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E Melamed

Publications and source records attributed to E Melamed.

At least 217 records · Page 12Linked to original sources
PubMed1983

Chronic L-dopa administration decreases striatal accumulation of dopamine from exogenous L-dopa in rats with intact nigrostriatal projections.

To examine whether chronic administration of L-dopa can affect its own utilization in striatum, rats were injected once daily for 30 days with L-dopa and carbidopa or with saline. On day 31, saline and L-dopa animals were sacrificed 1, 2, or 3 hours after L-dopa injection. In rats given long-term L-dopa, the elevations in striatal dopamine concentrations induced by L-dopa administration were smaller and of shorter duration than those in controls. Such changes did not occur in animals pretreated with L-dopa for only 10 days. Results suggest that prolonged L-dopa therapy may decrease striatal accumulation of dopamine from exogenous L-dopa even when the nigrostriatal projections are intact. Therefore, it is possible that declining efficacy of L-dopa in parkinsonism may be due to effects of the drug itself and not only to disease progression.

Animals↗
PubMed1982

Effects of oral L-tyrosine administration on CSF tyrosine and homovanillic acid levels in patients with Parkinson's disease.

To determine whether 1-tyrosine administration can enhance dopamine synthesis in humans as it does in rats, we measured levels of tyrosine and the major dopamine metabolite, homovanillic acid, in lumbar spinal fluids of 23 patients with Parkinson's disease before and during ingestion of 100 mg/kg/day of tyrosine. Nine patients took 100 mg/kg/day of probenecid in six divided doses for 24 hours prior to each spinal tap; 14 patients did not receive probenecid. L-tyrosine administration significantly increased CSF tyrosine levels in both groups of patients (p less than .01) and significantly increased homovanillic acid levels in the group of patients pretreated with probenecid (p less than .02). These data indicate that l-tyrosine administration can increase dopamine turnover in patients with disorders in which physicians wish to enhance dopaminergic neurotransmission.

Administration, Oral↗
PubMed1982

Stimulation of nigrostriatal dopamine neurones by nicotine.

In rats anaesthetized with urethane, firing of neurones of the substantia nigra zona compacta was accelerated after subcutaneous or iontophoretic administration of nicotine or after iontophoretic application of acetylcholine. The excitation was prevented by iontophoretic application of dihydro-beta-erythroidine, but not by atropine. The units were identified by antidromic stimulation as neurones of the nigrostriatal system; their activity was depressed by iontophoretically applied dopamine (DA). Under the same conditions of anaesthesia, a subcutaneous injection of nicotine produced an increase in DA turnover and in homovanillic acid levels in the striatum. The effect of nicotine on striatal DA turnover was comparable to that of electrical stimulation of the nigrostriatal pathway at the average frequency seen in the firing of zona compacta neurones after systemic administration of nicotine. These observations corroborate the idea that nicotine exerts an excitatory action at the level of nigral DA nerve cells. Observations made after electrical stimulation or haloperidol under urethane anaesthesia and after nicotine in unanaesthetized rats suggest that the relatively modest effect of nicotine on striatal DA turnover is due mainly to the short duration of drug action rather than to effects of the anaesthetic on DA metabolism.

Animals↗
PubMed1982

Huntington chorea is not associated with hyperactivity of nigrostriatal dopaminergic neurons: studies in postmortem tissues and in rats with kainic acid lesions.

We estimated dopamine release postmortem in the neostriatum of patients with Huntington disease (HD) and in controls. In HD, dopamine levels were unchanged in caudate and elevated in putamen, but homovanillic acid (HVA) and the ratio HVA:dopamine were unaltered in both nuclei. When rats were injected with kainic acid (an experimental model of HD), dopamine levels in striatum remained unchanged 2 to 30 days postoperatively; HVA and 3,4-dihydroxyphenylacetic acid (DOPAC) increased significantly from 2 to 18 days after injections but returned to normal levels later. These findings suggest that the nigrostriatal projection adapts to loss of striatal neurons that normally influence dopamine release and is not hyperactive in HD chorea.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1982

Compensatory mechanisms in the nigrostriatal dopaminergic system in Parkinson's disease: studies in an animal model.

