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PubMed1999

Effects of co-administration of anticonvulsant and putative anticonvulsive agents and sub/suprathreshold doses of L-dopa upon motor behaviour of MPTP-treated mice.

The effects of co-administration of the dopamine precursor, L-Dopa, with anticonvulsant and putative anticonvulsive agents upon the motor activity of hypoactive MPTP-treated C57 BL/6 mice were measured in six experiments. In each case, MPTP (2 x 40 mg/kg, s.c., separated by a 24-hr interval) was administered four to six weeks prior to behavioural testing. Thus, the effects of these agents combined with either a single acute, subthreshold dose (5 mg/kg, s.c.) of L-Dopa, or, with chronically-administered, suprathreshold doses (20 mg/kg, s.c.) of L-Dopa were studied. In the former, lamotrigine, FCE 26743 and L-Deprenyl, injected 60 min before subthreshold L-Dopa (5 mg/kg), each induced an antiparkinsonian action in MPTP-treated mice that consisted of dose-specific, as opposed to dose-related, elevations of locomotion and rearing behaviour. In the latter, lamotrigine (all three measures of activity at 3 mg/kg), FCE 26743 (locomotion and total activity at 3; rearing at 1 and 3 mg/kg) and L-Deprenyl (locomotion and total activity at 1 and 3mg/kg), but not phenytoin (neither at 1 nor 3 mg/kg), reinstated the motor activity-stimulating effects of the threshold dose of L-Dopa (20 mg/kg) in L-Dopa-tolerant, MPTP-treated mice. Neurochemical analyses confirmed severe DA depletions in MPTP-treated mice. Since neither lamotrigine, FCE 26743 nor L-Deprenyl, nor subthreshold L-Dopa, by themselves increased the motor behaviour of MPTP-treated mice, a synergistic effect of the co-administration is concluded. Further, since the suprathreshold dose of L-Dopa by itself failed to stimulate motor activity in the MPTP mice following chronic (25 daily injections) administrations of the compound, it is suggested that a restorative effect, in combination with lamotrigine, FCE 26743 or L-Deprenyl was evidenced. The potential therapeutic benefits of anticonvulsant or putative anticonvulsive compounds for parkinsonian symptoms are discussed.

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

PubMed2001

Co-administration of memantine and amantadine with sub/suprathreshold doses of L-Dopa restores motor behaviour of MPTP-treated mice.

The antiparkinsonian effects of the uncompetitive NMDA antagonists, memantine, amantadine and MK-801, in combination with an acute subthreshold dose of L-Dopa (5 mg/kg) in drug-naive MPTP-treated mice or a suprathreshold dose (20 mg/kg) in L-Dopa tolerant MPTP-treated mice were investigated. In the former case, memantine (locomotion: 3 mg/kg; rearing: 1 mg/kg) and amantadine (locomotion and rearing: 10 mg/kg) injected 60 min before the subthreshold dose of L-Dopa (5 mg/kg), each induced an antiparkinsonian action in hypokinesic MPTP-treated mice that consisted of dose-specific, as opposed to dose-related, elevations of locomotion and rearing behaviour. At the same time, higher doses of memantine reduced further the rearing (10 and 30 mg/kg) and locomotor (30mg/kg) behaviour of the MPTP-treated mice. MK-801 plus L-Dopa elevated locomotion (0.1 mg/kg) but reduced rearing at the 0.3 mg/kg dose. In control, saline-treated mice, memantine (3, 10 and 30 mg/kg) and MK-801 (0.1 and 0.3 mg/kg) increased locomotor behaviour but decreased rearing behaviour, while amantadine produced no effects. Memantine increased locomotor (1 and 3 mg/kg, s.c.; 1 mg/kg dose restored activity) and rearing (0.3 and 3 mg/kg) activity in the L-Dopa tolerant MPTP-treated mice, whereas amantadine (3 and 10 mg/kg) restored both locomotor (30 mg/kg significantly increased locomotion but did not restore the activity level) and rearing (3 mg/kg only) activity. MK-801 (0.1 and 0.3 mg/kg, s.c.) also increased significantly locomotor activity of L-Dopa-tolerant MPTP mice although the antikinetic action was not reversed, thereby precluding a restorative effect of the compound. These results, demonstrating both a synergistic and a restorative effect of the NMDA antagonists in coadministration with L-Dopa, demonstrate a putative antiparkinson action by these compounds in a functional animal model that incorporates the "wearing-off" complications of L-Dopa administration in the disorder.

