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PubMed1999

High midbrain [18F]DOPA accumulation in children with attention deficit hyperactivity disorder.

OBJECTIVE: Attention deficit hyperactivity disorder (ADHD) is a highly prevalent childhood psychiatric disorder characterized by impaired attention, excessive motor activity, and impulsivity. Despite extensive investigation of the neuropathophysiology of ADHD by a wide array of methodologies, the neurobiochemical substrate of this disorder is still unknown. Converging evidence, however, suggests a primary role of the dopaminergic system. METHOD: This study examined the integrity of presynaptic dopaminergic function in children with ADHD through use of positron emission tomography and the tracer [18F]fluorodopa ([18F]DOPA). Accumulation of [18F]DOPA in synaptic terminals, a measure of dopa decarboxylase activity, was quantified in regions rich in dopaminergic innervation, including caudate nucleus, putamen, frontal cortex, and midbrain (i.e., substantia nigra and ventral tegmentum). RESULTS: Accumulation of [18F]DOPA in the right midbrain was higher by 48% in 10 children with ADHD than in 10 normal children. Despite its magnitude, this difference would not have reached statistical significance if corrected by the Bonferroni test for multiple comparisons. However, [18F]DOPA in the right midbrain was correlated with symptom severity. No other dopamine-rich regions significantly differed between groups. CONCLUSIONS: These findings are suggestive of dopaminergic dysfunction at the level of the dopaminergic nuclei in children with ADHD. Abnormality in dopa decarboxylase activity may be primary or secondary to deficits in other functional units of the dopamine pathway (e.g., receptor, uptake transporter, vesicular transporter, degradation enzymes). Efforts toward defining the origin of this abnormality should help delineate mechanisms of midbrain control of attention and motor behavior important for the understanding of the causes and treatment of ADHD.

Adolescent↗
PubMed1982

Effect of pyridoxal phosphate deficiency on aromatic L-amino acid decarboxylase activity with L-DOPA and L-5-hydroxytryptophan as substrates in rats.

This paper describes the distribution of aromatic L-amino acid decarboxylase (AADC) activities in fourteen tissues (eight peripheral tissues and six brain regions) of semicarbazide (SC)-treated rats, using both L-DOPA and L-5-hydroxytryptophan (L-5-HTP) as substrates. The distribution of pyridoxal phosphate (PLP) was also measured in control and SC-treated rats. SC-treatment decreased the PLP concentration in all tissues (about 50-60% of control). AADC activities towards L-DOPA and L-5-HTP as substrates were also decreased significantly in almost all tissues of SC-treated rats. After the addition of exogenous PLP in vitro, AADC activities were recovered only partially in most tissues, but the recovery patterns were not parallel between L-DOPA and L-5-HTP as substrates. L-DOPA decarboxylase activity was more sensitive to PLP-deficiency than L-5-HTP decarboxylase activity in the same tissues. Serum AADC activities were decreased drastically using both L-DOPA and L-5-HTP as substrates. No serum AADC activity was detected in SC-treated rats using L-DOPA as substrate, but low activity was detected in the same sample using L-5-HTP as the substrate; both activities recovered completely after in vitro addition of 10 microM PLP in the incubation mixtures.

5-Hydroxytryptophan↗
PubMed1986

Perturbed pattern of catecholamine-containing neurons in mutant Drosophila deficient in the enzyme dopa decarboxylase.

