotachykinin, and preproenkephalin mRNA were compared between unilaterally dopamine-depleted rats that were either primed with a single administration of L-DOPA (50 mg/kg, i.p.) or with L-DOPA preceded by MK-801 (0.1 mg/kg, i.p.). Priming with L-DOPA enhanced the increase in dynorphin mRNA levels in the dorsolateral part of the dopamine-depleted striatum that occurred after SKF-38393. On the other hand, it had no significant effect on substance P or enkephalin mRNA levels. MK-801 prior to L-DOPA prevented the increased responsiveness of dynorphin regulation. However, it induced a decreased response to dopamine D1-receptor stimulation in the substance P mRNA levels in dorsal regions of the dopamine-depleted striatum. The levels of enkephalin mRNA after challenge with SKF-38393 were not affected by the MK-801 administration. These results demonstrate that the increased behavioral responsiveness to the D1-receptor agonist SKF-38393 after priming with L-DOPA is primarily related to the upregulation of dynorphin mRNA levels in the dopamine-depleted striatum.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed2002

Behavioral and anatomical effects of long-term L-dihydroxyphenylalanine (L-DOPA) administration in rats with unilateral lesions of the nigrostriatal system.

This study investigated behavioral and anatomical changes induced by long periods of L-DOPA treatment in the unilateral rat model of Parkinson's disease. After daily injections of L-DOPA (50 mg/kg, ip) given for 1, 4, 8, or 16 weeks, behavioral sensitization, expressed by contralateral turning and changes in its pattern, increased within the first week of treatment and remained unchanged thereafter. Dyskinetic movements, affecting the trunk and limbs of all treated rats, also developed within the first week of treatment and increased further during the 16 weeks of L-DOPA treatment. L-DOPA responsiveness was also accompanied by changes at the neuronal level, as shown by changes in the expression of c-fos in the dopamine-depleted striatum. Following 1 week of L-DOPA treatment there was a marked decrease in striatal c-fos expression, compared to single injections, especially evident in the medial and ventral regions and to a lesser extent in the dorsolateral regions of the striatum. This specific regional expression of c-fos was maintained throughout the 16 weeks of L-DOPA treatment. Overall, our results show that behavioral sensitization to L-DOPA starts relatively early during the treatment and include not only an increase in contralateral turning rate but also an increase in dyskinetic movements. Persisting c-fos expression in the dorsolateral striatum might be implicated in the development of dyskinesias when L-DOPA treatment is extended for periods longer than 1 week.

Animals↗
PubMed2003

Both short- and long-acting D-1/D-2 dopamine agonists induce less dyskinesia than L-DOPA in the MPTP-lesioned common marmoset (Callithrix jacchus).

The current concept of dyskinesia is that pulsatile stimulation of D-1 or D-2 receptors by L-DOPA or short-acting dopamine agonists is more likely to induce dyskinesia compared to long-acting drugs producing more continuous receptor stimulation. We now investigate the ability of two mixed D-1/D-2 agonists, namely pergolide (long-acting) and apomorphine (short-acting), to induce dyskinesia in drug-nai;ve MPTP-lesioned primates, compared to L-DOPA. Adult common marmosets (Callithrix jacchus) were lesioned with MPTP (2 mg/kg/day sc for 5 days) and subsequently treated with equieffective antiparkinsonian doses of L-DOPA, apomorphine, or pergolide for 28 days. L-DOPA, apomorphine, and pergolide reversed the MPTP-induced motor deficits to the same degree with no difference in peak response. L-DOPA and apomorphine had a rapid onset of action and short duration of effect producing a pulsatile motor response, while pergolide had a slow onset and long-lasting activity producing a continuous profile of motor stimulation. L-DOPA rapidly induced dyskinesia that increased markedly in severity and frequency over the course of the study, impairing normal motor activity by day 20. Dyskinesia in animals treated with pergolide or apomorphine increased steadily, reaching mild to moderate severity but remaining significantly less marked than that produced by L-DOPA. There was no difference in the intensity of dyskinesia produced by apomorphine and pergolide. These data suggest that factors other than duration of drug action may be important in the induction of dyskinesia but support the use of dopamine agonists in early Parkinson's disease, as a means of delaying L-DOPA therapy and reducing the risk of developing dyskinesia.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1994

Fibroblasts that express aromatic amino acid decarboxylase have increased sensitivity to the synergistic cytotoxicity of L-dopa and manganese.