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

PubMed2004

Temporal administration of entacapone with slow release L-dopa: pharmacokinetic profile and clinical outcome.

Entacapone is a specific, peripherally acting catechol- O-methyltransferase (COMT) inhibitor that prevents peripheral degradation of L-dopa, thus improving its bioavailability. Entacapone is known to have pharmacokinetics similar to standard L-dopa but not to that of controlled-release (CR) L-dopa. The aim was to determine whether delayed entacapone administration may prolong CR L-dopa half-life in comparison to the co-administration modality. We compared plasma L-dopa concentrations after co-administration of CR L-dopa and entacapone or after administration of CR and a delayed (30 and 90 minutes) entacapone dose in 10 parkinsonian patients. The area under the concentration-time curve and other pharmacokinetic parameters were not changed by the delayed administration of entacapone. Different temporal modalities of entacapone administration had similar effects on CR L-dopa pharmacokinetics and on L-dopa-induced clinical improvement.

Aged↗

PubMed1979

The effects of L-dopa on dorsal horn cell responses to innocuous skin stimulation.

The effects of L-DOPA on responses of dorsal horn cells to innocuous mechanical skin stimulation were studied. Following intravenous administration of L-DOPA (10--40 mg/kg) to cats with intact spinal cords, dorsal horn cells, which could be activated by only innocuous or innocuous and noxious stimuli, demonstrated increased reponses manifested by an increase in the average number of spikes per stimulus, increased receptive field size and occasional changes in adequate stimuli. When cats with acute cord transections were studied, L-DOPA increased the responses of cells located in lamina 4 and those cells which responded only to innocuous stimuli; cells which responded to noxious stimuli and those located in other laminae had depressed responses following L-DOPA administration. The inhibitory effects of L-DOPA were in part abolished, in spinal cats, by pretreatment with parachlorophenylalanine, a serotonin depletor. Studies of dorsal cells in chronic spinal cats indicated that the effects of L-DOPA were largely dependent on functioning terminals of descending suprasegmental pathways. The conclusion was reached that descending noradrenergic pathways, indirectly, cause an increase in transmission from cutaneous afferents to dorsal horn cells and that some of the inhibitory effects of L-DOPA described by others are a manifestation of L-DOPA interactions with inhibitory serotonergic systems.

Animals↗

PubMed1993

L-dopa induces Ca(2+)-dependent and tetrodotoxin-sensitive release of endogenous glutamate from rat striatal slices.

L-DOPA (10-1000 microM) concentration-dependently released glutamate (Glu) from superfused rat striatal slices. D-DOPA and dopamine (300 microM) produced no effects. The L-DOPA-induced release of Glu was not affected by 3-hydroxybenzylhydrazine (20 microM), an L-aromatic amino acid decarboxylase inhibitor. L-DOPA methyl ester (200 microM), a selective L-DOPA antagonist, antagonized the effect of L-DOPA in a competitive manner. Ca2+ deprivation and tetrodotoxin decreased L-DOPA (300 microM)-induced release of Glu. These findings indicate that L-DOPA induces a transmitter-like release of Glu via activation of a recognition site for itself.

Animals↗

PubMed1996

Monoamine oxidase-dependent metabolism of dopamine in the striatum and substantia nigra of L-DOPA-treated monkeys.

