Cerebral dopamine concentrations during levodopa treatment.
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Brain↗
Biomedical subjects
P Cumming
Publications and source records attributed to P Cumming.
Cerebral 6-[(18)F]fluoro-L-DOPA (FDOPA) metabolism in pig studied by positron emission tomography.
We measured 6-[(18)F]fluoro-L-DOPA (FDOPA) uptake and metabolism in the brain of 4-month-old female pigs (n = 8) using a high-resolution positron emission tomograph (PET) in 3D mode. The mean net blood-brain clearance of FDOPA (K(i)(D)) to striatum was 0.011 ml g(-1) min(-1). Correcting for the elimination of decarboxylated metabolites from striatum (k(loss) = 0.004 min(-1)) increased the apparent magnitude of the estimate of K(i)(D) by 50%, at the expense of doubling the variance of the mean estimate. The mean decarboxylation rate of FDOPA in striatum relative to the cerebellum input (k(3)(s)) was 0.008 min(-1). For multicompartmental analyses, the FDOPA partition volume (V(e)(D)) was constrained to the individual value observed in cerebellum (mean = 0.53 ml g(-1)), with correction for the presence in brain of the plasma metabolite 3-O-methyl-FDOPA (OMFD). Using the first 60 min of the dynamic PET scans, the rate constant of FDOPA decarboxylation (k(3)(D)) was estimated to be 0.037 min(-1 )in striatum, but was not significantly different than zero in frontal cortex. Fitting of a compartmental model correcting for elimination of decarboxylated metabolites to the complete PET frame-sequence (120 min) increased the variance of the estimate of k(3)(D) in striatum. The magnitude of k(3)(D) in striatum of young pig was less than values estimated previously in neonatal piglet, adult monkey, and human. MRI-based simulations predicted that recovery of radioactivity from pig striatum was highly sensitive to the volume of interest. We conclude that the spatial resolution of our tomograph reduces the apparent magnitude of k(3)(D) in striatum. However, anaesthetised pigs are an appropriate experimental model for PET studies of DOPA decarboxylation in striatum.
Aging↗
Pharmacokinetics of radiotracers in human plasma during positron emission tomography.
Many radiopharmaceuticals for positron emission tomography (PET) are substantially metabolized in peripheral organs. Pharmacological treatments intended to alter cerebral metabolism might also alter radiotracer metabolism, consequently altering the cerebral uptake. First-order rate constants for the metabolism of PET tracers can be calculated by a linear graphical method from the precursor and metabolite concentrations measured in plasma extracts fractionated by HPLC. We tested the effects of specific pharmacological challenges on the plasma kinetics of six tracers used for PET studies of neurotransmission. The rate of O-methylation of circulating [(18)F]fluorodopa, a tracer of dopa decarboxylase activity in brain, was unaffected by pretreatment with amantadine, an antagonist of glutamate receptors. [(11)C]Deprenyl, a tracer of monoamine oxidase activity, was rapidly metabolized to [(11)C]methamphetamine and polar metabolites in healthy volunteers. The net rate constant of this metabolism was three times higher in a group of subjects under treatment for epilepsy, consistent with induction of hepatic microsomal enzymes by antiepileptic drugs. [(11)C]Sch 23390, a ligand for dopamine D1 receptors, was rapidly metabolized to polar metabolites. The net rate constant of metabolism was unaffected by pretreatment with lorazepam. [(11)C]-(S)-Nicotine, a ligand for nicotinic receptors, was rapidly metabolized to [(11)C]-(S)-cotenine, which is less polar than the parent compound. Pretreatment with mazindol, a dopamine uptake inhibitor, was without effect on peripheral metabolism of [(11)C]-(S)-nicotine. [(11)C]WIN 35,428, a tropane derivative which labels dopamine uptake sites, was metabolized to a nonpolar metabolite, but so slowly that the rate constant of this process could not be calculated. [(11)C]Raclopride, a ligand for dopamine D2 receptors, was first metabolized to a nonpolar metabolite, which then yielded two hydrophilic metabolites. The initial metabolic step was substantially blocked by pretreatment with amphetamine, possibly indicative of competitive inhibition of microsomal oxidation. Together, these results indicate that the linear graphic method is useful for estimating the kinetics of the plasma metabolism of many widely used PET tracers. Drug-drug interactions were revealed in subjects treated with specific pharmacological agents prior to tracer administration.
Benzazepines↗
Cocaine withdrawal and the cerebral influx of [18F]fluoro-L-DOPA (FDOPA)
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Brain Chemistry↗
NMSP binding to dopamine and serotonin receptors in MPTP-induced parkinsonism: relation to dopa therapy.
