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PubMed1990

In vivo changes in responsiveness of the caudate nucleus to L-dopa infusion as a function of the estrous cycle.

In the present experiment we measured changes in the responsiveness of the nigrostriatal dopaminergic system to L-DOPA as a function of the estrous cycle in the freely behaving animal with push-pull perfusion. Intact female rats were implanted with a push-pull cannula directed at the caudate nucleus and perfused repetitively on each day of their estrous cycle. During the perfusion, the response of the caudate nucleus was tested with two successive increasing doses of L-DOPA (1.0 and 10 microM) infused directly through the push side of the cannula. In response to 1.0 microM L-DOPA, significantly greater dopamine release was obtained for female rats perfused on proestrus, with all 6 females showing maximal responsiveness at this estrous cycle stage. There was an overall 3-4 fold greater increase in dopamine release to the 10 microM L-DOPA infusion, regardless of estrous cycle day. However, with the use of this 10 microM L-DOPA dose, the significant effect at proestrus was maintained. These results demonstrate that the responsiveness of the caudate nucleus to L-DOPA is maximal at proestrus. These data together with previous work from our laboratory indicate that the natural physiological changes which occur in hormone levels, in particular changes in progesterone during proestrus, exert a substantial influence upon this extra-hypothalamic central nervous system site.

Animals↗
PubMed1990

Effects of L-dopa on extracellular dopamine in striatum of normal and 6-hydroxydopamine-treated rats.

In vivo microdialysis was used to examine the effect of L-3,4-dihydroxyphenylalanine (L-DOPA) administration upon dopamine (DA) in extracellular fluid both in intact striatum and in striatum of rats treated with the catecholaminergic neurotoxin 6-hydroxydopamine (6-HDA). Basal extracellular levels of DA were not significantly altered by 6-HDA unless the DA content of striatal tissue was reduced to less than 20% of control. Peripheral aromatic amino acid decarboxylase (AADC) inhibition (RO4-4602, 50 mg/kg i.p.) followed by L-DOPA treatment (100 mg/kg i.p.) elevated extracellular DA in striatum of control rats from 37 +/- 5 to 68 +/- 11 pg/sample (n = 7; values corrected for recovery of the dialysis probe). In animals with severe bilateral depletions of DA in striatal tissue (mean depletion 87%; n = 6), L-DOPA increased extracellular DA in striatum from 8 +/- 3 to 266 +/- 60 pg/sample. In animals with large unilateral depletions of DA in striatal tissue (mean depletion 96%; n = 6), the increase in extracellular DA in striatum after L-DOPA was greater on the lesion side (from 7 +/- 4 to 245 +/- 67 pg/sample) than on the intact side (from 28 +/- 11 to 61 +/- 8 pg/sample). Animals with unilateral DA depletions showed contralateral circling behavior after L-DOPA. Increases in extracellular DA approaching the magnitude of those occurring in DA-depleted striata were observed when intact animals were treated with nomifensine (5 mg/kg i.p.; n = 5), an inhibitor of high-affinity DA uptake, in addition to L-DOPA.

Animals↗
PubMed1993

Differential effect of systemic administration of bromocriptine and L-dopa on the release of acetylcholine from striatum of intact and 6-OHDA-treated rats.

A presumed balance between striatal dopaminergic and cholinergic systems forms a major theoretical framework for the development of new agents for the treatment of Parkinson's disease. We therefore studied the effect of two drugs currently used as anti-parkinsonian agents, bromocriptine (BROMO) and L-beta-3,4-dihydroxyphenylalanine (L-DOPA), on the release of striatal acetylcholine (ACh) in intact and 6-hydroxy-dopamine-treated rats using in vivo microdialysis. Lesioned rats with a > 90% tissue depletion of striatal dopamine (DA) had a significantly higher output of striatal ACh than unlesioned rats (88 fmol/min vs. 52 fmol/min; 0.3 mumol/l neostigmine in perfusate). BROMO (4 mg/kg) inhibited the output of striatal ACh in both groups. Whereas the lowest dose of L-DOPA (50 mg/kg) potently stimulated ACh output in lesioned rats, unlesioned rats were significantly less responsive. A higher dose of L-DOPA (100 mg/kg) stimulated ACh output to the same extent in both groups. At the highest dose tested, L-DOPA (200 mg/kg) given to intact rats did not further increase striatal ACh output. Thus, BROMO decreases whereas L-DOPA increases striatal ACh release after systemic application. Therapeutic as well as side effects of L-DOPA may therefore be mediated by neurochemical alterations that are more complex than previously thought.

