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At least 793 records · Page 44Linked to original sources
PubMed1991

L-dopa stimulates the release of [3H]gamma-aminobutyric acid in the basal ganglia of 6-hydroxydopamine lesioned rats.

L-DOPA stimulated the K(+)-induced [3H]GABA (gamma-aminobutyric acid) release from slices of substantia nigra pars reticulata, entopeduncular nucleus, globus pallidus and caudate-putamen isolated from the ipsilateral side of 6-hydroxydopamine-lesioned rats, but the release from ipsilateral subthalamic slices was not affected. In substantia nigra, L-DOPA stimulation (EC50 = 1 microM) of [3H]GABA release was dose-dependently blocked (IC50 = 0.1 microM for the stimulation caused by 10 microM L-DOPA) by the D1 antagonist SCH 23390, but was not affected by (-)-sulpiride, a D2 antagonist. SCH 23390 also blocked the stimulation in the other nuclei. The DOPA decarboxylase inhibitor NSD-1015 (500 microM) did not prevent the stimulation induced by L-DOPA in all of the studied nuclei. The results suggest that L-DOPA is able to activate D1 receptors located on the terminals of striatal projections via the dopamine formed by a decarboxylation mediated by an NSD-1015-resistant enzyme. Activation of the presynaptic D1 receptors results in stimulation of GABA release.

Animals↗
PubMed1994

Outflow of dopamine and noradrenaline originating from L-dopa and L-threo-DOPS in rat renal tissues.

1. The present study has examined the formation and outflow of newly-formed dopamine (DA) and noradrenaline (NA) in slices of the renal cortex of rats given L-beta-3,4-dihydroxyphenylalanine (L-DOPA) (10, 30 or 100 mg/kg i.p.) and L-threo-3-(3,4-dihydroxyphenyl)serine (L-DOPS) (10, 30 or 100 mg/kg i.p.), respectively. The outflow of 3,4-dihydroxyphenylacetic acid (DOPAC) and 3,4-dihydroxyphenylglycol (DOPEG), the deaminated metabolites of DA and NA, respectively, was also measured. 2. The accumulation of both newly-formed DA and DOPAC in renal tissues after the administration of L-DOPA was found to be dose dependent; after 30 or 100 mg/kg L-DOPA, the levels of both DA and DOPAC were, respectively, 3- and 20-fold those observed after the administration of 10 mg/kg L-DOPA. The outflow of DA and DOPAC in kidney slices of rats treated with L-DOPA was found to progressively decline with time and reflected the DA and DOPAC tissue contents. The rate constant (k) for DOPAC efflux (k = 0.0097) was higher (P < 0.01) than that for DA efflux (k = 0.0033) and did not depend on the dose of L-DOPA. DOPAC/DA perifusate ratios were 2-fold those occurring in the tissues. 3. The levels of NA in renal tissues of rats given 30 and 100 mg/kg L-DOPS were, respectively, 3- and 6-fold those observed after the administration of 10 mg/kg L-DOPS. The administration of L-DOPS was also found to be accompanied by the accumulation in renal tissues of DOPEG; this was, however, not dose dependent.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

The effect of chronic L-dopa treatment on the recovery of motor function in 6-hydroxydopamine-lesioned rats receiving ventral mesencephalic grafts.