We have initiated a study of catecholamine-containing neurons in Drosophila melanogaster because of the potential, with this organism, to perturb catecholamine metabolism using genetic tools. The major objectives of this study were (1) to define the pattern of catecholamine-containing neurons and (2) to determine the effect of the absence of dopa decarboxylase (DDC) enzyme activity on the catecholamine-containing neurons. We chose to analyze the catecholamine-containing neurons in the ventral ganglion of the larval CNS. To define the catecholamine-containing neurons, CNSs were dissected and reacted with glyoxylic acid. The catecholamine histofluorescence (CF) neuronal pattern (normal-CF neurons) in the wild-type ventral ganglion is stereotypic. In the mutant ventral ganglia, in the absence of DDC enzyme activity, most normal-CF neurons still exhibit CF, probably indicating the presence of accumulated L-dopa. Interestingly, in the mutant CNSs, additional novel neuronal subsets also exhibit CF. Analysis of CNSs from early developmental stages revealed that the novel-CF neurons become fluorogenic earlier than the normal-CF neurons in the mutant CNS. To determine whether neuronal subsets, in addition to the normal-CF, neurons are able to sequester catecholamines, CNSs from wild-type larvae were incubated in exogenous catecholamine (L-dopa or dopamine). Incubations in L-dopa or dopamine revealed normally nonfluorogenic neurons that are able to take up the amine and become fluorogenic. Among the neurons able to sequester L-dopa or dopamine are subsets that are similar to the novel-CF neurons in the mutant CNS. This similarity is best characterized by a major novel-CF neuronal cluster in the subesophageal-thoracic region. These results suggest that in the absence of DDC activity, subsets of normally nonfluorogenic neurons capable of sequestering L-dopa or dopamine accumulate the fluorogenic catecholamine. Hypotheses that might explain the mode of accumulation of the catecholamine within the novel-CF neurons are considered.

Animals↗
PubMed2001

Familial progressive supranuclear palsy: detection of subclinical cases using 18F-dopa and 18fluorodeoxyglucose positron emission tomography.

BACKGROUND: Progressive supranuclear palsy (PSP) is generally considered to be a sporadic disease; however, occasional cases of familial PSP have been described. The rarity of reports of familial PSP may be attributed in part to an inability to detect subclinical disease in affected relatives who subsequently die before symptoms clinically develop. OBJECTIVE: To study regional cerebral dopaminergic function and glucose metabolism in members of 2 large kindreds with familial PSP to identify subclinical cases. METHODS: Three clinically affected members from the 2 PSP kindreds were scanned with both (18)F-dopa and (18)fluorodeoxyglucose ((18)FDG) positron emission tomography (PET). Fifteen asymptomatic first-degree relatives were scanned with (18)F-dopa PET; 10 of them also underwent a second PET study with (18)FDG. RESULTS: All 3 clinically affected PSP patients showed a significant reduction in caudate and putamen (18)F-dopa uptake along with a significant reduction in striatal, lateral, and medial premotor area and dorsal prefrontal cortex glucose metabolism. In 4 of the 15 asymptomatic relatives, caudate and putamen (18)F-dopa uptake was 2.5 SDs lower than the normal mean. These 4 subjects and a fifth asymptomatic relative with normal (18)F-dopa uptake showed a significant reduction of cortical and striatal glucose metabolism in a pattern similar to that of their affected relatives. CONCLUSION: (18)F-dopa and (18)FDG PET allowed us to identify 5 cases with subclinical metabolic dysfunction among 15 subjects (33%) at risk for PSP, suggesting that this approach is useful for characterizing the pattern of aggregation in PSP kindreds.

Adult↗
PubMed1999

Effects of single and multiple treatments with L-dihydroxyphenylalanine (L-DOPA) on dopamine receptor-G protein interactions and supersensitive immediate early gene responses in striata of rats after reserpine treatment or with unilateral nigrostriatal lesions.