We tested the hypothesis that N-methylspiperone binding to dopamine D2 receptors must be reduced when L-dopa therapy of parkinsonism augments the binding of dopamine to the receptors and improves the clinical state expressed by the Hoehn & Yahr stage. A patient with MPTP-induced parkinsonism underwent two positron emission tomographic studies of the D2-like dopamine receptors with N-[11C]methylspiperone (NMSP). The first study took place 3 days after cessation of the L-dopa medication, the second 5 days after its resumption. Noticeable clinical deterioration occurred during both studies, consistent with significant dopamine receptor blockade by NMSP and elevated NMSP binding in both scans. The dopa treatment did not reduce the NMSP binding. On the contrary, the rate of binding of NMSP (k3) was increased on-dopa, compared to off-dopa. The increase was consistent with the slightly greater dopamine receptor density estimated after resumption of the dopa therapy. The NMSP binding to serotonin receptors suggested lower synaptic serotonin on-dopa than off-dopa. The results are consistent with negative correlation between the Hoehn & Yahr stage and the amount of dopamine bound to dopamine D2 receptors. Low synaptic serotonin may explain the depression seen in some patients on dopa for Parkinson's disease.
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
Trauma related symptoms in British soldiers 36 months following a tour in the former Yugoslavia.
This paper measures the prevalence of psychological symptoms in two British Infantry battalions, 36 months after being involved in peace keeping operations in the former Yugoslavia during November 1992-April 1993. Those deployed had a high level of post traumatic stress disorder (16%) compared to (9%) in the control group. However, there was a high level of probable psychiatric disorder in both the Bosnia and control group of around 25%. The possible explanations for these findings are discussed.
Adult↗
Compartmental analysis of dopa decarboxylation in living brain from dynamic positron emission tomograms.
The trapping of decarboxylation products of radiolabelled dopa analogs in living human brain occurs as a function of the activity of dopa decarboxylase. This enzyme is now understood to regulate, with tyrosine hydroxylase, cerebral dopamine synthesis. Influx into brain of dopa decarboxylase substrates such as 6-[18F]fluorodopa and beta-[11C]dopa measured by positron emission tomography can be analyzed by solution of linear differential equations, assuming irreversible trapping of the decarboxylated products in brain. The isolation of specific physiological steps in the pathway for catecholamine synthesis requires compartmental modelling of the observed dynamic time-activity curves in plasma and in brain. The several approaches to the compartmental modelling of the kinetics of labelled substrates of dopa decarboxylase are now systematically and critically reviewed. Labelled catechols are extensively metabolized by hepatic catechol-O-methyltransferase yielding brain-penetrating metabolites. The assumption of a fixed blood-brain permeability ratio for O-methyl-6-[18F]fluorodopa or O-methyl-beta-[11C]dopa to the parent compounds eliminates several parameters from compartmental models. However, catechol-O-methyltransferase activity within brain remains a possible factor in underestimation of cerebral dopa decarboxylase activity. The O-methylation of labelled catechols is blocked with specific enzyme inhibitors, but dopa decarboxylase substrates derived from m-tyrosine may supplant the catechol tracers. The elimination from brain of decarboxylated tracer metabolites can be neglected without great prejudice to the estimation of dopa decarboxylase activity when tracer circulation is less than 60 minutes. However, elimination of dopamine metabolites from brain occurs at a rate close to that observed previously for metabolites of glucose labelled in the 6-position. This phenomenon can cause systematic underestimation of the rate of dopa decarboxylation in brain. The spillover of radioactivity due to the limited spatial resolution of tomographs also results in underestimation of dopa decarboxylase activity, but correction for partial volume effects is now possible. Estimates of dopa decarboxylase activity in human brain are increased several-fold by this correction. Abnormally low influx of dopa decarboxylase tracers in the basal ganglia is characteristic of Parkinson's disease and other movement disorders. Consistent with postmortem results, the impaired retention of labelled dopa is more pronounced in the putamen than in the caudate nucleus of patients with Parkinson's disease; this heterogeneity persists after correction for spillover. Current in vivo assays of dopa decarboxylase activity fail to discriminate clinically distinct stages in the progression of Parkinson's disease and are, by themselves, insufficient for differential diagnosis of Parkinson's disease and other subcortical movement disorders. However, potential new avenues for therapeutics can be tested by quantifying the rate of metabolism of exogenous dopa in living human brain.
Animals↗
Effect of catechol-O-methyltransferase inhibition on brain uptake of [18F]fluorodopa: implications for compartmental modelling and clinical usefulness.
