Striatal [18F]fluorodopa utilization after COMT inhibition with entacapone studied with PET in advanced Parkinson's disease

The effect of peripheral catechol-O-methyltransferase (COMT) inhibition with entacapone on striatal uptake of 6-[18F]fluoro-L-dopa (FDOPA) was studied with PET both without and with entacapone in fifteen advanced parkinsonian patients and six healthy controls. Entacapone significantly enhanced the fraction of unmetabolized FDOPA in plasma from 16% to about 50% at 80 minutes after FDOPA injection in all subjects. The striatal to occipital ratios and the striatal FDOPA uptake, expressed as a modified decarboxylation coefficient (k3R0), was significantly increased in healthy controls, whereas in parkinsonian patients the increase was significant only in the caudate. On the other hand, the influx constant (Ki) decreased significantly in the caudate and putamen in parkinsonian patients; in healthy controls the Ki remained virtually unchanged. Effective peripheral COMT inhibition markedly increased the fraction of FDOPA in plasma and thus its availability in the brain for decarboxylation both in patients and control subjects. However, the change in striatal FDOPA uptake was modest in the advanced parkinsonian patients as compared to that in control subjects, because of the advanced disease, decreased storage capacity, or both.     

Homeobox gene product Nkx 6.1 immunoreactivity in nuclei of endocrine cells of rat and mouse stomach

Selegiline is used as an adjunct to levodopa in the symptomatic treatment of Parkinson's disease (PD). The normal daily dose of selegiline is 10 mg administered orally. This study, based on monoamine oxidase-B (MAO-B) inhibition, investigates whether a reduction in selegiline dose can provide the same beneficial effects seen with a 10-mg dose. The inhibition of platelet MAO-B activity against multiple dosing of selegiline (2.5, 5, and 7.5 mg) was predicted from the data obtained from literature (0.5, 1.0, 1.5, and 10 mg). A pharmacokinetic-pharmacodynamic model for selegiline was also developed. The data suggested that by 96 hours (four doses) the inhibition of platelet MAO-B activity is approximately 95% after a daily dose of 2.5 mg selegiline, whereas it takes only 48 hours (two doses) for doses of 5 mg and 7.5 mg to achieve this degree of inhibition. The pharmacokinetic-pharmacodynamic model was best described by a sigmoidal Emax model with an effect compartment. Based on the inhibition of MAO-B activity, a reduction in daily oral dose of selegiline appears possible without compromising the therapeutic effect. Therefore, lower doses of selegiline should be tested in clinical trials.     

Desmethylselegiline, a metabolite of selegiline, is an irreversible inhibitor of monoamine oxidase type B in humans

Selegiline, an irreversible and selective inhibitor of monoamine oxidase type B (MAO-B), is metabolized into desmethylselegiline, levomethamphetamine, and levoamphetamine. In animal experiments, desmethylselegiline also has been shown to be an irreversible inhibitor of MAO-B. This study investigated the inhibitory potential of MAO-B and the pharmacokinetics of desmethylselegiline in humans. A double-blind, crossover trial was performed to compare the effects of a single dose (10 mg) of selegiline or desmethylselegiline on MAO-B platelet activity. The urinary excretion of phenylethylamine, which is considered to be a parameter of MAO-B inhibition, also was measured. The concentrations of selegiline, desmethylselegiline, and their metabolites were measured in plasma after administration of the two compounds. Ten healthy volunteers participated in the study. There was a clear inhibition of platelet MAO-B by both compounds. Desmethylselegiline caused a 63.7 +/- 12.7% inhibition of platelet MAO-B compared with 96.4 +/- 3.9% caused by selegiline. The maximal inhibition by desmethylselegiline was reached significantly later after desmethylselegiline (time to reach maximal inhibition [tmax], 27 +/- 20 hours) than after selegiline administration (tmax, 1.4 +/- 1.4 hours). The platelet MAO-B activity returned to baseline levels within 2 weeks, thus reflecting the irreversible nature of the inhibition by both compounds. The cumulative 48-hour excretion of phenylethylamine was 33% lower after desmethylselegiline than after selegiline administration. All three major metabolites of selegiline could be detected in plasma after selegiline administration. Levoamphetamine was the only metabolite of desmethylselegiline. The area under the concentration-time curve from time 0 to 24 hours (AUC0-24) of desmethylselegiline was 33 times higher than that of selegiline, suggesting a better bioavailability of desmethylselegiline. Desmethylselegiline is an orally active, irreversible inhibitor of MAO-B and could possibly be used to treat Parkinson's disease in the same way as selegiline.     