The effects of monoamine oxidase (MAO) inhibitors on the metabolism of dopamine synthesized from exogenous L-DOPA were investigated in the striatum and substantia nigra of squirrel monkeys. Administration of a single dose of L-DOPA (methyl ester, 40 mg/kg, i.p.) caused a significant increase in the levels of dopamine, 3-4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) and in the DOPAC/dopamine ratio in the putamen, caudate and substantia nigra. These changes were more pronounced in the substantia nigra than in the striatum and within the striatum of L-DOPA-treated monkeys, levels of dopamine and its metabolites were higher in the putamen than in the caudate nucleus. When L-DOPA treatment was preceded by the injection of clorgyline or deprenyl at a concentration (1 mg/kg) which selectively inhibited MAO A or MAO B, respectively, striatal dopamine was increased while the striatal DOPAC and HVA levels and DOPAC/dopamine ratio were significantly reduced as compared to the values obtained with 1-DOPA alone. The two MAO inhibitors also counteracted the increase in the DOPAC and HVA levels and DOPAC/dopamine ratio induced by L-DOPA in the substantia nigra. Thus, both MAO A and MAO B contribute to the metabolism of dopamine when higher levels of this neurotransmitter are generated from L-DOPA in the squirrel monkey. The extent of reduction of dopamine catabolism (as assessed by the decrease in DOPAC and HVA levels) in the striatum and substantia nigra was similar with clorgyline and deprenyl even if the ratio MAO A/MAO B was approximately 1 to 10. This indicates that, though catalyzed by both MAO A and MAO B, dopamine deamination following treatment with L-DOPA preferentially involves MAO A.

Animals↗

PubMed1981

Studies on the mechanisms of L-dopa-induced salivary secretion.

Systemic administration of L-dopa and dopamine elicited a marked and sustained secretory response in the rat's submaxillary glands. These effects were blocked by pretreatment with phentolamine plus propranolol. Acute unilateral sympathectomy (decentralization or denervation) reduced the response to L-dopa by about 41-48%. But it left unchanged the secretory response to dopamine. Chemical sympathectomy by hexamethonium caused a similar reduction (45%) in the secretory response to L-dopa while parasympathectomy was unable to modify the salivary secretion caused by L-dopa or dopamine. Pretreatment with haloperidol reduced the salivary secretion to L-dopa in normal animals (unoperated glands), while the response to dopamine was unaffected. On the other hand, haloperidol did not alter the salivary response to L-dopa in animals with surgical sympathectomy (denervation) as compared to the same animals treated with L-dopa alone. From this study we conclude that the salivary secretion induced by L-dopa is mediated by both central and peripheral mechanisms. Dopaminergic receptors may be involved in the central effect and alpha- and beta-receptors in the peripheral response.

Animals↗

PubMed1983

Mediation and mechanisms of the hypotensive effect of L-dopa in the sea-gull: Larus argentatus.

We have investigated the mediation of the hypotensive action of L-DOPA after peripheral DOPA decarboxylase (DC) inhibition in the sea-gull, Larus argentatus. Vagotomy prevented the bradycardia and hypotension occurring after L-DOPA in birds pretreated with an inhibitor of peripheral DC. L-DOPA alone, given to intact birds, resulted in a slight increase in blood pressure (BP), accompanied by a tendency to bradycardia. Spinal transection in combination with vagotomy reversed the bradycardia and reinforced the increase in BP seen in intact birds after L-DOPA. The dopamine receptor antagonist spiroperidol did not alter the hypotension and bradycardia after L-DOPA in birds pretreated with a peripherally acting DC inhibitor. Yohimbine antagonized the effects of L-DOPA, restoring the BP to near basal values within 5 min after i.v. injections, while prazosin had no such effect. The heart rate returned towards basal values after both yohimbine and prazosin. We conclude that L-DOPA elicits its hypotensive action in the sea-gull via activation of central alpha-adrenoceptors, which may belong to the alpha 2-subtype. The bradycardia may involve central activation of adrenoceptors of both the alpha 1- and alpha 2-types. The hypotension and bradycardia are mediated via vagal activation and probably also inhibition of sympathetic nervous output. The functional significance of sympathetic fibres running along with the vagus nerve is suggested.

Animals↗

PubMedDate not supplied

Dopamine metabolism in the central nervous system after discontinuation of L-dopa therapy in patients with Parkinson disease.

The dopamine turnover rate in the central nervous system (CNS) of parkinsonian patients was studied by means of the intravenous probenecid test during drug holiday (DH) and alternate day L-dopa therapy (ADDT). After L-dopa therapy was stopped, the dopamine turnover rate decreased more rapidly in patients with the marked wearing-off phenomenon than that in patients without fluctuation of symptoms. The lumbar CSF concentrations of L-dopa and 3-O-methyldopa of patients with and without wearing-off phenomenon were similar during L-dopa therapy. DH improved the effect of L-dopa on parkinsonian symptoms; it did not affect, however, the metabolism of exogenous L-dopa. The dopamine turnover rate in the CNS before L-dopa therapy or on on-days did not differ between patients tolerating and those not tolerating ADDT. However, it was significantly lower on off-days in patients not tolerating ADDT than in those tolerating ADDT. The relationship between dopamine storage in the CNS and the response to L-dopa therapy is discussed.