Manganism, a neurodegenerative disease that can follow chronic exposure to Mn, has been associated with lesions in the basal ganglia and depletion of dopamine and its metabolites in this brain region. Herein, we have tested the hypothesis that oxidation of catechols is a critical component of Mn-induced cytotoxicity. To eliminate confounding metabolic pathways, a nonneuronal cell line, Chinese hamster ovary (CHO) fibroblasts, was transfected with a cDNA for bovine aromatic amino acid decarboxylase, and a high expressing clone was isolated (CHO/AADC). Exposure of wild-type (CHO/WT) or CHO/AADC cultures to L-dopa (62 to 500 microM) resulted in intracellular accumulation of L-dopa or L-dopa and dopamine, respectively, that was concentration-dependent. Intracellular catechol levels in CHO/AADC cells were double those in CHO/WT cultures. No dopac was identified intra- or extracellularly. Addition of MnCl2 (125 to 500 microM) resulted in cytotoxicity that progressed with increasing concentrations of L-dopa or Mn. Neither L-dopa nor MnCl2 alone was toxic at these concentrations, and cytotoxicity was completely abrogated by substitution of L-tyrosine for L-dopa. Although CHO/AADC cultures were more sensitive than CHO/WT to L-dopa and Mn, this was completely accounted for by the differences in intracellular catechol levels between the two cell lines. Preformed melanin or dopac were low-potency cytotoxins only at high MnCl2 concentrations. These results indicate that Mn and intracellular L-dopa and dopamine, but not extracellular dopac or melanin, are potent synergistic cytotoxins.

Animals↗
PubMed1982

Dopa-release from mouse neuroblastoma clone N 1 E-115 into the culture medium. A test for tyrosine hydroxylase activity.

Due to a lack of L-Dopa-decarboxylase, the mouse neuroblastoma clone N 1 E-115 contains a high intracellular Dopa-content compared to a low noradrenaline- and dopamine-content. Because of this decarboxylase deficiency, the N 1 E-115 clone releases more than 95% of the produced Dopa into the culture medium. After renewal of the culture medium, Dopa production of the cells can be measured by the increase of Dopa in the medium. Dopa production was linear during 2 h and varied from 50-180 micrograms/mg prot-1 x h-1 between different subcultures. Dopa release into the medium was used as an indirect measure for the tyrosine-hydroxylase activity. Several dopaminergic agonist and antagonists were tested. Dopa production could be blocked dose-dependent by apomorphine (1 X 10(-7)-1 x 10(-6) M), but not by lisuride hydrogen maleate and bromocryptine. Several dopaminergic and adrenergic antagonists failed to reverse the apomorphine induced blockade of the tyrosine-hydroxylase activity.

Animals↗
PubMed1975

Differences between (+)- and (-)-amphetamine in effects on locomotor activity and L-dopa potentiating action in mice.

The L-Dopa-potentiating effects of the two optical isomers of amphetamine, as well as the effects of their own, were investigated in mice, using locomotor activity as test parameter. The study was performed in three steps. First, the time-course were studied for the effects of (+)- and (-)-amphetamine and L-Dopa. Second, dose-response relationships were established for the amphetamine enantiomers. Third, the L-Dopa-potentiating effects, of a few, selected doses of the amphetamine isomers were investigated by establishing dose-response curves for L-Dopa with and without the amphetamines. All animals given L-Dopa were pretreated with an inhibitor of extracerebral aromatic amino acid decarboyxlase. (+)-Amphetamine, 0.5-8 mg/kg, caused a dose-dependent stimulation of locomotoractivity, whereas (-)-amphetamine, 1-4 mg/kg, caused a dose-dependent depression. Doses higher than 8 mg/kg of the laevo-isomer caused stimulation of the activity. (+)-Amphetamine, 0.25 mg/kg, and (-)-amphetamine, 0.5 mg/kg, i.e. doses without any effect on locomotor activity of their own, caused virtually the same shift to the left of the dose-response curve for L-Dopa. (-)-Amphetamine, 4 mg/kg which per se caused depression of locomotor activity, caused a marked potentiation of the L-Dopa-induced stimulation of motor activity. Thus, there does not exist a close correlation between the L-Dopa-potentiating action of the amphetamines and their stimulating properties per se.

Amphetamine↗
PubMed1991

The effect of long-term treatment with deprenyl on basal and L-dopa evoked dopamine release in vitro from the corpus striatum of aged rats.