Acetylcholine↗
PubMed1994

Excitotoxic lateral pallidotomy does not relieve L-dopa-induced dyskinesia in MPTP parkinsonian monkeys.

We attempted to relieve the marked overactivity known to occur in the lateral segment of the globus pallidus (GPL) in L-DOPA-induced dyskinesia (LID) by unilateral stereotaxic ibotenic acid lesioning of the GPL in 4 monkeys with MPTP-induced parkinsonism. Two already dyskinetic animals were pallidotomized to counteract LID once established, while 2 L-DOPA-naive MPTP-treated animals were pallidotomized before L-DOPA was ever administered in an attempt to prevent the development of the process conductive to LID. Acutely after the lesion, more prominent akinesia (particularly in the contralateral limbs) with contraversive body deviation and circling behavior were seen for 48 h. Flexor posturing of the contralateral forelimb persisted to a variable degree. When L-DOPA treatment was resumed or instituted 1 week postoperatively, ipsiversive circling behavior occurred in all animals and contralateral dyskinesia worsened in 3, whether L-DOPA or a selective dopamine D2 agonist was administered. Lesions in these 3 cases were fairly restricted to the GPL histologically. One monkey kept L-DOPA-naive before pallidotomy never developed LID contralaterally to the lesion despite treatment for several months. The lesion this time involved the entire GP. The fact that ablation of the GPL worsened LID suggests that a complex rearrangement of the balance of functional capacity between the GP and the subthalamic nucleus takes place in LID which is not amenable to correction merely by a lateral pallidotomy. Our observations also suggest that functional redundancy exists in striatopallidal circuits and that no single pathway is responsible for LID.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1996

Dopamine produced from L-DOPA is degraded by endogenous monoamine oxidase in neurons of the dorsal raphe nucleus of the rat: an immunohistochemical study.

The aim of the present study is to examine by immunohistochemistry whether dopamine produced from L-DOPA in serotonin neurons of the rat brain is degraded by endogenous monoamine oxidase (MAO). In rats that received intraperitoneally L-DOPA plus a peripheral decarboxylase inhibitor, carbidopa, a cluster of dopamine-immunoreactive neurons was found in the dorsal raphe nucleus (DR). In L-DOPA/carbidopa-injected rats that were pretreated with an intraperitoneal injection of a MAO inhibitor, pargyline, when compared with the L-DOPA/carbidopa-injected rats without the pargyline pretreatment, neurons of the cluster of the DR became much darker in dopamine staining. The distribution of dopamine-stained neurons in the DR of these rats corresponded very closely to the previously reported distribution of serotonin-immunoreactive neurons of normal rats. In normal or only pargyline-injected rats, dopamine-stained neurons were scarcely observed in the DR. We previously showed that serotonin neurons of the rat DR were induced to contain dopamine by the injection of L-DOPA plus carbidopa. These findings suggest that the newly produced dopamine from L-DOPA in serotonin neurons of the rat DR is degraded by endogenous MAO.

Animals↗
PubMed1977

Simple gas chromatographic analysis of plasma dopa and dopamine.