We studied effects of L-dihydroxyphenylalanine (L-DOPA) treatment in rats following reserpine treatment or unilateral 6-hydroxydopamine (6-OHDA) injections into medial forebrain bundle. Quantitative in situ hybridization for mRNA's coding for the zinc finger immediate early gene (IEG) zif/268 or Jun family IEG jun b revealed that single L-DOPA injections accentuated IEG expression 3- to 7-fold in the dopamine (DA)-depleted striatum. This increased IEG response did not derive from any alterations in DA receptor-G protein coupling, assayed by DA stimulation of 35S-guanosine-5' (gamma-thio) triphosphate (35S-GTP-gamma-S) binding to striatal sections. Reserpine treatment increased both basal and maximal striatal DA-stimulated 35S-GTP-gamma-S binding. The augmented IEG responses to single L-DOPA treatments involved dependency on both D1 and D2 receptors and acutely to N-methyl-D-aspartate (NMDA) channels. Repetitive L-DOPA treatments yielded persistently elevated (zif/268) or additionally up-regulated (jun b) IEG response in the denervated striatum and down-regulated IEG responses in the control striatum. Degraded L-DOPA responses and appearance of involuntary movements after chronic L-DOPA use in advanced Parkinson's disease may derive from these IEG changes.

Animals↗
PubMed1989

A new potential prodrug to improve the duration of L-dopa: L-3-(3-hydroxy-4-pivaloyloxyphenyl)alanine.

L-3-(3-Hydroxy-4-pivaloyloxyphenyl)alanine (1, NB-355) is a novel L-dopa prodrug. After oral administration with carbidopa in rats, 1 demonstrated 2.3 times longer duration (MRT) and 1.4 times larger bioavailability (AUC) on plasma L-dopa concentrations than those of L-dopa itself. Similar results were obtained in dogs. The prolonged profile of L-dopa was parallel to that of carbidopa, and the intact ester was undetectable in rat plasma. After intravenous administration in rats, 1 was converted quickly and completely to L-dopa in the systemic circulation. It was also noted that the oral LD50 value of 1 was greater than 6 g/kg in mice. These data suggest that 1 will offer long-lasting L-dopa therapy for the treatment of Parkinson's disease with little concern about toxicity.

Animals↗
PubMed1990

Hydrolysis and acyl migration of a catechol monoester of L-dopa: L-3-(3-hydroxy-4-pivaloyloxyphenyl)alanine.

Hydrolysis and acyl migration studies on L-3-(3-hydroxy-4-pivaloyloxyphenyl)alanine (1, NB-355), which produced long-lasting plasma L-dopa levels after oral dosing, have been conducted. Compound 1 exists as pure 4-O-pivaloyl-L-dopa in the solid state, but it converts rapidly to a mixture of the 3- and 4-O-isomers in solution. The rate of acyl migration increased with increases in pH and temperature, and the content of the 4-O-isomer in the equilibrium state was 53-59%. The hydrolysis rate of 1 to L-dopa (6) also increased with increases in pH and temperature, and accelerated steeply at neutral and alkaline pH. The rapid hydrolysis at neutral pH was not observed with O-pivaloyl-L-tyrosine (3), di-O-pivaloyl-L-dopa (4), or L-dopa methyl ester (5). Because of this chemical lability, 1 was hydrolyzed in rat plasma far faster than the other tested catechol esters. However, in rat intestinal homogenate at pH 6.0, 1 was hydrolyzed at the slowest rate among the tested esters, predominantly by a diisofluorophosphate (DFP)-sensitive esterase. Thus, 1 showed a unique in vitro profile on hydrolysis and acyl migration due to the existence of a neighboring hydroxyl group. The stability of 1 in the intestine might be essential for the long-lasting plasma L-dopa profile after oral dosing of 1.

Acylation↗
PubMed2006

Histamine H3 receptor agonists reduce L-dopa-induced chorea, but not dystonia, in the MPTP-lesioned nonhuman primate model of Parkinson's disease.