Immunoexpression of the steroidogenic enzymes 3-beta hydroxysteroid dehydrogenase and 17 alpha-hydroxylase, C17,20 lyase and the receptor for luteinizing hormone (LH) in the fetal rat testis suggests that the onset of Leydig cell steroid production is independent of LH action

OBJECTIVE: The objective of this study was to investigate the effect of selegiline first as monotherapy and then in combination with levodopa in the early phase of PD. METHODS: A total of 157 de novo PD patients were randomized to receive either selegiline or placebo in a double-blind study until levodopa therapy became necessary. Thereafter, the drugs were withdrawn for an 8-week washout period to evaluate the possible symptomatic effect of selegiline. RESULTS: Analysis of Kaplan-Meier survival curves for each group showed that selegiline delayed significantly the need for levodopa therapy (p = 0.028). The semiannual rate of disability progression was slowed down significantly in the selegiline group analyzed with the Unified Parkinson's Disease Rating Scale (total and motor scores; p < 0.001). Selegiline had a "wash-in" effect (i.e., an initial symptomatic amelioration of PD at 6 weeks and 3 months). However, after the 8-week washout period, no significant differences in the deterioration of disability between the groups was revealed in any of the scales, suggesting that besides having a slight symptomatic effect, selegiline may also have neuroprotective effects. Similarly, the progression of symptoms from baseline to the end of the washout period was significantly slower (p = 0.033) in the selegiline group when the progression was adjusted by the time to reach the end point. Selegiline was well tolerated. CONCLUSIONS: Selegiline delayed significantly the need to start levodopa in early PD. After a 2-month washout period (before the start of levodopa therapy) no significant symptomatic effect of selegiline was seen in comparison with the placebo group, supporting the concept of neuroprotective properties of the drug.     

Effect of catechol-O-methyl transferase inhibition on peripheral and central metabolism of 6-[18F]fluoro-L-dopa

In the presence of carbidopa, L-3,4-dihydroxy-6-[18F]fluorophenylalanine ([18F]fluoro-DOPA) is mainly metabolized by catechol-O-methyl transferase. We studied the effects of entacapone, a peripheral catechol-O-methyl transferase inhibitor, on striatal [18F]fluoro-DOPA uptake in rats. Rats were pretreated with carbidopa, entacapone or both before high specific activity (> 2 Ci/mmol) [18F]fluoro-DOPA administration. Entacapone alone antagonized the appearance of methylated metabolites in plasma, striatum and cerebellum but did not increase striatal [18F]fluoro-DOPA availability. Entacapone added to carbidopa significantly increased the striatum/cerebellum total radioactivity ratio (1.4 versus 1.2 in rats with carbidopa, 1.0 in controls) but significant levels of methylated metabolites were found in the brain. Entacapone added to carbidopa might increase the striatum/cerebellum total radioactivity ratio in humans undergoing [18F]fluoro-DOPA positron emission tomography (PET) studies. However, the appearance of methylated metabolites in the brain could hamper quantification of the PET data.     