Partial unilateral nigrostriatal lesions of varying severity (from mild to near-total) were produced in rats by intranigral injections of increasing doses of 6-hydroxydopamine. Severity of the lesions was estimated by measurement of striatal tyrosine hydroxylase activity. In such rats, surviving nigrostriatal neurons accelerated their rates of dopamine (DA) synthesis and release (estimated by the ratio of homovanillic acid to tyrosine hydroxylase) only when 60% of more of DA neurons had been destroyed. Striatal DA receptor supersensitivity (estimated by emergence of contraversive rotational behavior induced by apomorphine and L-dopa) developed only when 90% or more of striatal DA nerve terminals had been destroyed. Acceleration of DA turnover by surviving nigrostriatal neurons and the development of striatal DA receptor supersensitivity may represent two compensatory mechanisms through which the nigra adapts to its own destruction and may explain, in part, why clinical signs of parkinsonism emerge only after massive degeneration of DA neurons.

Animals↗
PubMed1981

Dopamine release in rat striatum after administration of L-dope as studied with in vivo electrochemistry.

The time-course of changes in dopamine (DA) release induced by systemic administration of L-DOPA was studied in the rat striatum using electrochemistry in vivo. Recordings were obtained from anesthetized animals in which carbon past microelectrodes were implanted stereotaxically into the striatum. Chronoamperometric measurements were made by applying 0.8 V for 1 sec, with an interval of 5 min between measurements; in some experiments, the potential was scanned every 5 min from 0 to 1.0 V. Administration of L-DOPA (50 mg/kg) after pretreatment with an inhibitor of peripheral aromatic amino acid decarboxylase (AAAD) produced a large rise in chronoamperometric currents, lasting for about 6 h. Different approaches were used to determined whether DOPA, DA or DA metabolites (all of which are oxidized at the potential chosen) were responsible for these DOPA-induced increases. (1) Rats were killed at different times after L-DOPA administration, and their striatal were analyzed biochemically for DOPA, DA, and DA metabolites. Comparison of time-courses indicated that the rise in chronoamperometric responses correlated with elevations in striatal 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) levels rather than with those of DOPA or DA, suggesting that DA metabolites contribute significantly to the increases in chronoamperometric responses observed after administration of L-DOPA. (2) Administration of L-DOPA after pretreatment with an inhibitor of central AAAD, a treatment that results in large increases in striatal DOPA levels but abolishes L-DO DA, suggesting that DA metabolites contribute significantly to the increases in chronoamperometric responses observed after administration of L-DOPA. (2) Administration of L-DOPA after pretreatment with an inhibitor of central AAAD, a treatment that results in large increases in striatal DOPA levels but abolishes L-DO DA, suggesting that DA metabolites contribute significantly to the increases in chronoamperometric responses observed after administration of L-DOPA. (2) Administration of L-DOPA after pretreatment with an inhibitor of central AAAD, a treatment that results in large increases in striatal DOPA levels but abolishes L-DOPA-induced formation of DA and DA metabolites (measured biochemically), failed to increase chronoamperometric responses. This finding indicates that exogenous L-DOPA entering the striatum is not detected with this technique and that it must be decarboxylated to produce the elevations of currents. (3) In animals pretreated with an inhibitor of monoamine oxidase to abolish formation of DOPAC and HVA, L-DOPA administration produced only a small and short lasting increase in chronomaperometric responses, despite sustained and large increases in striatal DA concentrations. By using the potential-scanning technique we showed that these increase in electrochemical responses occur at a potential at which DA but not methylated catechols are oxidized...

4-Butyrolactone↗
PubMed1981

Aromatic L-amino acid decarboxylase in rat corpus striatum: implications for action of L-dopa in parkinsonism.