In the present experiment, male rats (15-17 months) were injected with deprenyl (0.25 mg/kg) three times per week for six months. At 21-23 months of age the male rats were sacrificed, the corpus striatum removed and superfused in vitro. Basal and evoked dopamine and DOPAC levels, as obtained with either two infusions of L-dopa (L-dopa/L-dopa) or L-dopa followed by amphetamine (L-dopa/AMPH), were measured from effluent superfusion samples and compared with values obtained from similarly aged animals treated identically with saline and from that obtained with young (2-4 months) animals. Treatment with deprenyl resulted in significantly greater basal dopamine and significantly lower basal DOPAC output compared with basal release levels from saline-treated aged rats and young animals. Responses to L-dopa/L-dopa or L-dopa/AMPH evoked dopamine and DOPAC release did not differ between deprenyl and saline-treated aged rats, however, both groups showed a significantly reduced response profile to these stimulations (L-dopa/L-dopa or L-dopa/AMPH) compared to that of young rats. These results indicate that the selective Type-B monoamine oxidase inhibitor, deprenyl, exerts a basic change in dopamine metabolism within the corpus striatum of aged rats resulting in an increase of endogenous dopamine and a decrease in endogenous DOPAC output.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1997

Glia protect fetal midbrain dopamine neurons in culture from L-DOPA toxicity through multiple mechanisms.

Mesencephalic glia produce soluble factors that protect dopamine neurons from L-DOPA toxicity. The chemical composition of these soluble factors is unknown. We investigated the protective effect against L-DOPA neurotoxicity in midbrain dopamine neurons of fractions of different molecular size of glia conditioned medium and candidate neuroprotective agents produced by glia including neurotrophic factors and antioxidants. Protective effects were evaluated according to the number of tyrosine hydroxylase immunoreactive cells, high affinity dopamine uptake and levels of quinones. Both fractions of glia conditioned medium, smaller and larger than 10kD, protected against L-DOPA, but the fraction of smaller molecular size, that contains small free radical scanvenger molecules, was more effective than the fraction of larger molecular size, that contains large neurotrophic peptides. Among the neurotrophic factors GDNF and BDNF totally prevented L-DOPA neurotoxicity, while NGF and bFGF were less effective. However, only NGF significantly reduced the elevation of quinones induced by L-DOPA. Ascorbic acid, at the concentration found in glia conditioned medium, provided partial protective effect against L-DOPA toxicity. Glutathione, had neurotrophic effects on untreated midbrain dopamine neurons and prevented the effect of L-DOPA. In conclusion, the protective effect against L-DOPA neurotoxicity by glia conditioned medium is mediated by several compounds including neurotrophic factors and small antioxidants.

Animals↗
PubMed1992

Motor function, graft survival and gliosis in rats with 6-OHDA lesions and foetal ventral mesencephalic grafts chronically treated with L-dopa and carbidopa.

In rats with a unilateral 6-OHDA lesion of the nigrostriatal pathway, foetal ventral mesencephalic grafts implanted into the 6-OHDA-lesioned striatum produced a reduction in apomorphine-induced contralateral rotation, and complete abolition of (+)-amphetamine-induced ipsilateral rotation. The graft-induced reduction of apomorphine and (+)-amphetamine-induced rotation was not affected by chronic 27 week administration of L-DOPA and carbidopa to rats receiving foetal grafts. TH-immunohistochemistry revealed greater than 96% loss of dopamine cells in the substantia nigra ipsilateral to the 6-OHDA lesion in all animals, but cell loss in the ipsilateral ventral tegmental area was more variable (21-46% of the intact side). TH-positive cells in the intact substantia nigra and ventral tegmental area were not affected by chronic treatment with L-DOPA and carbidopa. In the lesioned striatum of rats receiving sham grafts, no TH-positive cells or fibres were seen. In the 6-OHDA-lesioned striatum of animals receiving foetal grafts, many TH-positive cells were seen in the grafts and chronic treatment with L-DOPA and carbidopa did not reduce cell survival. GFA-P immunohistochemistry revealed that a unilateral 6-OHDA lesion followed by a sham graft was not associated with a reactive gliosis reaction in the striatum at the time of study (38 weeks after lesion surgery and 30 weeks after sham-graft), and treatment of such rats with L-DOPA and carbidopa was also without effect on glia. In contrast there was a marked gliosis in the striatum surrounding foetal grafts which was unaffected by chronic treatment with L-DOPA and carbidopa. The grafts themselves were surrounded by a rim of glial cells, and the glial density within the grafts was higher in animals receiving chronic L-DOPA and carbidopa treatment. However, there was no obvious relationship between the number of TH-positive cells within the grafts, or graft volume, and glial cell density within the grafts. These results suggest that long-term treatment with L-DOPA and carbidopa does not impair either the behavioural recovery produced by foetal ventral mesencephalic grafts in rats or the long-term survival of grafts as revealed by TH-immunohistochemistry. The presence of a foetal graft is associated with a reactive gliosis in the implanted striatum, which was not altered by long-term treatment with L-DOPA and carbidopa. However such treatment did result in an increase in glial density within the grafts themselves.

Animals↗
PubMed2001

18F-DOPA positron emission tomography for tumour detection in patients with medullary thyroid carcinoma and elevated calcitonin levels.