The efficacy of levo-DOPA in the treatment of Parkinson's disease is potentiated by blockade of its peripheral metabolism with inhibitors of catechol-O-methyltransferase (COMT). Some COMT inhibitors may act entirely in the periphery (nitecapone, OR-462), while others may also have some activity in brain (entacapone, OR-611). We used positron emission tomography (PET) to test the effects of these two COMT inhibitors on the plasma kinetics and brain metabolism of the levo-DOPA analog 6-[18F]fluoro-L-dopa (FDOPA) in cynomolgus monkeys, employing a compartmental model for the assay of DOPA decarboxylase activity in living brain. Four monkeys each underwent two PET scans in the baseline condition, one PET scan after treatment with OR-462 (15 mg/kg, i.v.), and one PET scan after treatment with OR-611 (15 mg/kg, i.v.). Pharmacokinetic analysis of FDOPA metabolism in plasma indicated that these compounds blocked peripheral COMT activity by 80% for at least 60 minutes. Both COMT inhibitors increased the net availability of FDOPA in circulation, and increased the ratio of the radioactivity concentrations in striatum and occipital cortex, suggesting that [18F]fluorodopamine synthesis in striatum was potentiated. However, OR-611 treatment reduced the unidirectional (K1D) and net (Ki) blood-brain clearances of FDOPA, and also inhibited the rate of decarboxylation (k3D) of FDOPA in striatum. These observations suggest that high doses of OR-611 may partially antagonize the cerebral utilization of levo-DOPA. We used the present data to test the sensitivity of the compartmental model to the physiological constraint that the blood-brain permeabilities of the O-methylated plasma metabolite and FDOPA have a fixed ratio. In the groups with COMT inhibition, the estimates of k3D were insensitive to the magnitude of the permeability ratio. In the control group, the estimate of k3D increased by 40% as the magnitude of the constrained permeability ratio increased in the range of published estimates.
Animals↗
Enhanced [3H]DOPA and [3H]dopamine turnover in striatum and frontal cortex in vivo linked to glutamate receptor antagonism.
We tested the hypothesis that blockade of NMDA glutamate receptors in brain enhances dopamine turnover. We blocked this class of glutamate receptors in the rat brain in vivo with dizocilpine (MK-801) and measured the accumulation of radiolabeled DOPA and its metabolites as functions of time after intravenous bolus injection. Using the time courses of the accumulated metabolites, we calculated the turnover constants of enzymes mediating dopamine synthesis and catabolism. Dizocilpine treatment for 8 days enhanced the rates of DOPA decarboxylation and dopamine oxidation (monoamine oxidation) 4- and 16-fold, respectively, in neostriatum and 10- and 3-fold, respectively, in frontal cortex. The findings are not inconsistent with the hypothesis that the psychotomimetic properties of dizocilpine may be the manifestation of denervation hypersensitivity linked to activation of key enzymes of dopamine turnover in striatum.
Animals↗
[3H]DOPA formed from [3H]tyrosine in living rat brain is not committed to dopamine synthesis.
Tyrosine hydroxylase of catecholamine neurons catalyzes the synthesis of 3,4-dihydroxphenylalanine (DOPA), which is subsequently metabolized to dopamine by DOPA decarboxylase (DDC). However, DOPA is not committed to decarboxylation in vivo because export of DOPA from brain and metabolism of DOPA other than decarboxylation are possible. To estimate the relative magnitudes of the several fates of DOPA, the kinetics of the uptake and metabolism of L-[3H]tyrosine ([3H]Tyr, intravenous infusion) was measured in brain of rats pretreated with NSD 1015, an inhibitor of DDC. Some rats were pretreated with haloperidol before the blockade of DDC. The [3H]Tyr was incorporated into brain protein at a rate constant of 0.03 min(-1). The relative tyrosine hydroxylase activity in striatum was 0.005 min(-1) at 30 minutes after NSD 1015, 0.011 min(-1) 3 hours later, and 0.020 min(-1) after haloperidol treatment. The rate constant for the clearance of DOPA from brain (0.06 min(-1)) and earlier estimates of the rate constant of DDC activity in striatum (0.26 min(-1)) together predict that 80% of DOPA formed in normal rat striatum normally is available for dopamine synthesis. It follows that modulation of DDC activity can influence the rate of DA synthesis by affecting the relative magnitude of the several fates of DOPA in living brain.
Animals↗
The kinetic behaviour of [3H]DOPA in living rat brain investigated by compartmental modelling of static autoradiograms.