A method for gas chromatographic analysis of plasma dopa and dopamine is described. Deproteinized plasma was shaken with acid washed aluminium oxide at pH 8.8. Dopa and dopamine were eluted from alumina with weak acids and evaporated to dryness. The pentafluoropropionic derivative of dopamine and the trifluoroacetic derivate of dopa were made and injected into a gas chromatograph equipped with a 63Ni electron capture detector. Alpha-methyl derivatives of each substance were used as internal standards. Linearity of plasma working curves of each substance was good. This method was applied to the assay of plasma samples from Parkinsonian patients under treatment with L-dopa with or without peripheral dopa decarboxylase inhibitors. The method described is sensitive and simple enough to monitor the blood levels of dopa and dopamine of these patients.

Adult↗
PubMed1987

The Bereitschaftspotential, L-DOPA and Parkinson's disease.

Bereitschaftspotentials (BPs) prior to extension movements of the index finger were studied in normal subjects and in patients with Parkinson's disease. In both, BPs were studied before and after L-DOPA therapy; in addition, the normal subjects were studied after dopamine antagonists. In both patients and normal subjects, L-DOPA caused an increase in the amplitude of the early part of the BP and of the point of peak negativity, just prior to EMG onset (N1) but it did not cause an increase of the late lateralized part of the BP (NS' of Shibasaki); in normal subjects dopaminergic antagonists caused a decrease in the amplitude of the N1. Control experiments suggested that the change caused by L-DOPA was not the result of slower movement or poorer triggering when OFF drugs. For patients with Parkinson's disease there was no correlation between the change in their peak BP negativity (N1) after L-DOPA and their change in clinical mobility; in addition, there was no difference in the peak BP negativity of patients OFF therapy and that of age-matched normals, though there was a slight decrease in the amplitude of the early part of the BP for the patients with Parkinson's disease; this was the same part that had been enlarged by L-DOPA therapy. These findings suggest that the N1 is not affected by Parkinson's disease and that the effect of dopaminergic drugs on the N1 is mediated by actions on dopaminergic mechanisms elsewhere than in the striatum, perhaps in the cerebral cortex itself. The effect of L-DOPA will need to be taken into account in subsequent studies of the BP in Parkinson's disease.

Adult↗
PubMed1975

Narcotic withdrawal like mouse jumping produced by amphetamine and L-DOPA.

Upward jumping in mice that resembled the narcotic-withdrawal syndrome was produced by a combination of amphetamine (4 mg/kg) and L-DOPA (400 mg/kg) administration. Neither drug alone caused that jumping. Pretreatment with haloperidol (0.16 mg/kg) or pimozide (0.08 mg/kg) but not with phentolamine (10mg/kg) effectively blocked amphetamine-dopa jumping. After DOPA there was an increase in the brain levels of DOPA, dopamine and norepinephrine. Amphetamine, ineffective in itself, enhanced DOPA-induced elevation of brain DOPA and dopamine without affecting brain norepinephrine levels.

Amphetamine↗
PubMed1976

Effect of anticholinergic drugs on gastro-intestinal absorption of L-dopa in rats and in man.

Plasma L-DOPA levels in rats receiving L-DOPA by the oral route were decreased by the concomitant administration of trihexyphenidyl. Following systemic L-DOPA administration no differences were observed between control and trihexyphenidyl-treated rats. Effects similar to those of trihexyphenidyl were observed with atropine. These results indicate that trihexyphenidyl decreases L-DOPA gastrointestinal absorption probably by delaying gastric emptying. The presence in humans of this interaction between the two antiparkinsonian drugs was suggested by similar findings made either in a group of normal volunteers or in a group of parkinsonian patients. These observations suggest that at the clinical level in selected cases the concomitant administration of trihexyphenidyl to patients receiving L-DOPA may decrease the therapeutic efficacy of L-DOPA by reducing its gastrointestinal absorption.

Administration, Oral↗
PubMed1976

Modification of the L-DOPA reversal of reserpine akinesia by inhibitors of dopamine-beta-hydroxylase.