Adult↗

PubMed1991

Naloxone reverses L-dopa induced overstimulation effects in a Parkinson's disease animal model analogue.

Chronic L-DOPA treatment of Parkinson's disease frequently leads to the development of motoric overstimulation and hyperkinetic movements. To investigate this problem in the laboratory, rats surgically altered by unilateral 6-hydroxydopamine lesions (6-OHDA) were chronically treated with one L-DOPA (10 mg/kg i.p.) injection per day for 20 days. In this 6-OHDA rotation model, the unilateral dopamine denervation results in a profound contralateral sensory-motor neglect and the animals spontaneously rotate in a direction ipsilateral to the dopamine depleted hemisphere. Initially, the L-DOPA treatment did not alter the response bias but after several weeks, the response bias was reversed and the animals rotated in the formerly akinetic direction, contralaterally, at a significantly higher level. Using this overstimulation effect as an analogue of the clinically observed L-DOPA overstimulation, animals were given naloxone in conjunction with the L-DOPA treatment. Naloxone (0.10, 0.25 and 0.50 mg/kg i.p.) produced a dose related decrease in the L-DOPA induced contralateral rotation. Consistent with an expected selective effect on the L-DOPA induced rotation, a dose related increase in ipsilateral rotation was observed. These results suggest that naloxone can attenuate the overstimulation effect of L-DOPA and that this effect is not attributable to non-specific response suppression effects.

Animals↗

PubMedDate not supplied

Anorexigenic effects of d-amphetamine and l-DOPA in the rat.

The effect of amphetamine and l-dopa was compared in 22-hr food- and water-deprived rats. Amphetamine produced marked anorexia, and l-dopa significantly reduced food intake at 200 mg/kg. Following pretreatment with RO 4-4602, a decarboxylase inhibitor, 100 mg/kg of l-dopa, a dose that did not significantly affect eating, produced marked anorexia. The anorectic effect of both amphetamine and l-dopa was antagonized by propranolol, a beta adrenergic antagonist. Phentolamine, an alpha-adrenergic antagonist, potentiated the anorectic effect of amphetamine and l-dopa. Haloperidol (0.1 mg/kg), a dopamine antagonist, failed to prevent the anorexia due to amphetamine but accentuated that due to l-dopa. Methysergide, a serotonin antagonist, also failed to prevent the anorexigenic effect of amphetamine. Finally, the administration of l-dopa with or without peripheral decarboxylase inhibition resulted in more than twice the increase in hypothalamic dopamine levels without significant changes in 5-HT or norepinephrine levels. The data show that the anorexigenic effect of amphetamine and l-dopa are similar and indicate a functional role for both norepinephrine and dopamine neurons in feeding behaviour in the rat.

Animals↗

PubMed1994

Non-effective dose of exogenously applied L-dopa itself stereoselectively potentiates postsynaptic D2 receptor-mediated locomotor activities of conscious rats.

We attempted to clarify whether or not under inhibition of central dopa decarboxylase non-effective i.p. doses of L-dopa potentiate D2 receptor-mediated locomotor activities without conversion to dopamine in normal and i.v.t. 6-hydroxydopamine-treated rats. In normal rats, only the highest dose of quinpirole, a selective D2 agonist, at ranges used (0.01-1 mg/kg, s.c.) slightly increased the total counts of locomotor activities for 140 min after injection. A simultaneously injected non-effective dose of L-DOPA (30 mg/kg) potentiated locomotor activities by quinpirole (0.1 and 1 mg/kg). L-dopa potentiated quinpirole (1 mg/kg)-induced locomotor activities 90 to 140 min after the injection with marked increase in basal release of L-DOPA without increase in dopamine release simultaneously monitored during striatal microdialysis, compared to quinpirole alone. D-dopa (30 mg/kg) produced no potentiation. In 6-hydroxydopamine-treated rats, a non-effective dose of L-dopa (10 mg/kg) also potentiated quinpirole (0.3 mg/kg)-induced locomotor activities. L-dopa acting on a recognition site for itself stereoselectively potentiates postsynaptic D2 receptor-mediated locomotor activities of rats.

