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PubMed1975

Effect of L-DOPA on endogenous histamine metabolism.

To estimate the effect of long-term administration of L-3,4-dihydroxyphenylalanine (L-Dopa) on methylation of compounds not formed from it, the urinary excretion of histamine and its methylated metabolites was studied in rats and guinea pigs fed L-Dopa in their diets and in patients with Parkinson's disease being treated with L-Dopa. In the guinea pigs, but not in the rats, L-Dopa administration decreases excretion of histamine and of its methylated metabolites, methylhistamine and 1-methylimidazole-4-acetic acid. Because excretion of 1-methylimidazole-5-acetic acid, which comes from the diet and is not a metabolite of histamine, was unaffected by the L-Dopa treatment, the decreases were due to a specific effect of L-Dopa on histamine metabolism. When compared to normal control subjects, patients with Parkinson's disease excreted less histamine and methylhistamine, both before and during treatment with L-Dopa. Administration of the peripheral aromatic L-amino acid decarboxylase inhibitor, L-alpha-methyldopa hydrazine (MK 486), decreased urinary excretion of histamine markedly. Neither L-Dopa nor MK 486 appeared to influence excretion of the imidazoleacetic acids in the patients. The results suggest that L-Dopa may decrease histamine formation or release in some species but that it does not influence histamine methylation.

Acetates↗
PubMed1976

L-dopa-carbidopa: combined therapy for the treatment of Parkinson's disease.

It is now generally acknowledged that L-Dopa is the therapy of choice for Parkinson's Disease. However, L-Dopa has some short comings: It requires large daily dosage, the therapeutic benefits are achieved only after a delayed onset of 1-2 months, and it has a number of side effects both central and peripheral. In the last few years there has been an intense search for agents that are less toxic, more efficient and more rapidly acting that L-Dopa. The ideal agent has not yet been found. However, a combination therapy with L-Dopa and dopa decarboxylase inhibitors has shown promise. The decarboxylase inhibitors used have a large molecule which does not cross the blood brain barrier. Thus when L-Dopa and the decarboxylase inhibitor are given togehher, peripheral production of dopamine from L-Dopa is inhibited, therefore, rendering L-Dopa more readily and rapidly available for brain metabolism. In the present paper we present the results of the treatment of 50 patients on combined therapy using L-Dopa combined with Carbidopa.

Adult↗
PubMed1990

[Prevention by L-dopa of early renal consequences of diabetes induced by streptozocin in rats].

The early renal effects associated with streptozotocin-induced diabetes in rats (glomerular hyperfiltration and increase in filtration fraction) are similar to modifications reported in the early stage of human diabetic nephropathy. We examined the reversibility of these early renal diabetic effects by dopamine, which might correct glomerular hyperfiltration thanks to its preferential vasodilatory action on glomerular efferent arterioles. A dopamine prodrug, L-dopa was used to increase endorenal dopamine synthesis. Studies were carried out on streptozotocin-treated (60 mg/kg, i.v.) Wistar rats, supplemented with NPH insulin (2 to 3 U/day) such as to stabilize hyperglycemia at 22 mmol/l. One week after diabetes induction, animals were treated during a week either with L-dopa (10 mg/kg, s.c. twice daily) or L-dopa plus a dopa-decarboxylase inhibitor, carbidopa (10 mg/kg, s.c. 30 min before each L-dopa injection) or L-dopa plus a selective D1 receptor antagonist, SCH 23390 (100 micrograms/kg, s.c., with each L-dopa injection). Control diabetic animals received the solvent of L-dopa and control non-diabetic animals received the solvent of streptozotocin. After one week of L-dopa or other treatment, the renal functions of the rats were investigated (polyfructosan and PAH clearances) under inactin anaesthesia. As expected, streptozotocin induced glomerular hyperfiltration (1.3 +/- 0.07, n = 14, versus 0.93 +/- 0.05 ml/min.g kidney weight in non-diabetic controls, p less than 0.001) and an increase in filtration fraction (52.4 +/- 5.1 versus 32.1 +/- 1.7%, p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1988

Metabolites of 6-[18F]fluoro-L-dopa in human blood.