The kinetic behaviour of [3H]DOPA in living rat brain was investigated by compartmental modelling of measured activities from combined metabolite pools in a time-series (180 min) of static autoradiograms from right cerebral hemispheres. Two models of [3H]DOPA uptake and metabolism that incorporated the removal of the decarboxylation product, [3H]dopamine, from brain were significantly more accurate than a model in which [3H]dopamine accumulated irreversibly in situ. Present estimates of [3H]DOPA kinetic constants were compared to previously published results based on the analysis of measured activities from individual metabolite pools separated by chromatographic fractionation of [3H]DOPA metabolites in the left cerebral hemispheres of the same rats. Autoradiographic estimates of DOPA decarboxylase activity with respect to [3H]DOPA in brain (k3DOPA) were under-estimated several-fold relative to chromatographic estimates; this discrepancy is explained by post-mortem enzyme activity and omission of biological compartments from the models. However, autoradiographic estimates of the unidirectional blood-brain clearance of [3H]DOPA (K1DOPA) and monoamine oxidase activity with respect to [3H]dopamine in brain (k7DA') agreed with chromatographic estimates. This concordance represents the first empirical validation of compartmental modelling of autoradiographic data as a method for quantitatively investigating the kinetic behaviour of radiolabelled L-DOPA in living mammalian brain.
Animals↗
On the rate of decarboxylation of dopa to dopamine in living mammalian brain.
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Animals↗
On the accuracy of an [18F]FDOPA compartmental model: evidence for vesicular storage of [18F]fluorodopamine in vivo.
The biological accuracy of a nonlinear compartmental model describing the in vivo kinetics of L-3,4-dihydroxy-6-[18F]fluorophenylalanine ([18F]FDOPA) metabolism was investigated. Tissue activities for [18F]FDOPA and its labeled metabolites 3-O-methyl-[18F]FDOPA ([18F]OMFD), 6-[18F]fluorodopamine ([18F]FDA), L-3,4-dihydroxy-6-[18F]fluorophenylacetic acid ([18F]FDOPAC), and 6-[18F]fluorohomovanillic acid ([18F]FHVA) were calculated using a plasma [18F]FDOPA input function, and kinetic constants estimated previously by chromatographic fractionation of 18F-labeled compounds in plasma and brain extracts from rat. Present data accurately reflected the measured radiochemical composition in rat brain for tracer circulation times past 10 min. We formulated the hypothesis that the discrepancy between calculated and measured fractions of [18F]FDOPA and the deaminated metabolite [18F]FDOPAC at times earlier than 10 min reflected storage of [18F]FDA in vesicles without monoamine oxidase. This hypothesis explained the initially rapid appearance of [18F]FDOPAC in striatum by delayed transfer of [18F]FDA from cytosol into vesicles. We conclude that the simpler model of [18F]FDOPA compartmentation is accurate when the cytosolic and vesicular fractions of [18F]FDA are at steady-state; the approach to equilibrium has a time constant of 15-30 min. The present model is valid for positron emission tomography studies of [18F]FDOPA metabolism in living brain.
Animals↗
The effect of unilateral neurotoxic lesions to serotonin fibres in the medial forebrain bundle on the metabolism of [3H]DOPA in the telencephalon of the living rat.
We used quantitative autoradiography to measure the contribution of the 5-hydroxytryptamine (5-HT, serotonin) innervation of rat telencephalon to the synthesis of dopamine (DA) from exogenous L-DOPA. One week after stereotaxic infusions of 5,7-dihydroxy-tryptamine (5,7-DHT, 1.6 micrograms) into the right medial forebrain bundle (MFB), rats received [3H]DOPA (200 microCi,i.v.), which circulated for 90 min. The specific bindings in vitro of the 5-HT uptake site ligand [3H]citalopram and the DA uptake site ligand [125I]RTI-55 were measured in cryostat sections from the prosencephalon. In most structures ipsilateral to the lesion, [3H]citalopram specific binding was substantially reduced (50-90%). In the lateral habenula specific binding declined by only 30-40%, reflecting the presence of a 5-HT pathway deviating from the MFB at the mesencephalic flexure. [125I]RTI-55 binding in the basal ganglia was reduced by 50% on the side of the 5,7-DHT lesion, but was unperturbed in rats pretreated with desmethylimipramine (DMI). 5,7-DHT infusions decreased the synthesis of [3H]DA from [3H]DOPA in vivo in the basal ganglia by (40-90%). Pretreatment with DMI protected [3H]DA synthesis in the basal ganglia, but not in the olfactory tubercle and amygdala ipsilateral to the lesion. Whereas the 5-HT innervation does not contribute greatly to [3H]DA synthesis in the basal ganglia, a substantial proportion of [3H]DA synthesis in olfactory tubercle and amygdala requires an intact 5-HT innervation.