Animals↗

PubMed1994

Endogenously released L-dopa itself tonically functions to potentiate postsynaptic D2 receptor-mediated locomotor activities of conscious rats.

A non-effective dose of exogenously applied L-dopa itself stereoselectively potentiates postsynaptic D2 receptor-mediated locomotor activities of rats. We further attempted to clarify whether or not endogenously released L-dopa tonically functions to potentiate activities of these receptors, simultaneously monitoring locomotor activities and basal release of L-dopa and dopamine during striatal microdialysis in conscious rats. Quinpirole (1 mg/kg, s.c.) alone, a selective D2 agonist, increased locomotor activities and decreased basal L-dopa and dopamine release 20-140 min after injection. Pretreatment with alpha-methyl-p-tyrosine (3 mg/kg, i.p.), a tyrosine hydroxylase inhibitor, decreased locomotor activities and further decreased L-dopa release without modification of dopamine release, compared to quinpirole alone, whereas 3-hydroxybenzylhydrazine (100 mg/kg, i.p.), a central dopa decarboxylase inhibitor, further increased locomotor activities and markedly increased L-dopa release without modification of dopamine release. Endogenously released L-dopa itself functions tonically to potentiate activities of postsynaptic D2 receptors relevant to locomotor movement of rats.

Animals↗

PubMed1996

Synthesis and evaluation of radioiodinated 6-iodo-L-DOPA as a cerebral L-amino acid transport marker.

Regioselective radioiodination of N-trifluoroacetyl 3,4-dimethoxy-6-trifluoroacetoxymercurio-L-phenylalanine ethyl ester 1 under no-carrier-added condition gave 6-[125I]iodo protected L-DOPA with a labeling efficiency of more than 85%, and no-carrier-added 6-[125I]I-L-DOPA was obtained with a radio-chemical purity of over 95% after hydrolysis and chromatography. A nonradioactive standard of 6-iodo protected L-DOPA was synthesized by the iododemercuration of 6-mercuric trifluoroacetate protected L-DOPA 1 using I2 in chloroform. 6-[125I]I-L-DOPA showed high brain accumulation and rapid blood clearance in mice. The rat brain slice studies indicated high affinity of 6-[125I]I-L-DOPA for carrier-mediated and stereoselective active transport systems. The tissue homogenate analysis revealed that most of the accumulated radioactivity was intact 6-[125I]I-L-DOPA. Thus, 6-[123I]I-L-DOPA appears to be a suitable single photon emission computed tomography (SPECT) tracer for the selective measurement of cerebral L-amino acid transport, having no affinity for dopamine metabolism.

Amino Acids↗

PubMed2006

Subchronic administration of L-DOPA to adult rats with a unilateral 6-hydroxydopamine lesion of dopamine neurons results in a sensitization of enhanced GABA release in the substantia nigra, pars reticulata.

L-DOPA is the most effective pharmacological agent used for the symptomatic treatment of Parkinson's disease but long-term L-DOPA treatment induces involuntary abnormal movements such as dyskinesias. The present study, using in vivo microdialysis, investigated the effects of a single or subchronic administration of L-DOPA to adult rats with a unilateral 6-OHDA lesion of dopamine neurons on GABA release in the substantia nigra, pars reticulata (SNr). The results indicate that a challenge injection of L-DOPA (50 mg/kg, i.p.) significantly increases GABA levels in the SNr of rats treated with a daily repeated administration of L-DOPA (50 mg/kg, i.p.). Further statistical analysis between groups also showed that extracellular GABA levels were significantly higher in the subchronic L-DOPA group than in the group receiving only one injection of L-DOPA. These results show that the subchronic administration of L-DOPA results in a sensitization of enhanced extracellular GABA levels in the SNr.

Animals↗

PubMed2005

Pharmacological validation of a mouse model of l-DOPA-induced dyskinesia.