L-dopa-induced dyskinesia (LID) remains a major complication of the treatment of Parkinson's disease. The neural mechanisms underlying LID are thought to involve overactivity of striatal glutamatergic neurotransmission, with resultant underactivation of the output regions of the basal ganglia. Histamine H3 heteroreceptors can reduce glutamate and gamma-aminobutyric acid (GABA) transmission in the striatum and substantia nigra reticulata, respectively. Thus, we tested whether the histamine H3 receptor agonists immepip and imetit can alleviate LID in the MPTP-lesioned marmoset model of Parkinson's disease. Coadministration of immepip (1 mg/kg) with L-dopa (15 mg/kg) was associated with significantly less total dyskinesia than L-dopa alone. When dyskinesia was separately rated as chorea and dystonia, coadministration of L-dopa with either immepip or imetit (both 10 mg/kg) significantly reduced chorea but had no effect on dystonia. The antidyskinetic actions of the H3 agonists were not accompanied by alteration of the antiparkinsonian actions of L-dopa. However, immepip (10 mg/kg), when administered as monotherapy, significantly increased parkinsonian disability compared to vehicle. Overall, the results obtained in this study suggest that histamine H3 receptors may be involved in the neural mechanisms underlying L-dopa-induced dyskinesia in Parkinson's disease.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1988

Dementia and treatment with L-dopa in Parkinson's disease.

We compared the neuropsychological performance of patients with Parkinson's disease who were young at onset of the disease (mean age, 41.4 years) and had received prolonged L-dopa treatment (mean, 52.1 months) with nontreated patients of the same age. A similar comparison was made for patients who were older at onset of the disease (mean, 62.1 years). There were no significant differences in cognitive and memory functions between the L-Dopa-treated and untreated young patients, whereas the L-Dopa-treated patients in the older age group performed more poorly than untreated patients in some memory tests (Wechsler Memory Scale I: logical and visual) and cognitive functions (Wechsler Adult Intelligence Scale: similarities, block design, and cognitive flexibility). Treatment duration, disease duration, and mean L-Dopa dose were comparable for the two age groups. After linear effects of age and disease duration had been eliminated, the duration of L-Dopa treatment did not correlate with the cognitive variables studied. These observations suggest that treatment with L-Dopa may not be the cause of cognitive impairment in Parkinson's disease.

Adult↗
PubMed1995

Chronic L-DOPA administration induces dyskinesias in the 1-methyl-4- phenyl-1,2,3,6-tetrahydropyridine-treated common marmoset (Callithrix Jacchus).

Dyskinesias occur in the majority of patients with Parkinson's disease chronically treated with L-DOPA and also occur in several nonhuman primate species after 1-methyl-4phenyl-1,2,3,6-tetrahydropyridine (MPTP) and L-DOPA treatment. The common marmoset (Callithrix jacchus) shows parkinsonian motor deficits after MPTP administration, and we now report dyskinesias occurring in this species during chronic L-DOPA exposure. Marmosets rendered chronically parkinsonian after MPTP administration were treated orally with L-DOPA plus carbidopa for 3 weeks. After several days the animals began to display chorea, choreoathetosis, and dystonia. The severity of dyskinesias varied between the animals, with the most severely parkinsonian animals displaying the most dyskinetic movements. Each animal showed an idiosyncratic pattern of dyskinesias, which was highly reproducible. These L-DOPA-primed animals also received other D2 D1, and mixed D1/D2 agonist drugs. Quinpirole, bromocriptine, pergolide, apomorphine, and A-77636 all produce dyskinesias that were identical in character to those seen after L-DOPA administration, but the D1 agonist A-77636 gradually abolished dyskinesias while preserving its antiparkinsonian activity. The MPTP-treated marmoset provides a useful model in which to study dyskinesias in Parkinson's disease and to examine new therapeutic strategies aimed at alleviating this common side effect of chronic dopamine replacement therapy.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed2002

Systemic administration of dizocilpine maleate (MK-801) or L-dopa reverses the increases in GAD65 and GAD67 mRNA expression in the globus pallidus in a rat hemiparkinsonian model.