Pharmacokinetic-pharmacodynamic interactions between two selective monoamine oxidase inhibitors: moclobemide and selegiline

The objectives of this study were to assess potential pharmacokinetic and pharmacodynamic interactions between moclobemide and selegiline. Two groups of 12 healthy male and female subjects were treated with 200 mg moclobemide or 5 mg selegiline b.i.d. for 16 days. On study day 8, the alternative active drug or placebo was added to the respective treatments. Concentration-time profiles of moclobemide and two of its main metabolites and 3,4-dihydrox/phenylglycol (DHPG, a norepinephrine metabolite), 5-hydroxy-indoleacetic acid (HIAA, a serotonin metabolite), and 3,4-dihydroxyphenylacetic acid (DOPAC, a dopamine metabolite) in plasma as well as MAO-B activity and serotonin concentration in platelets were determined at steady state during monotreatment and combined treatment. The pharmacokinetic parameters of moclobemide and its metabolites changed on multiple dosing but were not influenced to a relevant extent by concomitant administration of selegiline. The measured pharmacodynamic parameters, expressed as the maximum effect on a study day and the area under the effect-time curve, characterized the drugs' influence on peripheral neurotransmitter metabolism. The most reliable variables to assess inhibition of MAO-A and -B in humans proved to be DHPG in plasma and serotonin in platelets and MAO-B activity in platelets, respectively. Several variables (DHPG, platelet serotonin) suggested that selegiline has some MAO-A inhibitory activity. This became particularly apparent upon addition of selegiline to moclobemide treatment; i.e., the effects of combined moclobemide and selegiline treatment were statistically greater than those of moclobemide monotreatment. Moclobemide alone exerted a slight inhibition of platelet MAO-B activity. The reported pharmacodynamic interactions are not considered to be clinically relevant. However, due to the previously found supraadditive tyramine potentiation upon simultaneous treatment, moclobemide and selegiline should only be combined when applying dietary restrictions with respect to tyramine.     

Impaired simultaneous cognitive task performance in Parkinson's disease: a dopamine-related dysfunction

Patients with Parkinson's disease (PD) have trouble programming two separate motor acts concurrently. We tested the hypotheses that (1) PD patients may also have difficulty processing two cognitive tasks simultaneously, and (2) the expected deficit may be related to the striatal dopaminergic depletion. We used auditory and visual choice reaction time (CRT) tasks, presented either separately or concurrently, and compared the performance of three groups of PD patients: a group of patients under their usual dose of levodopa ("standard"); a group assessed both at the time of maximal clinical benefit ("on" state) and at the time of minimal clinical benefit (treatment withdrawn for about 18 hours; "off" state); and a group of recently diagnosed untreated patients ("de novo"). Compared with controls, standard and "on" state patients had a normal performance for both separate and concurrent CRT tasks. In contrast, "off" state and de novo patients had a normal performance in the separate CRT tasks but significant deficits in the concurrent CRT tasks. These results suggest that adequate dopaminergic transmission is necessary for concurrent processing of cognitive information and that the striatum integrates the sensorimotor information required to program cognitive acts.     

Effect of selegiline against selective neurotoxins

The complexity of the pharmacological activity of selegiline cannot be considered only as a result of a simple MAO-B inhibition. The mechanism of its neuroprotective action against the noradrenergic neurotoxin DSP-4 was widely studied (-)-p-fluoro-deprenyl (PFD), the chemical derivative of selegiline, with its possible metabolites were also involved into these studies. The results suggested that the uptake inhibitory effect of selegiline, and mainly that of its metabolite (-)-methylamphetamine (MA), played an essential role in the protection. MA was more potent to inhibit the uptake of noradrenaline and dopamine, than the parent compound. Neither selegiline nor its metabolite inhibited the reuptake of serotonin. In respect of the protection against DSP-4 induced toxicity PFD and its metabolites behaved similarly to selegiline, but their effects were more lasting than that of selegiline. After oral treatment selegiline undergoes an intensive "first pass" metabolism, which leads to an enhanced formation of MA. The better understanding of the fate of selegiline in the body, including its pharmacokinetic behaviour and metabolism, may contribute to a better knowledge of the complex pharmacological activity of the drug. The results could be summarised as follows. a) MAO-B inhibition-which is due to the parent compound-is an irreversible "hit and run" effect, the level of which after an initial phase is independent of the presence of the substance which caused it. b) The uptake inhibition is a reversible process and strictly proportional to the concentration of the substance responsible for the effect. In this respect the uptake inhibitory action of the metabolites exceeds that of the parent compounds. The role of the reversible uptake inhibition in neuroprotection may partly explain the need of the daily administration of selegiline to parkinsonian patients in spite of the irreversible MAO-B inhibitory action of the drug.     