The effect of the dopamine-beta-hydroxylase inhibitors (DBHI) FLA-63 and U10,157 on the reversal of reserpine akinesia by L-DOPA in mice was investigated both behaviourally and by measurement of the cerebral amines dopamine and noradrenaline. Pretreatment of reserpinised animals with intraperitoneal, but not oral, FLA-63 produced hypermotility in the first hour after L-DOPA administration, compared to animals receiving L-DOPA alone. This enhanced activity was associated with an increase in dopamine, but no significant change in the noradrenaline content of whole brain. Pretreatment with both oral and intraperitoneal FLA-63 caused dose-dependent suppression of locomotor activity in the second and third hours after L-DOPA. This suppression was associated with a significant decrease in brain noradrenaline in the presence of a significant elevation in brain dopamine. Pretreatment of animals with U10,157 produced similar but less marked behavioural responses. The results do not appear to be due to stressful effects of DBHI's, causing release of corticosteroids; neither corticosterone nor beta-methasone had any significant effect on L-DOPA-induced locomotor activity in reserpinised animals, although they did increase spontaneous motor activity in normal animals. The data presented support the concept that both noradrenaline and dopamine are responsible for the gross motor activity induced by L-DOPA in the reserpinised mouse.

Adrenal Cortex Hormones↗
PubMed1984

In vivo and in vitro evidence of dopaminergic system down regulation induced by chronic L-DOPA.

The biochemical modifications which occur in the dopaminergic system after chronic administration of L-DOPA are investigated. Levels of DA and of its metabolite 3-methoxytyramine (3-MT), an expression of the amount of DA released, were raised to the same extent in controls given a single dose of 1-DOPA and in chronically treated rats given 100 mg/kg of 1-DOPA plus 25 mg/kg of benserazide twice a day for 24 days. However, the reduction in neuronal function expressed by the decrease in 3-MT which follows treatment with DA agonists such as piribedil and apomorphine was less pronounced in the chronically L-DOPA treated rats. This suggests that such treatment causes a down regulation of DA receptors. These in vivo results were confirmed by in vitro analysis of DA receptor activity after chronic L-DOPA. Under these conditions there was a significant reduction in the number of [3H]-spiperone and [3H]-ADTN binding sites with no changes in their affinity. The in vivo and in vitro findings both suggest the involvement of a subsensitive compensatory mechanism or down regulation of dopaminergic neurons after chronic treatment with L-DOPA.

Animals↗
PubMed1994

L-dopa induced increases in brain uric acid in an animal model of Parkinson's disease: a relationship to behavioral activation.

Rats with severe unilateral dopamine denervation (> or = 95% dopamine deficit), produced by intracerebral injection of 6-hydroxydopamine (6-OHDA) into the ventral tegmentum nigrostriatal dopamine neurons, were administered 25 mg/kg L-dopa (3,4-dihydroxyphenylalanine) methyl ester/2 mg/kg carbidopa. The neurochemical effects of the L-dopa treatment on uric acid in the cortex and striatum of the intact and 6-OHDA hemisphere were measured. In comparison to saline animals, uric acid concentrations in brain were increased in the L-dopa treated animals. There were no interhemispheric differences in the uric acid concentrations either in the L-dopa or in the saline treated animals. Interhemispheric differences were, however, observed in terms of the correlations obtained between L-dopa and uric acid concentrations in the intact vs. the 6-OHDA hemisphere. Statistically significant correlation coefficients were found in the striatal and cortex samples obtained from the 6-OHDA hemisphere. Furthermore, high correlation coefficients were observed between contralateral rotation frequencies and uric acid concentrations in the cortex and striatum of the 6-OHDA hemisphere. In contrast, only low and statistically non significant correlations were observed in the tissue samples obtained from the intact hemisphere. These observations suggest that L-dopa activation of the dopamine supersensitive receptors of the DA denervated hemisphere and the associated metabolism of purines with high energy phosphate bonds (e.g. ATP and GTP) increases uric acid as an end-product of purine metabolism. These findings are consistent with other findings indicating that uric acid in the brain can provide an index of metabolic activation in brain tissue.