We studied the distribution of aromatic L-amino acid decarboxylase (AAAD) activity in striatal compartments of rats. After near-total destruction of nigrostriatal dopaminergic neurons, 15 to 20% of the initial enzyme activity remained. Striatal enzyme activity remained unchanged after destruction of serotoninergic terminals by electrolytic raphe lesions. Combined raphe-nigrostriatal lesions or nigrostriatal lesions alone produced similar decreases in striatal decarboxylase. Intrastriatal injection of kainic acid (which selectively destroys striatal interneurons and efferent neurons and also induces marked glial proliferation) reduced activity by 20%. Only 7% of initial striatal activity (perhaps localized in capillaries) remained after combined nigrostriatal-kainic acid lesions. These findings indicate that after degeneration of dopaminergic terminals, striatal interneurons and efferent neurons, but not serotonergic terminals of glia, contain an important fraction of the residual AAAD. This compartment may be the site of enzymatic conversion of exogenous L-dopa to dopamine in the parkinsonian striatum.

Animals↗
PubMed1981

The site of dopamine formation in rat striatum after L-dopa administration.

Unilateral nigrostriatal lesions produced by injecting 6-hydroxydopamine stereotaxically into both the substantia nigra and the medial forebrain bundle reduced striatal tyrosine hydroxylase activity and dopamine (DA) concentrations by 95% (compared with the intact, contralateral striata) but lowered dopa decarboxylase (DDC) activity by only 80%. L-Dopa administration increased DA concentrations in both lesioned and unlesioned sides; absolute increases were higher in control striata and pretreatment with carbidopa (an inhibitor of peripheral DDC) amplified the increases on both sides. Animals given both of the above lesions plus intrastriatal kainic acid injections exhibited a further reduction in DDC activity, i.e., to only 6% of the activity measured in intact, contralateral striata. Kainic acid lesions alone reduced striatal DDC activity by 20%, without affecting striatal tyrosine hydroxylase activity or DA concentrations, and diminished DA formation from exogenous L-dopa. These observations indicate that DA formation from exogenous L-dopa within the striatum occurs mainly, but not exclusively, within DA terminals. Some DA formation persists after most DA neurons have been destroyed; it may occur within kainic acid-sensitive striatal interneurons or efferent neurons. The DA formed outside DA neurons is apparently able to stimulate postsynaptic DA receptors and to mediate some of the behavioral effects of L-dopa, since L-dopa continued to induce circling behavior in animals with unilateral nigrostriatal lesions, even when these lesions approached totality.

Animals↗
PubMed1980

Decarboxylation of exogenous L-DOPA in rat striatum after lesions of the dopaminergic nigrostriatal neurons: the role of striatal capillaries.

In rats with unilateral nigrostriatal lesions, L-DOPA-induced dopamine increases in ipsilateral striata were further enhanced after inhibition of DOPA decarboxylase in cerebral microvessels by carbidopa. DOPA levels were similar, but dopamine increases in lesioned striata were smaller, after carbidopa and DOPA (100 mg/kg) than after DOPA alone (500 mg/kg). These findings suggest that after degeneration of dopaminergic terminals, striatal decarboxylation of exogenous DOPA occurs partly, but not exclusively, in tbe capillaries.

Animals↗
PubMed1980

Partial lesions of the dopaminergic nigrostriatal system in rat brain: biochemical characterization.