The effect of treatment for 5 weeks with L-DOPA (200 mg/kg/24 h) plus carbidopa (25 mg/kg/24 h) on the behavioral recovery produced by rat fetal ventral mesencephalon grafts implanted into the striatum of 6-hydroxydopamine-lesioned rats was assessed. Animals with unilateral 6-hydroxydopamine lesions of the nigrostriatal pathway and a sham graft (Group A) showed persistent high rates of rotation in response to the administration of apomorphine (0.5 mg/kg, s.c.) (contralateral rotation) or (+)-amphetamine (5 mg/kg, i.p.) (ipsilateral rotation). Treatment of sham-grafted animals with L-DOPA plus carbidopa had no effect on the rate of rotation to apomorphine or (+)-amphetamine (Group B). The proportion of animals showing marked stereotypy following apomorphine administration was greater in sham-grafted animals receiving L-DOPA and carbidopa than in sham-grafted animals alone. Animals receiving unilateral 6-hydroxydopamine lesions followed by a fetal graft (Group C) showed a reduction in apomorphine-induced contralateral rotation and a complete reversal of (+)-amphetamine-induced ipsilateral rotation when assessed 6 weeks later. The reductions in apomorphine- and (+)-amphetamine-induced rotational behaviour produced by the fetal graft in animals with a 6-hydroxydopamine lesion were not altered by treatment with L-DOPA plus carbidopa (Group D). The proportion of animals showing marked apomorphine-induced stereotypy did not change significantly in either group over time. In rats with a unilateral 6-hydroxydopamine lesion receiving fetal dopamine grafts, treatment with high doses of L-DOPA and carbidopa for 5 weeks does not have a detrimental effect on the functional activity of the grafts as assessed by reduction of apomorphine- and (+)-amphetamine-induced motor asymmetry. The continuation of L-DOPA therapy may not adversely affect fetal graft survival and growth in patients with Parkinson's disease.

Animals↗
PubMed1986

The sialagogue response of striatal dopamine receptors to L-dopa is not influenced by castration or chronic estrogen treatment.

The secretory response of salivary glands to L-dopa, elicited by stimulation of dopamine receptors in the striatum and the circling behavior induced by apomorphine in animals bearing a unilateral kainic lesion of the entopeduncular nucleus, was studied in intact and ovariectomized female rats. Castration did not modify the sialagogue response to L-dopa, while the turning behavior was significantly increased. Daily administration of 17-beta-estradiol benzoate during 7 days to ovariectomized rats decreased the circling activity to the level of intact female rats, while the salivary secretion to L-dopa was unaffected. The above findings suggest that the sialagogue response induced by L-dopa may be due to the interaction of this agonist with D1 striatal receptors, whose activity is not influenced by estrogens. However, we cannot rule out any possible alteration in the metabolism and/or presynaptic conversion of L-dopa to dopamine by estrogen treatment. The changes in turning behavior may be attributed to an antidopaminergic effect of estrogens and/or, like L-dopa, to modifications in the metabolism of apomorphine induced by the hormone.

Animals↗
PubMed1986

[18F]fluoro-L-dopa for the in vivo study of intracerebral dopamine.

6-[18F]Fluoro-L-dopa was designed to trace the dopamine metabolism in the brain with positron tomography. 6-[18F]Fluoro-L-dopa resembles natural L-dopa biochemically, it crosses the blood-brain barrier with the similar kinetics, it is decarboxylated by dopa decarboxylase and is stored intraneuronally in vesicles. In addition the rate of O-methylation of 6-[18F]fluoro-L-dopa by catechol-O-methyl transferase is only 1/4 of that of natural L-dopa. The low rate of O-methylation, especially in the periphery, is particularly beneficial for PT investigations of the brain. The radiotracer has been synthesized using a variety of electrophilic fluorinating agents.

Animals↗
PubMed1991

New rapid analysis method demonstrates differences in 6-[18F] fluoro-L-dopa plasma input curves with and without carbidopa and in hemi-MPTP lesioned monkeys.

Kinetic modeling of the PET tracer 6-[18F]fluoro-L-dopa ([18F]Dopa), used to measure presynaptic dopamine function, requires the accurate determination of the plasma input curve. We have developed a new method that uses alumina extraction preceded by cation and anion exchange resins to determine the parent compound, [18F]Dopa and its critical metabolite 3-O-methyl-6-[18F]fluoro-L-dopa. Using this method we found that carbidopa increases the plasma input of [18F]Dopa while decreasing the rate of metabolite formation, and that previous drug treatment can significantly effect [18F]Dopa metabolism.

Animals↗
PubMed1989

Feasibility study of fluorine-18 labeled dopa for melanoma imaging.