Influence of repeated levodopa administration on rabbit striatal serotonin metabolism, and comparison between striatal and CSF alterations

Parkinson's disease (PD) is characterized by decreased striatal dopamine, but serotonin (5-HT) is also reduced. Because 5-HT decreases following a single levodopa injection, levodopa has been suggested to contribute to PD's serotonergic deficits. However, in a recent study, rat striatal serotonin levels were reported to increase following 15-day levodopa administration. To address this issue, we administered levodopa (50 mg/kg) to rabbits for 5 days, then measured serotonin, its precursors tryptophan and 5-hydroxytryptophan (5-HTP), and its major metabolite 5-hydroxyindole-acetic acid (5-HIAA) in striatum and CSF. Striatal serotonin and tryptophan were unchanged, while 5-HTP and 5-HIAA increased 4- and 7-fold, respectively. CSF 5-HTP and 5-HIAA were also significantly increased. In levodopa-treated animals, 5-HTP concentrations were moderately correlated (r = 0.679) between striatum and CSF, while weak correlations were present between striatal and CSF concentrations of both serotonin and 5-HIAA. These results suggest that repeated levodopa treatment increases striatal serotonin turnover without changing serotonin content. However, levodopa-induced alterations in striatal serotonin metabolism may not be accurately reflected by measurement of serotonin and 5-HIAA in CSF.     

Assessment of clinical assessment reliability among researchers of a multicenter clinical trial

Formal studies examining the antiparkinsonian efficacy of levodopa and pergolide monotherapy in de novo Parkinson's disease (PD) are lacking. The authors conducted a preliminary, 6-month, open-label parallel experimental study with de novo consecutive PD patients who were randomly assigned to three daily doses of pergolide (n = 10; mean age, 63.7 years; mean Hohen & Yahr score, 1.5; mean final dose, 2.8 mg daily) or levodopa (n = 10; mean age, 67.3 years; mean Hohen & Yahr score, 1.8; mean final dose, 435 mg daily). Doses were titrated individually according to patients' evaluation of their own functional ability, known side-effects, and a monthly administration of the Unified Parkinson's Disease Rating Scale (UPDRS) by a clinician blind to the treatment regime. All patients completed the study. There were no significant basal differences between groups and no significant treatment ortreatment-by-time effects in UPDRS scores (according to two-way ANOVA). A clear time effect was observed for most of the functional and motor variables (p < 0.001), with significant improvement during the first month that was maintained for the duration of the study in both groups. Side effects were mild, transient, and comparable. In this preliminary study, pergolide and levodopa exhibited similar symptomatic efficacy and incidence of side effects in the short-term treatment of de novo PD patients at their usual age of clinical manifestation.     