This study examined the consequences of systemic treatment with either L-dopa or MK-801 on the levels of mRNAs encoding the 65 and 67 kDa isoforms of glutamate decarboxylase (GAD65 and GAD67) in the striatum and globus pallidus (GP) of rats rendered hemiparkinsonian by intranigral 6-hydroxydopamine injection. GADs mRNA levels were assessed by means of in situ hybridization histochemistry. In the striatum, dopamine denervation resulted in increased GAD67 mRNA levels at the rostral and caudal levels, whereas GAD65 showed selective increase at the caudal level. L-dopa and MK-801 treatments showed differential effects on the two GAD isoform levels in rats with 6-hydroxydopamine lesion. The lesion-induced increases in GAD67 transcripts were potentiated by L-dopa but unaffected by MK-801, whereas the increases in GAD65 were suppressed by MK-801 but unaffected by L-dopa. These data suggest a heterogeneity of glutamate-dopamine interaction in the anteroposterior extent of the striatum and show that NMDA-mediated mechanisms are involved in the 6-hydroxydopamine lesion-induced transcriptional changes in striatal GAD65 but not GAD67. In GP, the 6-OHDA lesion elicited increases in both GAD65 and GAD67 mRNA levels. L-dopa or MK-801 treatment suppressed the lesion-induced augmentations in the two GADs mRNA levels. These results indicate that dopamine denervation-induced changes in the functional activity of GP neurons involve both dopamine and glutamate NMDA receptor-mediated mechanisms. Comparison between the effects of L-dopa and MK-801 treatments on markers of the activity of striatal and pallidal GABA neurons further suggest that the impact of these treatments at the GP level do not depend solely on the striatopallidal input.

Animals↗
PubMed1998

Protein L-dopa as an index of hydroxyl radical attack on protein tyrosine.

It is widely believed that hydroxyl radicals generated in vivo contribute to damage to macromolecules, such as proteins and DNA. We evaluated methodology based on the transformation of protein tyrosine to L-Dopa, via aromatic ring hydroxylation, as an index of hydroxyl radical attack on proteins. The catechol structure of Dopa makes it amenable to isolation with alumina, followed by HPLC analysis, typically used for the measurement of catecholamines. Because a level of controversy exists about the formation of Dopa by hydroxyl radicals, we conducted a systematic study of the formation of Dopa from tyrosine, tyrosine dipeptides, pure proteins (chymotrypsin and myelin basic protein), and endogenous proteins in tissue homogenates (rat brain), exposed to hydroxylating conditions (Fe2+/EDTA/ascorbate at neutral pH). Dopa residues in peptides and proteins were liberated by acid hydrolysis with 6 M HCl at 145 degrees C for 1 h. A marked lability of Dopa in 6 M HCl under hydrolysis conditions was prevented with added phenol; chymotrypsin and precipitated pellets of brain protein were also protective. Overall recoveries (hydrolysis plus purification procedures) averaged 83.4 +/- 1.7%. This improved analytic procedure may be useful for studying protein damage by hydroxyl radicals.

Animals↗
PubMed1996

Generation of DOPA-producing astrocytes by retroviral transduction of the human tyrosine hydroxylase gene: in vitro characterization and in vivo effects in the rat Parkinson model.

Astrocytes secreting high levels of L-3,4-dihydroxyphenylalanine (DOPA) have been generated by retrovirus-mediated transfer of the human tyrosine hydroxylase (TH) gene. Immature astrocytes obtained from prenatal rat brain were cocultured with TH virus producing psi-2 cells that had been pretreated with the mitosis inhibitor mitomycin-C. During the first week of coculture DOPA production gradually increased to reach a plateau after 7-9 days. At this time point virtually all cells were GFAP positive and over 80% of them expressed TH. DOPA production in the transduced astrocytes was largely independent of exogenous cofactor, and DOPA release into the medium was not influenced by addition of either KCl or tetrodotoxin or by removal of Ca2+ from the culture medium, indicating that the newly synthesized DOPA was constitutively released from the cells. Transplantation of the TH-transduced astrocytes to the striatum in unilaterally 6-hydroxydopamine lesioned rats reduced apomorphine-induced turning by about 50% at 2 weeks postgrafting. Microscopic analysis revealed that the transduced astrocytes survived very well after transplantation and that some of the grafted cells had migrated out, partly along blood vessels, into the surrounding striatum. TH expression was observed in cells with both the appearance of mature GFAP-positive astrocytes, as well as in more immature-looking cells. However, only a few percent of all transplanted cells maintained significant expression of the transgene, as determined by TH immuno-histochemistry. The results show that primary astrocytes may be highly useful as gene carriers for ex vivo gene therapy in the CNS. With future improvement in the gene transduction procedure for more efficient, sustained expression of the TH transgene in vivo, genetically engineered DOPA-producing astrocytes hold great promise as a tool to explore the potential of ex vivo gene therapy in Parkinson's disease.