Feasibility of fluorine-18 labeled L-dopa for melanoma imaging was investigated. In B16 melanoma-bearing mice given 2-[18F]fluoro-L-dopa, the radioactivity in the B16 decreased for the first 60 min and then remained constant, while all other tissues investigated decreased with time. High tumor uptake ratios for all other tissues except for the pancreas were obtained at 120 min. 6-[18F]Fluoro-L-dopa showed a similar tissue distribution. However, the B16 uptake was about half that value for the 2-fluoro analogue. A higher incorporation rate of 2-[18F]fluoro-L-dopa into the acid-precipitable fraction of the melanoma also showed that the 2-[18F]fluoro-L-dopa was a preferable melanin precursor. Among the four kinds of non-melanoma tumors in mice or rats three tumors showed an uptake of 2-[18F]fluoro-L-dopa similar to the B16 at 60 min. However, larger melanoma-to-tissue uptake ratios were observed when compared to non-melanoma tumors.

Animals↗
PubMed2004

The neurobehavioral changes induced by bilateral rotenone lesion in medial forebrain bundle of rats are reversed by L-DOPA.

Rotenone (an inhibitor of mitochondrial complex I) has been proposed as a model of Parkinson's disease (PD) as it induces nigrostriatal degeneration associated with alpha-synuclein inclusions. So far, only peripherally administered rotenone has been used as a model of PD. There has not been any investigation on the neurobehavioral changes induced by bilateral lesions of dopaminergic neurons by rotenone in rats. In the present study, rotenone (3 microg) was administered bilaterally stereotaxically into the medial forebrain bundle (MFB) to produce parkinsonian symptoms. Behavioural and biochemical data showed a strong increase in catalepsy, a decrease in locomotor activity and a significant depletion of dopamine levels in the striatum as compared to sham-lesioned animals. If the locomotor deficits are caused by the depletion of dopaminergic neurons, then L-DOPA should counteract motor deficits because L-DOPA therapy reverses mostly all motor deficits in human Parkinsonian patients. To examine the effectiveness of L-DOPA in reversing the motor deficit in rats, two different doses of L-DOPA (5 and 10 mg/kg) in combination with the peripheral amino acid decarboxylase inhibitor benserazide were daily administrated intraperitonially for a period of 31 days lesioned animals. L-DOPA plus benserazide counteracted catalepsy dose-dependently and increased locomotor activity. The results indicate that rotenone infused into the MFB destroys dopaminergic neurons, induces pakinsonian symptoms that are reversed by the clinically effective anti-parkinsonian drug L-DOPA. Therefore, sterotaxically infused rotenone may be useful for screening drugs for the treatment of PD.

Analysis of Variance↗
PubMed2003

Pharmacokinetics of L-dopa in plasma and extracellular fluid of striatum in common marmosets.

L-3, 4-Dihydroxyphenylalanine (L-dopa) has been widely used for the treatment of Parkinson's disease (PD), but its pharmacokinetics in the striatum have hardly been investigated, especially in primates. In this study, we examined the concentration of L-dopa in plasma and in the extracellular fluid (ECF) of the striatum in common marmosets using microdialysis and high-performance liquid chromatography (HPLC) with electrochemical detection. With a clinically therapeutic dosage of L-dopa/benserazide (20/5 mg/kg, p.o.), the t(max) of L-dopa was 30 min in plasma and 60-90 min in ECF of striatum. Mean C(max) was 20.3 microM in plasma and 442.9 nM in ECF of striatum, which is about 2.2% of that in plasma. The L-dopa concentration in ECF is much lower than those previously applied during in vivo studies for L-dopa toxicity.

Animals↗
PubMed2006

The novel adenosine A2a antagonist ST1535 potentiates the effects of a threshold dose of l-dopa in unilaterally 6-OHDA-lesioned rats.

Adenosine A2a antagonists can modulate dopamine-mediated motor behaviours, however, their ability to induce rotational behaviour in 6-hydroxydopamine (6-OHDA)-lesioned rats and to potentiate the effects of l-dopa differs. We now report on the effects of the novel A2a antagonist ST1535 on rotational responses in this model. When administered alone, ST1535 (2.5-40 mg/kg po) enhanced exploratory behaviour and produced a dose-related increase in ipsilateral rotation in rats with a unilateral 6-OHDA lesion of the nigro-striatal pathway. Administration of ST1535 (40 mg/kg po) in combination with a high dose of l-dopa (12 mg/kg ip) caused marked contraversive rotation but did not alter the rotational response produced by l-dopa alone. In contrast, when administered in combination with l-dopa (7 mg/kg ip) that alone produced a submaximal circling response, ST1535 enhanced the intensity and duration of rotation. These results suggest that ST1535 is able to alter dopamine-mediated behaviour when given alone and to potentiate the effects of submaximal doses of l-dopa. ST1535 may be useful in the treatment of Parkinson's disease and effective in reducing the use of l-dopa.