The metabolites of 6-[18F]fluoro-L-dopa in the blood plasma of healthy humans have been identified as 3-O-sulfato-6[18F]fluoro-L-dopa, 3-O-methyl-6-[18F]fluoro-L-dopa, 6-[18F] fluorodopamine, and 6-[18F]fluorohomovanillic acid. The time course of these metabolites was followed up to 2 hr. The findings have implications for the use of 6-[18F]fluoro-L-dopa as tracer for cerebral dopamine metabolism. Despite the variety of metabolites in the peripheral blood there are only two 18F-carrying compounds, 6-[18F]fluoro-L-dopa and 3-O-methyl-6-[18F]fluoro-L-dopa, that can cross the blood-brain barrier. After 1 hr, the plasma concentration of 3-O-methyl-6-[18F]fluoro-L-dopa reaches approximately 20% that of 6-[18F]fluoro-L-dopa but the mean concentration of the O-methylated metabolite over the same interval is less than 5% that of 6-[18F]-fluoro-L-dopa.

Adult↗
PubMed1981

[Effect of L-DOPA on brain serotonin metabolism related to tryptophan concentrations in plasma and brain of rats].

Changes in tryptophan (Trp) concentrations in the peripheral and brain tissues and their influences on brain serotonin (5-HT) metabolism were investigated after i.p. administrations of L-DOPA alone and in combination with Ro4-4602 in male Wistar rats. L-DOPA alone elicited marked increases of both plasma free and liver Trp levels, and a slight increase of brain Trp level. Concomitant application of L-DOPA and Ro4-4602 did not change peripheral Trp concentrations but did reduce brain Trp level. Brain 5-HT levels were reduced in proportion to the increase of dopamine (DA) level by L-DOPA alone and Ro4-4602 plus L-DOPA. A marked increase of 5-HIAA level was exhibited by L-DOPA alone, while Ro4-4602 plus L-DOPA increased 5-HIAA levels slightly despite a marked decrease in 5-HT levels. The decrease of 5-HT and increase of 5-HIAA levels were also observed after administration of L-DOPA to neonatal rats in which the brain tryptophan hydroxylase was considered to be saturated. These results suggest that changes in 5-HT metabolism after L-DOPA injections are not only caused by DA which displaces 5-HT from vesicular stores, but also by changes in Trp concentrations in the plasma and brain which alter 5-HT synthesis and turnover.

Animals↗
PubMed1982

Effects of L-dopa on epinephrine concentration in rat brain: possible role of inhibition of norepinephrine N-methyltransferase by S-adenosylhomocysteine.

L-Dopa injected at 200 mg/kg i.p. into rats caused a slight reduction in hypothalamic concentration of epinephrine and completely prevented the accumulation of epinephrine after monoamine oxidase inhibition. The lowering of epinephrine concentration was greater with L-dopa than with D-dopa, was dose-related over a dosage range of 50 to 200 mg/kg of L-dopa and was not prevented by a dopamine receptor antagonist. Hypothalamic norepinephrine N-methyltransferase activity measured in vitro was not altered in rats treated with L-dopa. L-Dopa injection decreased S-adenosylmethionine (SAMe) concentration and increased S-adenosylhomocysteine (SAH) concentration in hypothalamus, probably a result of extensive O-methylation of L-dopa and its metabolites. The decrease in SAMe and epinephrine concentration and the increase in SAH concentration occurred at lower doses of L-dopa in carbidopa-pretreated rats than in control rats. Norepinephrine N-Methyl-transferase activity assayed in vitro was markedly inhibited by SAH; the inhibition was competitive with SAMe as the variable substrate and the Ki for SAH was 1.9 x 10(-5) M. Increasing the SAH/SAMe ratio in in vitro experiments sharply reduced norepinephrine N-methyltransferase activity. The apparent inhibition of hypothalamic epinephrine synthesis in vivo after L-dopa injection is suggested to be a consequence of the increased SAH/SAMe ratio.