Dyskinesia (abnormal involuntary movements) is a common complication of l-DOPA pharmacotherapy in Parkinson's disease, and is thought to depend on abnormal cell signaling in the basal ganglia. Dopamine (DA) denervated mice can exhibit behavioral and cellular signs of dyskinesia when they are treated with l-DOPA, but the clinical relevance of this animal model remains to be established. In this study, we have examined the pharmacological profile of l-DOPA-induced abnormal involuntary movements (AIMs) in the mouse. C57BL/6 mice sustained unilateral injections of 6-hydroxydopamine (6-OHDA) in the striatum. The animals were treated chronically with daily doses of l-DOPA that were sufficient to ameliorate akinetic features without inducing overt signs of dyskinesia upon their first administration. In parallel, other groups of mice were treated with antiparkinsonian agents that do not induce dyskinesia when administered de novo, that is, the D2/D3 agonist ropinirole, and the adenosine A2a antagonist KW-6002. During 3 weeks of treatment, l-DOPA-treated mice developed AIMs affecting the head, trunk and forelimb on the side contralateral to the lesion. These movements were not expressed by animals treated with ropinirole or KW-6002 at doses that improved forelimb akinesia. The severity of l-DOPA-induced rodent AIMs was significantly reduced by the acute administration of compounds that have been shown to alleviate l-DOPA-induced dyskinesia both in parkinsonian patients and in rat and monkey models of Parkinson's disease (amantadine, -47%; buspirone, -46%; riluzole, -33%). The present data indicate that the mouse AIMs are indeed a functional equivalent of l-DOPA-induced dyskinesia.

Adenosine A2 Receptor Agonists↗

PubMed2001

COMT-dependent protection of dopaminergic neurons by methionine, dimethionine and S-adenosylmethionine (SAM) against L-dopa toxicity in vitro.

L-dopa may be toxic to dopamine neurons, possibly due to catechol-autoxidation. Catechols are O-methylated by catechol-O-methyltransferase (COMT) in a SAM consuming reaction, preventing the initiation of catechol autoxidation. We hypothesized that SAM or SAM-precursors ameliorate L-dopa neurotoxicity, in a COMT-dependent fashion. We tested this hypothesis in primary mesencephalic cultures by adding 200 microM L-dopa with 2 mM methionine or 1 mM dimethionine or 0.5 mM SAM with or without 0.2 microM of the COMT-inhibitor 2', 5'-dinitrocatechol (OR 486). L-dopa was found to be neurotoxic as the surviving neurons had fewer and shorter processes. Methionine, dimethionine and SAM all protected DA neurons against damaged induced by L-dopa. The COMT inhibitor dinitrocatechol (DNC) completely abolished the protective effect against L-dopa toxicity. We conclude that supplementation with methionine, dimethionine or SAM ameliorates L-dopa neurotoxicity to dopamine neurons, while inhibition of COMT may aggravate or unmask L-dopa neurotoxicity.

Animals↗

PubMed1996

Differential neurotoxicity induced by L-DOPA and dopamine in cultured striatal neurons.

The neurotoxicity of L-DOPA and dopamine (DA) on striatal neurons was examined by using primary cultures of rat striatum. Exposure to L-DOPA and DA at concentrations of 30-300 microM induced dose-dependent cell death in both younger cultures (3 days in culture, 3 DIC) and elder cultures (10 days in culture, 10 DIC). The cytotoxicity of L-DOPA and DA was also dependent on the exposure time (6-24 h). Ascorbic acid (200 microM) inhibited both L-DOPA- and DA-induced cytotoxicity in 3 DIC cultures, whereas it provided significant protection against DA- but not L-DOPA-induced cytotoxicity in 10 DIC cultures. The L-DOPA cytotoxicity in 10 DIC cultures was prevented by a non-NMDA receptor antagonist, 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), and by an NMDA receptor antagonist, MK-801. Neither antagonist prevented DA cytotoxicity. D-DOPA did not affect the viability of 10 DIC cultures, though it elicited marked toxicity in 3 DIC cultures. These results suggest that there are two components in the mechanisms that mediate the L-DOPA neurotoxicity on striatal neurons: one is autoxidation-relevant and the other is autoxidation-irrelevant. With respect to the latter, glutamate receptor stimulation may be involved. In contrast, autoxidation plays an important role in DA neurotoxicity.

Animals↗