Adenine↗
PubMed2004

Validation of the l-dopa-induced dyskinesia in the 6-OHDA model and evaluation of the effects of selective dopamine receptor agonists and antagonists.

Current treatments for Parkinson's disease (PD) rely on a dopamine replacement strategy and are reasonably effective, particularly in the early stages of the disease. However, chronic dopaminergic therapy is limited by the development of a range of side effects, including dyskinesia. This has led to a search for alternative treatments. Transplantation of foetal nigral dopamine neurons is a rational approach and many studies have shown that it can improve motor functions in parkinsonian rodents, primates and man. Recently, however, two clinical trials have reported an exacerbation of dyskinesias in some transplanted patients, raising concerns about the safety of the transplantation strategy. To study this issue, we have reproduced the l-dopa-induced dyskinesia model developed by Cenci et al. [M.A. Cenci, C.S. Lee, A. Bjorklund, l-DOPA-induced dyskinesia in the rat is associated with striatal overexpression of prodynorphin- and glutamic acid decarboxylase mRNA, Eur. J. Neurosci. 10 (1998) 2694-2706] in the rat. We find that their abnormal involuntary movements rating scale is easy to apply and consistent to use. Moreover, the Schallert forelimb placing test has been used to assess l-dopa-induced recovery of function and we find that the rats continue to show good recovery on this test, even while they are exhibiting abnormal dyskinetic side effects. To further evaluate this model, we have studied the effects of selective dopamine receptor antagonists and agonists for D1, D2 and D3 receptors. Antagonists of all three receptors are able to block the l-dopa-induced dyskinesia without interfering with the beneficial effects of l-dopa on the placing test. This indicates that the effects of chronic l-dopa on recovery of parkinsonian symptoms and on induction of dyskinetic side effects can be dissociated, which may provide the basis for developing novel combination treatments, e.g. using grafts while blocking the unwanted adverse effects of the drugs.

Animals↗
PubMed2004

Recovery, innervation profile, and contractile properties of reinnervating fast muscles following postnatal nerve crush and administration of L-Dopa.

Muscle and peripheral nerve development is clearly dependent on their interaction during early postnatal life. Furthermore, muscle or peripheral nerve activity plays a crucial role in the maturation of the neuromuscular system. In this study, the possible involvement of spinal catecholamines in fast muscle recovery after nerve crush is investigated. Sciatic nerve crush was performed on the fourth to fifth postnatal day. Following that, L-Dopa was administered daily [150 mg/kg body weight (BW)] i.p., until the 21st day after birth. L-Dopa-treated and control groups were then examined electrophysiologically for the contractile properties of extensor digitorum longus (EDL) muscles. Two experimental groups were included in this study: (i) rats whose sciatic nerve was crushed and were treated with L-Dopa and (ii) rats whose sciatic nerve was crushed and were not treated with L-Dopa. The number of motoneurones for both groups was estimated by HRP retrograde labelling. The results showed that the operated L-Dopa-treated EDL muscles of the rats exhibited limited atrophy, slighter impairment of maximal tetanic tension, lesser resistance to fatigue, and polyneuronal innervation than the controls. The number of motoneurones was the same for the operated muscles in both groups of animals and was within the normal ranges. Our findings suggest that catecholamines of locomotion during the early stages of development may have a beneficial effect on fast muscle recovery following nerve crush. The action of L-Dopa is attributed to noradrenaline, which acts through descending spinal noradrenergic pathways, possibly via a(2)-adrenergic receptors at the spinal level.

Animals↗
PubMed2006

Increases in transepithelial vectorial Na+ transport facilitates Na+-dependent L-DOPA transport in renal OK cells.