Animals↗
PubMed1995

Intrarenal production of dopamine and natriuresis following DOPA and saline infusions in healthy human volunteers.

The interactions of intrarenal dopamine (DA) synthesis and natriuresis were studied in 11 healthy volunteers by giving a low and high sodium diet (LoSo, 50 mmol Na+; HiSo, 250 mmol Na+). On 2 days in both dietary phases an acute saline load was given, without or with an infusion of the DA precursor 3, 4-dihydroxyphenylalanine (DOPA) 0.15 microgram kg-1 min-1. Urinary excretion rates of sodium (UNa V), DOPA (UDOPA V), DA (UDA V) and noradrenaline (NA; UNA V), hormonal parameters, blood pressure (BP), glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) were measured. On HiSo UDOPA V increased by 35% (P < 0.05) while UDA V remained unchanged. Only weak correlations were found between 24h UNa V and UDA V (r = 0.23) or UDOPA V (r = 0.39). On both diets and without the DOPA infusions, the saline infusions enhanced UNa V but did not increase UDA V. The DOPA infusions caused no significant change of UNa V, in spite of five- to eight-fold increases in UDA V. During LoSo the DOPA infusion only caused a slightly larger increase of UNa V after the saline infusion, when expressed as percentage change to the pre-saline UNa V (119 +/- 25% without DOPA infusion, 244 +/- 56%, P < 0.05 with DOPA infusion). On HiSo the DOPA infusion did not affect UNA V. The dietary sodium intake and the DOPA infusions did not influenced BP, GFR, or ERPF. In conclusion, dietary sodium intake or acute sodium loads did not clearly modulate UDA V.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1995

The effect of carbidopa and entacapone pretreatment on the L-dopa pharmacokinetics and metabolism in blood plasma and skeletal muscle in beagle dog: an in vivo microdialysis study.

The effects of carbidopa and entacapone pretreatment on the pharmacokinetics and metabolism of i.v. administered L-3,4-dihydroxyphenylalanine (L-dopa) have been examined in vivo in blood plasma and skeletal muscle extracellular fluid (ECF), in beagle dog, by microdialysis. Both with or without carbidopa, blood plasma L-dopa levels declined biexponentially after the i.v. administration of L-dopa. In contrast to blood plasma, a monoexponential decline was observed in muscle ECF in both these pharmacological conditions. Pretreatment with carbidopa had no significant effect on the pharmacokinetic parameters of L-dopa in blood plasma, but resulted in an increase in the area under the concentration versus time curve (AUC) and elimination half-life (t1/2) of L-dopa in muscle ECF (0.61 hr), compared with values achieved after L-dopa alone. Carbidopa pretreatment enhanced the accumulation of 3-O-methyldopa (3-OMD) and dopamine (DA) in muscle ECF but decreased that of L-3,4-dihydroxyphenylacetic acid (DOPAC) in both blood plasma and muscle ECF. Entacapone had a pronounced inhibitory effect on the formation of 3-OMD, resulting in a reduction of the AUC for 3-OMD by 98% and 85% in blood plasma and muscle ECF, respectively. Pretreatment with carbidopa plus entacapone enhanced the Tmax of L-dopa in muscle ECF compared with the values achieved after pretreatment with carbidopa alone. In addition, the elimination half-life (2.66 hr) and volume of distribution by area of L-dopa in blood plasma and its AUC and t1/2 in muscle ECF (1.80 hr) were enhanced substantially. No DA was detected, but DOPAC levels were enhanced in both blood plasma and muscle ECF. These results suggested that carbidopa has a L-dopa-sparing effect in skeletal muscle, which is further enhanced by entacapone.

Animals↗
PubMed1993

Impact of L-dopa on striatal acetylcholine release: effects of 6-hydroxydopamine.