Animals↗
PubMed1998

In vivo L-DOPA production by genetically modified primary rat fibroblast or 9L gliosarcoma cell grafts via coexpression of GTPcyclohydrolase I with tyrosine hydroxylase.

To investigate the biochemical requirements for in vivo L-DOPA production by cells genetically modified ex vivo in a rat model of Parkinson's disease (PD), rat syngeneic 9L gliosarcoma and primary Fischer dermal fibroblasts (FDFs) were transduced with retroviral vectors encoding the human tyrosine hydroxylase 2 (hTH2) and human GTP cyclohydrolase I (hGTPCHI) cDNAs. As GTPCHI is a rate-limiting enzyme in the pathway for synthesis of the essential TH cofactor, tetrahydrobiopterin (BH4), only hTH2 and GTPCHI cotransduced cultured cells produced L-DOPA in the absence of added BH4. As striatal BH4 levels in 6-hydroxydopamine (6-OHDA)-lesioned rats are minimal, the effects of cotransduction with hTH2 and hGTPCHI on L-DOPA synthesis by striatal grafts of either 9L cells or FDFs in unilateral 6-OHDA-lesioned rats were tested. Microdialysis experiments showed that those subjects that received cells cotransduced with hTH2 and hGTPCHI produced significantly higher levels of L-DOPA than animals that received either hTH2 or untransduced cells. However, animals that received transduced FDF grafts showed a progressive loss of transgene expression until expression was undetectable 5 weeks after engraftment. In FDF-engrafted animals, no differential effect of hTH2 vs hTH2 + hGTPCHI transgene expression on apomorphine-induced rotation was observed. The differences in L-DOPA production found with cells transduced with hTH2 alone and those cotransduced with hTH2 and hGTPCHI show that BH4 is critical to the restoration of the capacity for L-DOPA production and that GTPCHI expression is an effective means of supplying BH4 in this rat model of PD.

3T3 Cells↗
PubMed2000

Combined use of the adenosine A(2A) antagonist KW-6002 with L-DOPA or with selective D1 or D2 dopamine agonists increases antiparkinsonian activity but not dyskinesia in MPTP-treated monkeys.

The novel selective adenosine A(2A) receptor antagonist KW-6002 improves motor disability in MPTP-treated parkinsonian marmosets without provoking dyskinesia. In this study we have investigated whether KW-6002 in combination with l-DOPA or selective D1 or D2 dopamine receptor agonists enhances antiparkinsonian activity in MPTP-treated common marmosets. Combination of KW-6002 with the selective dopamine D2 receptor agonist quinpirole or the D1 receptor agonist SKF80723 produced an additive improvement in motor disability. Coadministration of KW-6002 with a low dose of L-DOPA also produced an additive improvement in motor disability, and increased locomotor activity. The ability of KW-6002 to enhance antiparkinsonian activity was more marked with L-DOPA and quinpirole than with the D1 agonist. However, despite producing an enhanced antiparkinsonian response KW-6002 did not exacerbate L-DOPA-induced dyskinesia in MPTP-treated common marmosets previously primed to exhibit dyskinesia by prior exposure to L-DOPA. Selective adenosine A(2A) receptor antagonists, such as KW-6002, may be one means of reducing the dosage of L-DOPA used in treating Parkinson's disease and are potentially a novel approach to treating the illness both as monotherapy and in combination with dopaminergic drugs.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed2002

Electromyographic activity patterns of ankle flexor and extensor muscles during spontaneous and L-DOPA-induced locomotion in freely moving neonatal rats.