In spite of the availability of numerous procedures, diagnostic imaging of tumour manifestations in patients with medullary thyroid carcinoma and elevated calcitonin levels is often difficult. In the present study, the new procedure of fluorine-18 dihydroxyphenylalanine positron emission tomography (18F-DOPA PET) was compared with the established functional and morphological imaging methods. After evaluation of the normal distribution of 18F-DOPA, 11 patients with medullary thyroid carcinoma were examined using 18F-DOPA PET. Results of 18F-fluorodeoxyglucose (18F-FDG) PET, somatostatin receptor scintigraphy (SRS) and morphological tomographic imaging (CT/MRI) were available for all patients. All individual procedures were evaluated without reference to prior information. Data assessment for each patient was based on cooperation between experienced radiologists and specialists in nuclear medicine, who considered all the available findings (histological results, imaging, follow-up studies). This cooperation served as the gold standard against which the results of the individual procedures were evaluated. A total of 27 tumours were studied [three primary tumours (PT)/local recurrence (LR), 16 lymph node metastases (LNM) and eight organ metastases (OM)]. 18F-DOPA PET produced 17 true-positive findings (2 PT/LR, 14 LNM, 1 OM), 18F-FDG PET 12 (2 PT/LR, 7 LNM, 3 OM), SRS 14 (2 PT/LR, 8 LNM, 4 OM) and morphological imaging 22 (3 PT/LR, 11 LNM, 8 OM). The following sensitivities were calculated with respect to total tumour manifestations: 18F-DOPA PET 63%, 18F-FDG PET 44%, SRS 52%, morphological imaging 81%. Thus, the morphological imaging procedures produce the best overall sensitivity, but the specificity for PT/LR (55%) and LNM (57%) was low. With respect to lymph node staging, the best results were obtained with 18F-DOPA PET. 18F-DOPA PET is a new functional imaging procedure for medullary thyroid carcinoma that seems to provide better results than SRS and 18F-FDG PET. Moreover, the data indicate that no single procedure provides adequate diagnostic certainty. Therefore, 18F-DOPA PET is a useful supplement to morphological diagnostic imaging, improving lymph node staging and enabling a more specific diagnosis of primary tumour and local recurrence.

Aged↗
PubMed2006

L-DOPA inhibits depolarization-induced [3H]GABA release in the dopamine-denervated globus pallidus of the rat: the effect is dopamine independent and mediated by D2-like receptors.

The effect of L-DOPA on [(3)H]GABA release in slices of globus pallidus from 6-OHDA-lesioned rats was studied. Release was evoked by high (15 mM) K(+). The lesion reduced dopamine content and dopamine synthesized from L-DOPA. The inhibition of DOPA decarboxylase blocked dopamine synthesis. Endogenous dopamine released by high K(+) inhibited [(3)H]GABA release in normal but not in lesioned slices. L-DOPA inhibited (IC(50) = 0.44 microM) evoked [(3)H]GABA release. The inhibition was via D2-like receptors but not mediated by dopamine. The turning behavior induced by L-DOPA methyl ester (25 mg/kg, i.p.) was not abolished by the DOPA decarboxylase inhibitor 3-hydroxybenzylhydrazine but in this condition it was abolished by sulpiride. Results suggest that L-DOPA acting as D2-like agonist inhibits GABA release in the rat globus pallidus and induces turning behavior in rats with unilateral lesions of the dopamine innervation. L-DOPA could control Parkinson's disease symptoms acting not only as dopamine precursor but also by itself.

Animals↗
PubMed1998

Modulatory effects of L-DOPA on D2 dopamine receptors in rat striatum, measured using in vivo microdialysis and PET.

Putative modulatory effects of L-3,4-dihydroxyphenylalanine (L-DOPA) on D2 dopamine receptor function in the striatum of anaesthetised rats were investigated using both in vivo microdialysis and positron emission tomography (PET) with carbon-11 labelled raclopride as a selective D2 receptor ligand. A single dose of L-DOPA (20 or 100mg/kg i.p.) resulted in an increase in [11C]raclopride binding potential which was also observed in the presence of the central aromatic decarboxylase inhibitor NSD 1015, confirming that the effect was independent of dopamine. This L-DOPA evoked D2 receptor sensitisation was abolished by a prior, long-term administration of L-DOPA in drinking water (5 weeks, 170mg/kg/day). In the course of acute L-DOPA treatment (20mg/kg), extracellular GABA levels were reduced by approximately 20% in the globus pallidus. It is likely that L-DOPA sensitising effect on striatal D2 receptors, as confirmed by PET, may implicate striato-pallidal neurones, hence a reduced GABA-ergic output in the projection area. Since the L-DOPA evoked striatal D2 receptor supersensitivity habituates during long-term treatment, the effects reported here may contribute to the fluctuations observed during chronic L-DOPA therapy in Parkinson's disease.

Animals↗