We investigated the effects of the dopamine (DA) precursor L-dihydroxyphenylalanine (L-DOPA) on electrically evoked acetylcholine (ACh) overflow from rat striatal slices. Some animals were pretreated 1 to 2 months earlier with 6-hydroxydopamine, (6-OHDA), a catecholamine neurotoxin, so as to selectively destroy DA terminals (98.6% striatal DA depletion). Although the addition of L-DOPA (10 microM) produced a 37% inhibition of ACh overflow in slices from lesioned rats, it failed to affect ACh overflow in slices from intact animals. In contrast, ACh overflow from intact slices exposed to L-DOPA and to the DA uptake inhibitor nomifensine (1 microM) was 22% greater than in the presence of nomifensine without L-DOPA. ACh overflow from slices prepared from lesioned rats was 45% greater with both drugs than in the presence of nomifensine by itself. Superfusion with the aromatic L-amino acid decarboxylase (AADC) inhibitor NSD-1055 (250 microM) abolished the inhibitory effects of L-DOPA, as did L-sulpiride (1 microM), an inhibitor of DA receptors of the D2 subtype. These results suggest that inhibition of ACh overflow by L-DOPA is mediated by DA formed from exogenous L-DOPA which then acts on D2 receptors. They further indicate that the net impact of the loss of nigrostriatal terminals is an increased dopaminergic inhibition of striatal cholinergic interneurons in response to exogenous L-DOPA. This appears to result in large part from a lesion-induced reduction in high-affinity reuptake of DA formed from exogenous L-DOPA.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1977

[Central action of beta-phenylethylamine derivatives (10). Effect of L-Dopa on metaraminol induced motor activity (author's transl)].

The present experiments were undertaken in investigate the effects of Ro4-4602 plus L-Dopa on biphasic action induced by metaraminol (MA) in mice. The following results were obtained: Spontaneous motor activity (SMA) suppressed by MA was recovered by pretreatment of Ro4-4602 plus L-Dopa and increased by more than 100 mg/kg of L-Dopa. However, SMA was increased by more than 400 mg/kg of L-Dopa in saline pretreated mice. In MA pretreated mice, SMA by L-Dopa markedly increased in proportion to the doses of MA. The peak time of SMA by L-Dopa in MA pretreated mice was observed to be faster than that in saline pretreated mice. When L-Dopa was injected into MA and saline pretreated mice, there was no significant difference of brain dopamine content between the two groups. From the above results, it is considered that the enhanced effect of L-Dopa in MA pretreated mice may be due to production of a supersensitivity to catecholamines in the central nervous system. MA induced hyper-motor activity was enhanced by pretreatment of Ro4-4602 plus L-Dopa which have no influence on SMA.

Animals↗
PubMed1989

Combined measurements of plasma aromatic L-amino acid decarboxylase and DOPA as tumour markers in diagnosis and follow-up of neuroblastoma.

As neuroblastoma, the most common solid tumour in childhood, may contain all the constituents of the catecholamine biosynthesis cascade, some of these constituents may be produced in excess in a varying mixture reflecting the wide variability in expression of differentiated features of the tumour. We have measured plasma levels of norepinephrine (NE), epinephrine (E), dopamine (DA) and 3,4-dihydroxyphenylalanine (DOPA), and plasma activities of dopamine beta-hydroxylase (DBH) and aromatic L-amino acid decarboxylase (ALAAD) in 18 patients with neuroblastoma, in 13 at various times during the course of their disease. Activities of serum lactic dehydrogenase (LDH), serum levels of ferritin (FER) and neuron-specific enolase (NSE), and urinary vanilmandelic acid (VMA) were also determined. NE, E and DBH were found not to reflect tumour activity. In untreated active neuroblastoma DOPA or ALAAD (10 out of 10) or both (six out of 10) were clearly elevated. In all 13 patients where samples were obtained during chemotherapy, ALAAD activities fell within the normal range, while DOPA decreased more slowly. During relapse, DOPA and, especially, ALAAD, rapidly increased; in all six patients who had a relapse both DOPA and ALAAD were elevated. In complete remission (eight patients), ALAAD was normal in all patients, but DOPA remained elevated in the one patient who later experienced a relapse. Our preliminary conclusion is that combined measurements of plasma ALAAD and DOPA may be useful markers for neuroblastoma activity at diagnosis, but even more so in indicating residual disease (DOPA) and in the early detection of relapse (ALAAD).