The present study evaluated the hypothesis of whether increases in vectorial Na+ transport translate into facilitation of Na+-dependent L-DOPA uptake in cultured renal epithelial tubular cells. Increases in vectorial Na+ transport were obtained in opossum kidney (OK) cells engineered to overexpress Na+-K+-ATPase after transfection of wild type OK cells with the rodent Na+-K+-ATPase alpha1 subunit. The most impressive differences between wild type and transfected OK cells are that the latter overexpressed Na+-K+-ATPase accompanied by an increased activity of the transporter. Non-linear analysis of the saturation curve for l-DOPA uptake revealed a Vmax value (in nmol mg protein/6 min) of 62 and 80 in wild type and transfected cells, respectively. The uptake of a non-saturating concentration (0.25 microM) of [14C]-L-DOPA in OK-WT cells was not affected by Na+ removal, whereas in OK-alpha1 cells accumulation of [14C]-L-DOPA was clearly dependent on the presence of extracellular Na+. When Na+ was replaced by choline, the inhibitory profile of neutral l-amino acids, but not of basic and acidic amino acids, upon [14C]-L-DOPA uptake in both cell types, was significantly greater than that observed in the presence of extracellular Na+. It is concluded that enhanced ability of OK cells overexpressing Na+-K+-ATPase to translocate Na+ from the apical to the basal cell side correlates positively with their ability to accumulate L-DOPA, which is in agreement with the role of Na+ in taking up the precursor of renal dopamine.

Animals↗
PubMed2005

Enhanced striatal opioid receptor-mediated G-protein activation in L-DOPA-treated dyskinetic monkeys.

Long-term l-3,4-dihydroxyphenylalanine (L-DOPA) treatment in Parkinson's disease leads to dyskinesias in the majority of patients. The underlying molecular mechanisms for L-DOPA-induced dyskinesias (LIDs) are currently unclear. However, the findings that there are alterations in opioid peptide mRNA and protein expression and that opioid ligands modulate dyskinesias suggest that the opioid system may be involved. To further understand its role in dyskinesias, we mapped opioid receptor-stimulated G-protein activation using [35S]guanylyl-5'-O-(gamma-thio)-triphosphate ([35S]GTPgammaS) autoradiography in the basal ganglia of normal and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned squirrel monkeys administered water or L-DOPA. Subtype-selective opioid receptor G-protein coupling was investigated using the mu-opioid agonist [D-Ala, N-Me-Phe, Gly-ol]-enkephalin, delta-agonist SNC80 and kappa-agonist U50488H. Our data show that mu-opioid receptor-mediated G-protein activation is significantly enhanced in the basal ganglia and cortex of L-DOPA-treated dyskinetic monkeys, whereas delta- and kappa-receptor-induced increases were limited to only a few regions. A similar pattern of enhancement was observed in both MPTP-lesioned and unlesioned animals with LIDs suggesting the effect was not simply due to a compromised nigrostriatal system. Opioid receptor G-protein coupling was not enhanced in non-dyskinetic L-DOPA-treated animals, or lesioned monkeys not given L-DOPA. The increases in opioid-stimulated [35S]GTPgammaS binding are directly correlated with dyskinesias. The present data demonstrate an enhanced subtype-selective opioid-receptor G-protein coupling in the basal ganglia of monkeys with LIDs. The positive correlation with LIDs suggests this may represent an intracellular signaling mechanism underlying these movement abnormalities.

Animals↗
PubMed2004

Antinociceptive mechanism of L-DOPA.

The mechanism of L-DOPA for antinociception was investigated. Nociceptive behaviors in mice after an intrathecal (i.t.) administration of substance P were evaluated. L-DOPA (i.t.) dose-dependently attenuated the substance P-induced nociceptive behaviors. Co-administration of benserazide (i.t.), a DOPA decarboxylase inhibitor, abolished the antinociceptive effect of L-DOPA. The L-DOPA-induced antinociception was antagonized by sulpiride, a D2 blocker, but not by SCH 23390, a D1 blocker. These results suggest that L-DOPA relieves pain after conversion to dopamine, with the dopamine sedating pain transmission by way of the dopamine D2 receptor.