5,7-Dihydroxytryptamine↗
In vivo regulation of DOPA decarboxylase by dopamine receptors in rat brain.
To test the hypothesis that dopamine (DA) receptors influence cerebral DOPA-decarboxylase (DDC) activity in vivo, we used HPLC to measure the kinetics of the cerebral uptake and metabolism of [3H]DOPA in carbidopa-treated rats, and in rats also treated acutely with a DA receptor antagonist (flupenthixol, 2 mg/kg, intraperitoneally) or a DA receptor agonist (apomorphine, 200 microg/g, subcutaneously). The unidirectional blood-brain clearance of [3H]DOPA (K1DOPA, 0.030 mL g(-1) min(-1)) increased by 50% after flupenthixol. The magnitudes of the relative DDC activity (k3DOPA) in striatum (0.20 min(-1)), olfactory tubercle (0.11 min(-1)), and hypothalamus (0.15 min(-1)) of carbidopa-treated rats were doubled with flupenthixol, but cortical DDC activity was unaffected (0.02 min(-1)). Apomorphine reduced the magnitude of k3DOPA in striatum by 20%. The rate constant for catabolism of [3H]DA formed in brain (k7', monoamine oxidase [MAO] activity), which ranged from 0.025 min(-1) in striatum to 0.08 min(-1) in hypothalamus of carbidopa-treated rats, globally increased 2- to 4-fold after flupenthixol, and decreased to 0.003 min(-1) in striatum after apomorphine. These in vivo results confirm the claim that acute blockade of DA receptors with flupenthixol stimulates the synthesis of [3H]DA from [3H]DOPA, and that this [3H]DA is subject to accelerated catabolism. Conversely, activation of the DA receptors with apomorphine inhibits DDC activity and DA catabolism.
Animals↗
Controversies arising from recent FDOPA articles.
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Blood-Brain Barrier↗
Characterization of the antinociceptive properties of cimetidine and a structural analog.
The antinociceptive and pharmacological properties of the H2 receptor antagonist cimetidine and a novel cimetidine analog, SKF92374, were characterized. On both the hot-plate and tail-flick nociceptive tests, cimetidine and SKF92374 induced complete, dose-related analgesic responses when injected into the lateral ventricle of rats. SKF92374 showed strong similarities to cimetidine in analgesic efficacy, slope of dose-response curves and chemical structure, suggesting that these compounds share a common analgesic mechanism. In contrast, histamine induced submaximal antinociceptive effects, and the H3 antagonist thioperamide, a known HA-releasing drug, had little or no analgesic effects. Compared with cimetidine, SKF92374 showed very weak activity (400-fold lower affinity) on H2 receptors in vitro (isolated guinea pig atrium) and in vivo (rat gastric secretion). In addition, SKF92374 (100 microM) had neither agonist nor antagonist action on guinea pig ileum H1 receptors. SKF92374 was also a weak competitive antagonist of N alpha-methylhistamine-induced inhibition of electrically induced contractions of the guinea pig ileum (Kd = 5.2 microM), an H3 receptor-mediated response. Autoradiographic binding assays in guinea pig brain confirmed a weak antagonism of H3 receptors by SKF92374. The compound (up to 10 microM) also had no effect on unpurified rat brain histamine N-methyltransferase activity. These results support the hypothesis that cimetidine induces analgesia by a novel brain mechanism unrelated to H1, H2 or H3 receptors.
Analgesics, Non-Narcotic↗
Metabolism and blood-brain clearance of L-3,4-dihydroxy-[3H]phenylalanine ([3H]DOPA) and 6-[18F]fluoro-L-DOPA in the rat.
6-[18F]fluoro-L-DOPA (FDOPA) has been used as a tracer for the cerebral activity of L-3,4-dihydroxyphenylalanine (DOPA)-decarboxylase in studies of positron emission tomography (PET). However, the substitution of fluorine on the aromatic ring may alter the disposition and metabolism of FDOPA from that of endogenous DOPA. In the present study, the kinetics of the peripheral metabolism and the facilitated unidirectional blood-brain clearance of [3H]DOPA and FDOPA were compared in Wistar rats pretreated with carbidopa. In arterial plasma, FDOPA was O-methylated with an apparent rate constant (0.031 min-1) 3-fold that of [3H]DOPA in the same rats. The O-methylated metabolite of FDOPA (OMe-FDOPA) was eliminated from plasma at a rate constant (0.018 min-1) 3-fold that of OMe-[3H]DOPA. The mean unidirectional blood-brain clearance of FDOPA (4.5 mL.hg-1.min-1) in six brain regions was 60% higher than that of [3H]DOPA.
Animals↗