Aromatic-L-Amino-Acid Decarboxylases↗
PubMed1987

Some aspects on L-dopa decarboxylase and p-tyrosine decarboxylase in the central nervous and peripheral tissues of the American cockroach Periplaneta americana.

1. Aromatic amino acid decarboxylase activities toward L-DOPA (L-3,4-dihydroxyphenylalanine), 5-HTP (5-hydroxytryptophan) and p-tyrosine in different tissues of the sclerotized and newly ecdysed cockroach were analyzed. 2. The ratios of enzyme activity with regard to L-DOPA and p-tyrosine varied considerably in the tissues and between the two different growth stages. 3. A DOPA decarboxylase and a p-tyrosine decarboxylase were separated by gel filtration and ion exchange chromatography. 4. The optimal pH requirement for both enzymes was 7.5 with the exception of the one decarboxylating 5-HTP. 5. The molecular weights of the cockroach brain DOPA decarboxylase and tyrosine decarboxylase were estimated to be 120,000 and 100,000, respectively. 6. Unlike the mammalian aromatic amino acid decarboxylase, the cockroach DOPA decarboxylase cannot be activated by a small amount of benzene. 7. An increase of over 50-fold of DOPA decarboxylase activity and a 50% reduction of tyrosine decarboxylase activity in the epidermal tissue of the newly ecdysed animals was observed. 8. In the fully sclerotized cockroach, a reversible endogenous inhibitor(s) of DOPA decarboxylase in the integument was observed, suggesting that the DOPA decarboxylase is suppressed in the epidermal tissues when ecdysis does not occur.

Animals↗
PubMed2002

Behavior of fluorinated analogs of L-(3,4-dihydroxyphenyl)alanine and L-threo-(3,4-dihydroxyphenyl)serine as substrates for Dopa decarboxylase.

We have determined the kinetic parameters for Dopa decarboxylase (DDC) of three ring-fluorinated analogs of 3,4-dihydroxyphenylalanine (Dopa). The rank order of catalytic efficiency of decarboxylation (k(cat)/K(m)) is Dopa>6-F-Dopa>2-F-Dopa>5-F-Dopa. This rank is consistent with previous in vivo and in vitro studies which indicate that, of the fluorinated analogs, 6-F-Dopa has pharmacokinetics that are most suited for positron emission tomographic (PET) evaluation of dopamine function. The effectiveness of PET as a diagnostic tool, the convenient half-life of (18)F (110 min) and the favorable pharmacokinetics of 6-[(18)F]FDOPA have combined to make this an extremely valuable reagent to study dopaminergic activity. The reactions of the related fluorinated DOPS analogs show that, while 6-F-threo-3,4-(dihydroxyphenyl)serine (DOPS) is decarboxylated at approximately the same rate as the non-fluorinated substrate, 2-F-threo-DOPS is not converted into the corresponding amine. In both cases a Pictet-Spengler condensation with the pyridoxal 5(')-phosphate (PLP) cofactor occurs to produce tetrahydroisoquinolines. Condensation of fluorinated catecholamines and catechol amino acids with endogenous aldehydes will be investigated as an approach to study possible mechanisms of L-Dopa-linked neurotoxicity.

Dihydroxyphenylalanine↗
PubMed1997

The kinetic behaviour of [3H]DOPA in living rat brain investigated by compartmental modelling of static autoradiograms.