Pharmacokinetic evaluation of a selegiline pulsatile oral delivery system

Selegiline is a selective, irreversible inhibitor of MAO-B, used in the treatment of Parkinson's disease, either alone or as an adjunct to L-DOPA. The sole recommended dosing regimen is 5 mg given in the morning and at noon with breakfast and lunch. A pulsatile oral dosage form was developed to mimic the conventional tablet release from two oral administrations separated by 4 h, to permit once-daily dosing and increase compliance. The pharmacokinetics of the pulsatile delivery system was studied in six healthy male volunteers. The plasma concentration-time profile from the pulsatile system of selegiline and metabolites is dissimilar to that obtained from the 5 mg bid administration of the conventional tablet and cannot be considered to be bioequivalent. The initial pulse of the delivery system is rapidly absorbed but to a lesser extent than the conventional regimen; the second pulse exhibits absorption which is delayed and prolonged. The decrease in the selegiline concentration may be due to the less absorptive surface of the lower GI tract which is available to the second pulse. Another reason could be the disparity between the in vitro and in vivo release profiles from the second pulse. Compartmental analysis indicates that the ratio of formation-absorption rate constant for the selegiline to N-desmethylselegiline pathway decreases from 1.57 +/- 1.04 for the first pulse to 0.61 +/- 0.54 for the second pulse of the pulsatile delivery system, suggesting that the upper portion of the GI tract has a greater capacity to convert selegiline to N-desmethylselegiline than the lower GI tract. The lack of in vivo and in vitro correlation is most likely due to site specific absorption/metabolism. Regimen has been previously shown to be a significant factor in estimating the extent of selegiline and metabolite exposure following oral administration. The inequivalence of dosing regimens of the same total daily dose may ultimately be linked to the saturability of gut wall metabolism. This phenomenon may preclude the development of novel delivery systems designed to mimic the recommended dosing regimen of the conventional Eldepryl tablet.     

Anticonvulsant efficacy of L-deprenyl (selegiline) during chronic treatment in mice: continuous versus discontinuous administration

We have previously reported that L-deprenyl (selegiline), an irreversible inhibitor of monoamine oxidase type B (MAO-B), exerts anticonvulsant activity against different seizure types in mice and rats. The anticonvulsant effect of L-deprenyl was rapid in onset but short lasting, arguing in favor of other, reversible mechanisms of L-deprenyl as a basis for the anti-seizure activity. For further evaluation, we administered L-deprenyl continuously via subcutaneously implanted osmotic minipumps in mice and determined the threshold for myoclonic seizures induced by i.v. infusion of pentylenetetrazol repeatedly during prolonged treatment, with treatment periods lasting from 2 to 4 weeks. For comparison with continuous administration via minipumps, L-deprenyl was injected once daily at a dose (10 mg/kg) known to produce complete and irreversible inhibition of MAO-B and anticonvulsant effects after acute administration in rodents. Continuous administration of L-deprenyl, 50 or 100 mg/kg per day, led to a progressive increase in seizure threshold in the absence of any observable adverse effects, while administration of 10 mg/kg per day via minipumps was devoid of any significant anticonvulsant effect. When 10 mg/kg were administered once daily in the afternoon for 4 weeks and the seizure threshold was determined repeatedly in the morning, no significant anticonvulsant effect was observed. The data argue against a critical role of MAO-B inhibition in the anticonvulsant activity of L-deprenyl but suggest that other, reversible biochemical and cellular effects known to occur at higher doses of this drug are involved in this respect. In view of the short half-life of L-deprenyl, these reversible effects can only be maintained during chronic treatment when the drug is given continuously such as via implanted minipumps.     

G-CSF increases secretion of urokinase-type plasminogen activator by human lung cancer cells