Animals↗
PubMed1996

Behavioral and neurochemical effects induced by chronic L-DOPA administration.

L-DOPA, in combination with benserazide, in the ratio 4:1 (w/w), was administered orally to rats. In the staircase maze test a low dose of L-DOPA (3 mg/kg/day) reduced the increase in errors caused by 20 days interruption of daily training, while a higher dose (30 mg/kg/day) was ineffective. A decrease in levels of dopamine in the olfactory system and DOPAC in the striatum was seen at all tested doses of L-DOPA, while an increase in 5-HT levels was seen in the hippocampus and in the striatum. 5-HIAA levels did not change. Levels of ACh in the olfactory system were reduced at all doses of L-DOPA, while in the hippocampus this effect was seen only at the dose of 90 mg/kg/day. The density of muscarinic receptors was not altered. All tested doses of L-DOPA caused norepinephrine levels to fall in the hippocampus and increase in the striatum. The density of alpha 1-adrenoceptors was reduced only at the two lower doses of L-DOPA. A comparison of the neurochemical results with the behavioral modifications seen in the staircase maze test suggests that the catecolaminergic systems are implicated in the memory process.

Acetylcholine↗
PubMed1995

L-DOPA reverses altered gene expression of substance P but not enkephalin in the caudate-putamen of common marmosets treated with MPTP.

The mRNA levels encoding neuropeptides were measured in the caudate nucleus, putamen and nucleus accumbens of common marmosets exposed to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine pyridine (MPTP). Motor deficits induced by MPTP treatment were characterized by akinesia, postural abnormalities and rigidity. Seven days after MPTP treatment, there was a marked increase in levels of enkephalin mRNA in the caudate nucleus and putamen. In contrast, the hybridization signal for substance P mRNA was reduced. Alterations in the mRNA encoding neuropeptides were similar but less extensive in marmosets at 18-50 months following MPTP treatment. No significant changes in enkephalin or substance P mRNA in the nucleus accumbens were observed at either time. Treatment with L-DOPA plus carbidopa for 4 weeks reversed MPTP-induce motor deficits and other behavioural abnormalities. The decrease in substance P mRNA in the striatum of MPTP-treated animals was reversed by L-DOPA treatment and reached levels above those found in normal animals. In contrast, the increase in enkephalin mRNA in marmosets treated with MPTP was not altered by L-DOPA treatment. In the nucleus accumbens the levels of peptide mRNA were not affected by L-DOPA treatment. Loss of nigral dopamine cells in a primate species causes opposing alterations in the expression of enkephalin and substance P mRNA in the caudate nucleus and putamen. No changes were observed in the nucleus accumbens, which reflects the resistance of the mesolimbic neurons to MPTP toxicity. While the decrease in substance P mRNA was reversed by L-DOPA treatment, the increase in enkephalin mRNA was not. This may partly indicate the greater effect of L-DOPA on the direct GABA pathway compared to the indirect output pathway from the striatum.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1985

Changes in brain catecholamine levels following DL-dopa are not potentiated by deuterium substitution.

Adult male Wistar rats were treated with either DL-dopa, D3-DL-dopa or vehicle and sacrificed at various time intervals after treatment. Brain dopamine and noradrenaline concentrations were measured using quantitative mass spectrometric analysis. After treatment with DL-dopa or D3-DL-dopa, total dopamine levels increased above control values; however, no differences were observed between the two drug treatments. Total noradrenaline levels were not significantly altered by treatment with either DL-dopa or D3-DL-dopa. Deuterium substitution did not appear to affect catecholamine deamination or beta-hydroxylation in vivo.

Animals↗
PubMed1995

Effect of chronic L-dopa administration on serum luteinizing hormone levels in male rats.