The kinetic behaviour of [3H]DOPA in living rat brain was investigated by compartmental modelling of measured activities from combined metabolite pools in a time-series (180 min) of static autoradiograms from right cerebral hemispheres. Two models of [3H]DOPA uptake and metabolism that incorporated the removal of the decarboxylation product, [3H]dopamine, from brain were significantly more accurate than a model in which [3H]dopamine accumulated irreversibly in situ. Present estimates of [3H]DOPA kinetic constants were compared to previously published results based on the analysis of measured activities from individual metabolite pools separated by chromatographic fractionation of [3H]DOPA metabolites in the left cerebral hemispheres of the same rats. Autoradiographic estimates of DOPA decarboxylase activity with respect to [3H]DOPA in brain (k3DOPA) were under-estimated several-fold relative to chromatographic estimates; this discrepancy is explained by post-mortem enzyme activity and omission of biological compartments from the models. However, autoradiographic estimates of the unidirectional blood-brain clearance of [3H]DOPA (K1DOPA) and monoamine oxidase activity with respect to [3H]dopamine in brain (k7DA') agreed with chromatographic estimates. This concordance represents the first empirical validation of compartmental modelling of autoradiographic data as a method for quantitatively investigating the kinetic behaviour of radiolabelled L-DOPA in living mammalian brain.

Animals↗
PubMed1975

Rat brain regional uptake and decarboxylation of L-DOPA following carotid injection.

Using the carotid injection technique, the regional uptake and decarboxylation of L-DOPA at the blood-brain barrier in the rat was studied. After a single intracarotid injection in the rat followed by decapitation 15 S later, the uptake of L-DOPA was measured relative to tritiated water injected simultaneously as a diffusible internal standard. Decarboxylation was investigated with an injection mixture of L-[carboxy-14C]DOPA and L-[2,3-3H]DOPA. Uptake of L-DOPA studied over the range of 15-5,076 nmol/ml appeared to be a composite of two separate mechanisms. The saturable component had a half-maximal velocity transport value, K-t, of 336 muG. A diffusional, nonsaturable component had a diffusion constant of 0.018. A regional study showed that uptake operated at approximately the same rate in the various brain areas despite marked regional variation in catecholamine concentration. The decarboxylation of L-DOPA also occurred at a similar rate in all regions. Even when L-DOPA was injected at a concentration of 3 mM, 33-51% was decarboxylated within the 15-S period. These results support the hypothesis that L-DOPA movement into the brain occures via a neutral amino acid transport mechanism common to cerebral capillaries of different regions of the brain.

Animals↗
PubMed1998

The antiparkinsonian drug budipine stimulates the activity of aromatic L-amino acid decarboxylase and enhances L-DOPA-induced dopamine release in rat substantia nigra.

The present study examined the effects of the antiparkinsonian drug budipine on dopamine synthesis and release from L-DOPA in the substantia nigra of reserpine-treated rats. Budipine (at 100 microM, but not 10 microM) applied by reverse dialysis to the nigra caused a small and significant rise in dopamine recovery in normal rats, but not in rats pretreated with reserpine (4 mg/kg i.p. for 18 hours) and alpha-methyl-p-tyrosine (alpha-MPT; 200 mg/kg i.p. for 1 hour to limit dopamine synthesis to L-DOPA). L-DOPA applied to the nigra by reverse dialysis in reserpine + alpha-MPT-treated rats, increased the recovery of dopamine when applied at 5 or 10 microM, but not at 2 microM. Coadministration of budipine (10 microM) significantly enhanced L-DOPA-induced dopamine (and DOPAC) release with 5 microM L-DOPA, but not with 2 or 10 microM L-DOPA. This potentiation was even more pronounced when the budipine concentration was raised to 100 microM (equivalent to approximately 10 microM extracellularly). Pretreating rats with budipine (5, 12.5, or 20 mg/kg i.p.) for 1 hour significantly raised the activity of the enzyme L-aromatic amino acid decarboxylase in the striata and nigras of intact rats, as well as in rats pretreated with reserpine alone (5 mg/kg i.p.), without altering tissue levels of dopamine or its metabolites. It is suggested that the beneficial effects of budipine, when used as an adjunct to L-DOPA therapy of Parkinson's disease, may be due to an increase in the bioconversion of L-DOPA with a consequent rise in synaptic dopamine. These actions of budipine may be related to its weak NMDA receptor antagonist property.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1999

Microdialysis study of the effects of the antiparkinsonian drug budipine on L-DOPA-induced release of dopamine and 5-hydroxytryptamine by rat substantia nigra and corpus striatum.