Animals↗
PubMed1998

Effects of repeated administration of l-DOPA and apomorphine on circling behavior and striatal dopamine formation.

We tested the circling response to l-DOPA and apomorphine administration in rats with unilateral 6-hydroxydopamine (6-OHDA) lesions of the substantia nigra. Rats demonstrated a progressively diminished circling response when l-DOPA-carbidopa was repeatedly administered at 120 min intervals. This decreasing response was not present when apomorphine was administered under the same conditions. We also perfused l-DOPA directly into the striatum in vivo of rats with an ipsilateral 6-OHDA nigrotomy at 60 min intervals and monitored striatal dopamine levels with the technique of brain microdialysis. Dopamine formation increased from the first to the fifth trial. This may be secondary to the decrease in uptake sites which accompanies the loss of striatal dopamine nerve terminals. We postulate that the continued presence of dopamine at striatal receptor sites conditions a short-term loss of dopamine receptor sensitivity and a consequent decreased circling response. The observation that desensitization (as measured by decreasing circling) was not present following repeated apomorphine administration may be attributable to its shorter duration of action. We also perfused l-DOPA into the striatum of normal rats and noted a progressive decrease in striatal dopamine levels from the first to the fifth trial. Since this occurred following direct administration of l-DOPA into the striatum, the decrease could not be accounted for by peripheral pharmacodynamics or bioavailability of l-DOPA in the striatum. Since this decrease in dopamine formation was seen only in the normal striatum, its relevance to the diminished behavioral response is unclear.

Animals↗
PubMed1999

Inactivation of creatine kinase induced by dopa and dopamine in the presence of ferrylmyoglobin.

We investigated the effect of dopa and dopamine on creatine kinase (CK) activity in the presence of ferrylmyoglobin (ferrylMb). CK was sharply inhibited by dopa and dopamine in the presence of ferrylMb. Dopa and dopamine markedly promoted the reduction of ferrylMb to metmyoglobin (metMb). The semiquinone from dopa and dopamine may be involved in CK inactivation. During inactivation of the enzyme, both kinetic parameters Vmax and Km changed. In addition, reduced glutathione restored the activity of CK at an early stage. These results suggest that inactivation of CK is dominantly due to oxidation of sulfhydryl (SH) groups of the enzyme. Other catechols, such as adrenaline and noradrenaline, little inactivated CK activity, whereas they promoted the reduction of ferrylMb to metMb. Other SH enzymes, including alcohol dehydrogenase (ADH) and glyceraldehyde-3-phosphate dehydrogenase (GAPDH), were inactivated to a lesser extent by dopa and dopamine in the presence of ferrylMb. Adrenaline and noradrenaline did not significantly prevent the inactivation of ADH and very slightly inhibited GAPDH. These results suggest that dopa and dopamine act as prooxidants to inactivate SH enzymes in the presence of ferrylMb.

Alcohol Dehydrogenase↗
PubMed2000

MK801 influences L-DOPA-induced dopamine release in intact and hemi-parkinson rats.

In vivo microdialysis was used to investigate the influence of dizocilpine (MK801) on basal and levodopa (L-DOPA)-induced extracellular dopamine levels in striatum and substantia nigra of intact and 6-hydroxydopamine-lesioned rats. In lesioned rats, extracellular dopamine was decreased in striatum but not in substantia nigra. L-DOPA (25 mg/kg i.p. after benserazide 10 mg/kg i. p.) increased the dopamine levels in striatum and substantia nigra of intact and dopamine-depleted rats. This increase was significantly higher in dopamine-depleted compared to intact striatum. Pretreatment with MK801 (0.1 and 1.0 mg/kg i.p.) dose-dependently attenuated the L-DOPA-induced dopamine release in substantia nigra of intact rats. In dopamine-depleted striatum, MK801 enhanced L-DOPA-induced dopamine release. The present results indicate that the influence of MK801 on L-DOPA-induced dopamine release in striatum and substantia nigra depends on the integrity of the nigrostriatal pathway. In Parkinson's disease, NMDA receptor antagonists could be beneficial by enhancing the therapeutic efficacy of L-DOPA at the level of the striatum.

Adrenergic Agents↗