AIMS: To examine the feasibility of using the human iris in vivo for the assessment of the interaction between tyramine and monoamine oxidase (MAO) inhibitors. To examine the relative roles of the two forms of MAO in terminating the response to sympathomimetic amines in the iris, by comparing the effects of single oral doses of moclobemide, a selective MAO-A inhibitor, and selegiline, a selective MAO-B inhibitor, on mydriatic responses to tyramine. METHODS: Twelve healthy male volunteers participated in three monthly sessions, each associated with ingestion of one capsule (moclobemide 450 mg, selegiline 10 mg, or placebo), according to a double-blind, balanced, cross-over design. Tyramine hydrochloride eye-drops (75 mM, 2 x 10 microl) were instilled three times in the left conjuctival sac at 40 min intervals. Pupil diameter was monitored with a binocular infrared television pupillometer before and for 4.5 h after ingestion of the capsule. The pupillary response to tyramine was expressed as the area under the pupil diameter x time curve (arbitrary units). A blood sample was taken before and 2 h after ingestion of the capsule, for the assay of platelet MAO-B activity, and plasma 3,4-dihydroxyphenylglycol (DHPG) concentration, an index of MAO-A activity. Platelet MAO activity was assayed radiochemically, using [14C]-phenylethylamine as substrate, and plasma DHPG by high performance liquid chromatography (h.p.l.c.). The results were analysed using analysis of variance with repeated measures, followed by Bonferroni's corrected t-test, using a significance criterion of P < 0.05. RESULTS: Both moclobemide and selegiline, compared with placebo, caused significant miosis in the right (untreated) eye. The changes in pupil diameter (mm +/- s.e. mean) from the pretreatment measurement were: placebo -0.09 +/- 0.07, moclobemide -0.52 +/- 0.09, selegiline -0.26 +/- 0.1. The mydriatic response to tyramine was potentiated by moclobemide, compared with the response recorded in the presence of placebo. The responses to tyramine (arbitrary units +/- s.e. mean) were: placebo 77.08 +/- 11.65, moclobemide 140.25 +/- 18.9, selegiline 72.75 +/- 12.35. Both moclobemide and selegiline significantly reduced platelet MAO activity, compared with placebo. The changes in platelet MAO activity (nmol h(-1) mg(-1) protein +/- s.e. mean) from the pretreatment level were: placebo 0.5 +/- 0.62, moclobemide -6.7 +/- 0.66, selegiline -17.7 +/- 0.87. Moclobemide significantly reduced plasma DHPG concentration, compared with placebo. The changes in plasma DHPG concentration (nmol l(-1) +/- s.e. mean) from the pretreatment level were: placebo -0.01 +/- 0.24, moclobemide -4.98 +/- 0.32, selegiline -0.51 +/- 0.26. CONCLUSIONS: The potentiation of tyramine-evoked mydriasis by moclobemide is likely to reflect the inhibition of MAO-A activity in the iris, consistent with the activity of this enzyme in sympathetic nerve terminals. The lack of effect of selegiline on tyramine-evoked mydriasis argues against a role of MAO-B in terminating the effects of sympathomimetic amines in the iris. The effects of the two drugs on platelet MAO activity and plasma DHPG concentration are in agreement with previous reports and consistent with the relative selectivity of moclobemide for MAO-A and of selegiline for MAO-B. The miosis caused by the two MAO inhibitors is likely to be due to a central sympatholytic action of the drugs.     

Three-dimensional positron emission tomography imaging system and its application for medical use

Current positron emission tomography is capable for three dimensional data acquisition and reconstruction (3D PET). The main advantage of 3D PET is its detectability for lower tracer concentrations. The images by a 3D PET have better signal to noise ratios compared to those by conventional 2D PET. This point is especially important for the studies of distributions of ligands for neuroreceptors such as F-18 FDOPA and C-11 YM-01951, since these ligands show low accumulation in brain. Reduction of scanning time is useful as well for patients are permitting extended scanning periods     

Reduced striatal tyrosine hydroxylase activity is not accompanied by change in responsiveness of dopaminergic receptors following chronic treatment with deprenyl