Various doses of 6-hydroxydopamine injected into the rat substantia nigra produced partial, dose-dependent lesions of the dopaminergic nigrostriatal tract. The resulting reduction in striatal dopamine concentrations and tyrosine hydroxylase activities tended to be proportional, allowing these measurements to serve as indices for lesion severity in any particular animal. Lesions destroying two-thirds or more of the nigrostriatal neurons accelerated dopamine's synthesis in, and release from, surviving neurons, as indicated by increased striatal levels of the dopamine metabolites dihydroxyphenylacetic acid and homovanillic acid. Formation of these metabolites was also enhanced in dendrites of dopaminergic neurons in the substantia nigra. Supersensitivity of striatal postsynaptic receptors, as judged by induction of rotational behavior after apomorphine or L-DOPA administration, occurred when 90% or more of the nigrostriatal neurons had been destroyed. In contrast, rotational behavior could be induced by amphetamine in animals with only 50% of these neurons destroyed.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1980

Nonaminergic striatal neurons convert exogenous L-dopa to dopamine in parkinsonism.

In intact striatum, the enzyme dopa decarboxylase is localized predominantly in dopaminergic nerve terminals. In Parkinson disease, loss of dopaminergic neurons is associated with massive depletion of striatal decarboxylase activity. Nevertheless, efficacy of exogenous L-dopa in parkinsonism is generally believed to result from its enzymatic decarboxylation to dopamine in the corpus striatum. It has previously been suggested that, after degeneration of nigrostriatal pathways, decarboxylation of administered L-dopa may occur mainly at such striatal sites as surviving dopaminergic terminals, serotonergic neurons, or capillaries; but currently available data do not favor these hypotheses. Recent experimental studies indicate that a substantial amount of decarboxylase activity is localized in striatal interneurons or efferent neurons that may not normally synthesize monoamines. We propose that after depletion of dopaminergic terminals, these nonaminergic striatal neurons may contain a large fraction of residual dopa decarboxylase activity and may represent an important locus for conversion of administered dopa to functional dopamine in the parkinsonian corpus striatum.

Corpus Striatum↗
PubMed1980

The decarboxylation of DOPA in the parkinsonian brain: in vivo studies on an animal model.

The site of decarboxylation of exogenously administered L-DOPA was studied in corpora striata of rats with near-total unilateral nigrostriatal lesions. After DOPA administration, the absolute increases in dopamine (DA) levels were lower in lesioned than in unlesioned striata, suggesting that, in the intact striatum, a major part of exogenous DOPA is decarboxylated in DA neurons. DOPA can also be decarboxylated outside DA neurons, however, as shown by our finding that relatively higher DOPA decarboxylase than tyrosine hydroxylase activity or DA concentration remains in striata after the nigrostriatal lesions. Also, the percentage increases in DA formation after DOPA administration were much higher in lesioned than in control striata. Rats with both raphé and nigrostriatal lesions failed to exhibit further reductions in striatal DOPA decarboxylase activity or diminished biochemical or behavioral (turning behavior) reactions to DOPA. Inhibition of the DOPA decarboxylase contained in brain capillary endothelial cells did not abolish DA formation in lesioned striata or circling behavior after DOPA administration. These findings all suggest an additional cell type in the striatum as the site of DOPA's decarboxylation in the absence of DA neurons.

Animals↗
PubMed1980

Plasma tyrosine in normal humans: effects of oral tyrosine and protein-containing meals.

To test the effects of tyrosine ingestion and concurrent food consumption on plasma tyrosine levels and on the plasma tyrosine ratio, we measured plasma neutral amino acid levels in 11 subjects who consumed a diet containing 113 g protein and who also took 100 mg/kg/day of L-tyrosine (in three equally divided doses) before meals. Plasma tyrosine levels rose significantly (p less than 0.025) during the day when subjects consumed the diet alone; they increased markedly after tyrosine ingestion (p less than 0.005). Tyrosine administration did not affect plasma concentrations of the other neutral amino acids that compete with tyrosine for entry into the brain. Thus, the plasma tyrosine ratio increased from 0.13 to 0.21 (p less than 0.001) on the day fed subjects received the tyrosine. These observations indicate that tyrosine administration might increase brain tyrosine levels and perhaps accelerate catecholamine synthesis in humans with diseases in which catecholamine synthesis or release is deficient.

Administration, Oral↗