In rats, hindlimb postural and locomotor functions mature during the first 3 postnatal weeks. Previous evidence indicates that maturation of descending monoaminergic pathways is important for the postnatal emergence of locomotion with adequate antigravity postural support. Here we have studied the effect of the monoamine precursor L-DOPA on locomotor activity in freely moving postnatal rats (7-9 days old) using electromyographic recordings from ankle extensor (soleus) and flexor (tibialis anterior or extensor digitorum longus) muscles. Before pharmacological treatment, both muscles were usually silent at rest, and during spontaneous movements there was a high degree of coactivation between the two antagonists. This was due to a longer electromyographic (EMG) burst duration in flexors, which partly overlapped with the extensor burst. L-DOPA administration (150 mg/kg) resulted in a marked increase in postural tonic EMG activity in extensors which appeared gradually within 10 min after injection and was sufficient for the pups to maintain a standing posture with the pelvis raised above ground. Thereafter, episodes of locomotion characterized by rhythmic reciprocal bursts of EMG activity in flexor and extensor muscles were seen. The L-DOPA-induced rhythmic EMG pattern was also seen in postnatal rats subjected to a midthoracic spinal cord transection, indicating that the effect of L-DOPA on motor coordination is exerted primarily at the level of the spinal pattern generator. Analysis of EMG burst characteristics showed that the pattern of L-DOPA-induced locomotion in both intact and spinalized postnatal rats resembled in some respects that observed in adults during spontaneous locomotion. The appearance of reciprocal activation during L-DOPA-induced locomotion in neonates was primarily due to a shortening of the EMG burst duration in flexors, which reduced the degree of antagonist coactivation. These results show that the spinal cord has the potential to produce coordinated overground locomotion several days before such movements are normally expressed in the freely moving animal.

Animals↗
PubMed1975

Cyclic adenosinemonophosphate in cerebrospinal fluid. Effects of theophylline, L-dopa and a dopamine receptor stimulant in rats.

The effects of L-Dopa and the dopamine receptor stimulant ET-495 on cisternal cAMP levels were studied in rats. L-dopa (100-200 mg/kg) increased cisternal cAMP levels by 60 to 80% of controls. When peripheral Dopa-decarboxylase was inhibited, smaller doses of L-Dopa were effective. Fla-63, an inhibitor of dopamine-beta-hydroxylase lowered the increase induced by L-Dopa which was completely suppressed by propranolol, not by phentolamine, suggesting that the cAMP increase is mediated through a central beta-adrenoceptor stimulation. ET-495 failed to influence cAMP levels which argues against a dopamine-sensitive adenylate cyclase involved in the L-Dopa effect. Moreover, large increases of cisternal cAMP were observed after treatment with theophylline , not papaverine which suggests different effects of these "phosphodiesterase inhibitors" on the cyclic AMP systems in the central nervous system or on transport mechanisms.

Animals↗
PubMed1976

Alteration of basal ganglia evoked responses by reserpine and L-dopa.

The effects of reserpine and L-Dopa on basal ganglia evoked potentials were investigated in cats. The caudate response resulting from substantia nigra stimulation and the substantia nigra response elicited by globus pallidus stimulation were increased at several hours after the systemic administration of reserpine. L-Dopa in the presence of dopa decarboxylase inhibition (MK-486) depressed these responses and reversed the effect of reserpine at 0.5 h after administration. Reserpine did not reverse the L-Dopa effect. Reserpine and L-Dopa caused no significant change in responses between other basal ganglia structures. These data give evidence that the basal ganglia are major sites for reserpine and L-Dopa action.

Animals↗