Deprenyl is the only selective monoamine oxidase B (MAO-B) inhibitor that is in clinical use for the treatment of Parkinson's disease. Our previous studies showed that chronic treatment of rats with low (MAO-B selective) doses of deprenyl inhibited dopamine (DA) re-uptake and enhanced DA release in the striatum. These changes could affect DA synthesis rate by activation of negative feedback loops. Chronic deprenyl treatment has also been suggested to cause down-regulation of release-modulating DA receptors. The effects of chronic and acute treatment with deprenyl on ex vivo striatal tyrosine hydroxylase activity were therefore studied, by determination of steady-state tissue level of DOPA following administration of NSD-1015 (100 mg/kg i.p.). In addition, we assessed changes in the in vivo sensitivity of dopaminergic receptors from the reduction in DOPA extracellular level after systemic apomorphine administration (2.5 mg/kg s.c.), following elevation of microdialysate DOPA by systemic or local aromatic amino acid decarboxylase inhibition with NSD-1015. Chronic treatment with deprenyl (0.25 mg/kg s.c. daily for 21 days) caused a significant reduction in tyrosine hydroxylase activity to 60% of control, with no change in the apomorphine-induced reduction of microdialysate DOPA and DOPAC. The reduction in tyrosine hydroxylase activity is compatible with our previous results showing an increase in striatal DA extracellular level following chronic treatment with deprenyl. The increased extracellular striatal DA level could reduce tyrosine hydroxylase activity through activation of a negative feedback loop, by activation of either presynaptic or postsynaptic DA receptors.     

L-DOPA exacerbates amphetamine-induced dopamine depletion

Administration of L-DOPA to Parkinson patients has been suggested to exacerbate "functional denervation" of the nigrostriatal system. Therefore, experiments were conducted to determine if L-DOPA combined with the DOPA decarboxylase inhibitor, Ro4-4602 (benserazide hydrochloride) would potentiate amphetamine-induced neurotoxicity. Mice received two injections of saline or benserazide + L-DOPA (25.0 or 100.0 mg/kg) interspersed with four injections of amphetamine (15.0 mg/kg) at 2-h intervals. Significant depletion of striatal dopamine, DOPAC, and HVA was evident 1 wk following amphetamine administered with or without 25.0 mg/kg L-DOPA + benserazide, whereas 100.0 mg/kg L-DOPA + benserazide potentiated amphetamine-induced depletion of striatal dopamine (17 vs 28% of control values). This enhanced toxicity may be consequent to increased dopamine turnover following L-DOPA (360 vs 231%), a situation akin to that observed in compromised dopaminergic nigrostriatal systems of parkinsonian patients. Furthermore, striatal 5-HT was not altered by amphetamine alone, whereas concurrent administration of L-DOPA/ benserazide depleted 5-HT to 82% of control values. No changes were evident in the frontal cortex following amphetamine with or without concurrent L-DOPA/benserazide; however, L-DOPA/benserazide administered alone reduced 5-HT and 5-HT turnover to 58% of control values.     

In vivo studies on striatal dopamine D1 and D2 site binding in L-dopa-treated Parkinson's disease patients with and without dyskinesias

Dyskinesias are usually seen in Parkinson's disease (PD) patients after several years of L-dopa therapy. Their presence has been attributed to supersensitivity of striatal D1 and D2 receptors. We have used PET to assess striatal D2 receptor binding in untreated PD patients and striatal D1 and D2 binding in L-dopa-treated PD patients. Untreated patients showed a 14% increase in mean D2 receptor binding in the putamen contralateral to the more affected limbs (p < 0.02). Treated patients were segregated into subgroups according to the presence or absence of dyskinesias. There were no differences in mean caudate and putamen D1 and D2 binding between dyskinetic and nondyskinetic patients, matched for duration of clinical disease. Both dyskinetic and nondyskinetic PD subgroups showed a similar 16% reduction of mean caudate D2 binding (p < 0.01) with normal D2 binding in putamen. Mean caudate and putamen D1 binding potentials of both subgroups were reduced by 10% compared with those of controls, though this trend did not reach significance. Putamen D1 binding, however, showed a negative correlation with duration and L-dopa treatment (p < 0.03). These findings suggest that, while exposure of PD patients to L-dopa may be associated with reductions in caudate D2 and caudate and putamen D1 receptor, dyskinesias are unlikely to result from alterations in striatal dopamine receptor binding.     