The purpose of this study was to determine if systemic treatment with the antiparkinsonian drug budipine was capable of influencing the release of dopamine newly synthesised from L-DOPA in the substantia nigra and corpus striatum of the monoamine-depleted rat. Dual probe microdialysis was therefore employed in freely moving animals pretreated with reserpine (4 mg/kg i.p. 18-20 h earlier) and alpha-methyl-p-tyrosine (200 mg/kg i.p. 45 min earlier). Budipine (10 mg/kg i.p.) alone evoked a small but significant increase in basal dopamine efflux in nigra, though not in striatum, but did not affect the spontaneous outputs of DOPAC, 5-HT, or 5-HIAA in either structure. A threshold amount of L-DOPA (25 mg/kg i.p.) stimulated the release of dopamine, DOPAC, and 5-HT (but not 5-HIAA), both in nigra and striatum. The L-DOPA-induced releases of dopamine and DOPAC were greatly accentuated by pretreatment with budipine (10 mg/kg i.p. 45 min earlier), which delayed rather than potentiated the nigral and striatal effluxes of 5-HT. A higher dose of L-DOPA (100 mg/kg i.p.) did not significantly raise the outputs of dopamine or 5-HT, but greatly magnified that of DOPAC. In these experiments, pretreatment with budipine (10 mg/kg i.p.) facilitated the formation of DOPAC from L-DOPA, without increasing the extracellular concentration of dopamine. We conclude from these findings that budipine, at a therapeutically relevant dose, potentiates the release of dopamine newly synthesised from L-DOPA from either end of the nigrostriatal dopamine axis. This effect of budipine could be related to the drug's recently described ability to increase the activity of the converting enzyme, aromatic L-amino acid decarboxylase, and could explain the clinical efficacy of budipine as an adjunct to L-DOPA therapy of Parkinson's disease in man. The significance of 5-HT release to the antiparkinsonian L-DOPA, and the delay in this release caused by budipine, remain to be established.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1999

The alpha2-adrenergic receptor antagonist idazoxan reduces dyskinesia and enhances anti-parkinsonian actions of L-dopa in the MPTP-lesioned primate model of Parkinson's disease.

Dopamine replacement therapy in patients with Parkinson's disease is plagued by the emergence of abnormal involuntary movements known as L-dopa-induced dyskinesias. It has been demonstrated that yohimbine can reduce L-dopa-induced dyskinesia in the MPTP-lesioned primate model of Parkinson's disease. Yohimbine is, among other things, an alpha-adrenergic receptor antagonist. In this study, we demonstrate that the selective and potent alpha2-adrenergic receptor antagonist idazoxan reduces L-dopa-induced dyskinesia in the MPTP-lesioned marmoset model of Parkinson's disease. The alpha2-adrenergic receptor antagonists rauwolscine and yohimbine also reduce L-dopa-induced dyskinesia. Furthermore, we demonstrate that coadministration of idazoxan with L-dopa can provide an anti-parkinsonian action more than twice the length of that seen with L-dopa alone. However, idazoxan as a monotherapy displayed no anti-parkinsonian actions. We propose that idazoxan in combination with L-dopa may provide a novel approach to the treatment of Parkinson's disease that will not only reduce the dyskinetic side effects, but extend the anti-parkinsonian actions of L-dopa. Idazoxan, as an adjunct to dopamine replacement, may prove useful in the treatment of parkinsonian patients at all stages of disease progression.

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