We examined whether the repeated oral administration with a high dose of L-3-(3,4-dihydroxyphenyl)-alanine (L-DOPA) in 0.5% carboxymethyl cellulose increases serum luteinizing hormone (LH) levels in male rats. Serum LH levels were increased 4 h after a single administration of 1000 mg/kg L-DOPA to male rats, and returned to control levels within 8 h after administration. Four hours after a single administration, serum LH levels were significantly increased by L-DOPA at 1000 mg/kg, but not at 20, 100 or 200 mg/kg. Decreases in body weight and relative weight of the prostate were observed after 7 and 14 days of administration of 1000 mg/kg per day L-DOPA, but no changes were observed in weight of the testis, epididymis or seminal vesicle. The administration of L-DOPA at 500 or 1000 mg/kg per day for 7 or 14 days resulted in increased basal serum LH levels and decreased basal serum prolactin levels 24 h after the last administration. Serum testosterone levels tended to be higher in treated than in control rats. The levels of two metabolites of dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), in rats treated with 500 mg/kg per day tended to be slightly higher than those in control rats after 7 days of administration. Levels of DA, DOPAC and HVA were significantly increased after 7 and 14 days of administration of 1000 mg/kg per day and after 14 days of administration of 5000 mg/kg per day. The level of norepinephrine, but not its metabolite 3-methoxy-4-hydroxyphenylglycol, was significantly increased after only 7 days of administration of 1000 mg/kg per day. No significant changes were observed in levels of 5-hydroxytryptamine or its metabolite 5-hydroxyindole-3-acetic acid with administration of 500 or 1000 mg/kg per day. These findings suggest that a prolonged treatment with a high dose of L-DOPA in male rats induces release of LH from the pituitary, resulting in sustained elevation of LH levels in peripheral circulation.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1986

Biphasic actions of L-DOPA on the release of endogenous dopamine via presynaptic receptors in rat striatal slices.

In rat striatal slices, 30 nM of L-DOPA increased the impulse (5 Hz)-evoked release of dopamine (DA), without increasing the spontaneous release and tissue content of DA. The minimum dose required to increase spontaneous DA release was 0.1 microM and the dose which led to an accumulation of DA was 100 microM. In the presence of NSD-1055, a DOPA-decarboxylase inhibitor, L-DOPA-induced increases in spontaneous DA release were prevented and L-DOPA produced dual actions on the evoked release of DA, a stereoselective propranolol-sensitive increase at 30 nM and a stereoselective sulpiride-sensitive decrease at 1 microM. L-DOPA produces dual presynaptic regulatory actions on DA release, via facilitatory beta-adrenoceptors at 30 nM and inhibitory DA receptors at 1 microM. The primary action of L-DOPA appears to be the facilitation of release of DA rather than the conversion to DA.

Animals↗
PubMed1991

Dopamine uptake inhibition potentiates the effects of L-DOPA on rat substantia nigra zona compacta neurons.

Intracellular electrophysiological recordings (current and voltage-clamp mode) were used to assess whether the actions of L-DOPA on rat substantia nigra zona compacta neurons maintained in vitro are potentiated by drugs that block the dopamine uptake system (cocaine and nomifensine). Bath application of L-DOPA (100 microM) hyperpolarized the dopaminergic cells and inhibited the spontaneous occurring action potential discharge. Under voltage-clamp experiments, L-DOPA produced an outward current that was related to the hyperpolarization of the membrane. In the presence of 10 microM cocaine and 10 microM nomifensine, the cellular responses to L-DOPA application were augmented and prolonged. In contrast to this, amphetamine (a dopamine releasing drug), did not augment the membrane response to L-DOPA. Cocaine (10 microM), nomifensine (10 microM) and amphetamine (3 microM), slightly hyperpolarized the membrane potential and inhibited the firing activity of the cells. It is concluded that the dopamine uptake system have an important role in regulating the cellular responses (membrane hyperpolarization or outward current) to L-DOPA application in the substantia nigra zona compacta.

Action Potentials↗