Oral Dyskinesias and striatal lesions in rats after long-term co-treatment with haloperidol and 3-nitropropionic acid

The pathophysiologic basis of tardive dyskinesia remains unclear. It has been proposed that tardive dyskinesia may be a result of excitotoxic neurodegeneration in the striatum caused by a neuroleptic-induced increase in striatal glutamate release and impaired energy metabolism. To investigate this hypothesis, haloperidol decanoate (38 mg/kg/four weeks intramuscularly) and the succinate dehydrogenase inhibitor 3-nitropropionic acid (8 mg/kg/day via subcutaneous osmotic mini-pumps), were administered alone or together for 16 weeks to four-months-old rats. Control rats received sesame oil intramuscularly and had empty plastic tubes subcutaneously. Vacuous chewing movements, a putative analogue to human tardive dyskinesia, were recorded during and after drug treatment. Haloperidol alone, 3-nitropropionic acid alone, and 3-nitropropionic acid+haloperidol treatments induced an increase in vacuous chewing movements. However, vacuous chewing movements were more pronounced and appeared earlier in rats treated with 3-nitropropionic acid+haloperidol. After drug withdrawal, increases in vacuous chewing movements persisted for 16 weeks in the haloperidol alone and 3-nitropropionic acid+haloperidol group and for four weeks in the 3-nitropropionic acid alone group. Brains from each group were analysed for histopathological alterations. Bilateral striatal lesions were present only in rats with high levels of vacuous chewing movements in the 3-nitropropionic acid+haloperidol-treated rats. Nerve cell depletion and astrogliosis were prominent histopathologic features. There was selective neuronal sparing of both large- and medium-sized aspiny striatal neurons. These results suggest that mild mitochondrial impairment in combination with neuroleptics results in striatal excitotoxic neurodegeneration which may underlie the development of persistent vacuous chewing movements in rats and possibly irreversible tardive dyskinesia in humans.     

Differential effects of levodopa on dopaminergic function in early and advanced Parkinson's disease

The effect of levodopa on L-[11C]DOPA influx rate was evaluated in patients with early and advanced Parkinson's disease (PD) by using positron emission tomography (PET). The patients were scanned both drug-free and after a subsequent therapeutic levodopa infusion. Regional analysis of striatal L-[11C]DOPA influx rate showed a correlation to the degenerative loss of nerve terminals reported at postmortem analysis in PD. Levodopa induced markedly differential effects on the striatal L-[11C]DOPA influx rate in early and advanced patients. In patients with mild PD, levodopa infusion decreased L-[11C]DOPA influx, whereas in patients with advanced PD, levodopa induced significant upregulation of L-[11C]DOPA influx. These changes were confined to the putamen and were, in both patient categories, most prominent in the dorsal part of the region. The present investigation demonstrates a marked shift in the modulatory action of levodopa with the advancement of PD and suggests the induction of positive feedback in advanced PD. These findings could help explain the less graded clinical response to levodopa in advanced PD and would thus have importance for the understanding of the pathogenesis underlying motor fluctuations.     

Effect of monoamine oxidase A and B and of catechol-O-methyltransferase inhibition on L-DOPA-induced circling behavior

The effect of enzyme-inhibiting adjuvants on L-DOPA + benserazide-induced contralateral turning in unilateral 6-hydroxydopamine (6-OHDA)-lesioned rats was studied. Both the number of turns and the duration of turning were examined. Inhibition of MAO-A with 10 mg/kg Ro 41-1049 increased both parameters; inhibition of COMT with 30 mg/kg Ro 40-7592 had a similar effect. In contrast, inhibition of MAO-B with 10 mg/kg Ro 19-6327 did not change turning behavior. A further potentiation of turning behavior was observed after the combined administration of both the MAO-A and COMT inhibitor. MAO-A inhibition in conjunction with MAO-B inhibition prolonged the duration of L-DOPA-induced turning but had no effect on the number of turns. However, in conjunction with COMT inhibition, 10 mg/kg of the MAO-B inhibitor, Ro 19-6327, significantly affected both the number and duration of turning behavior. An even further potentiation of turning behavior was observed after the combined administration of all three enzyme-inhibitors.