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Biomedical subjects

Y S Ding

Publications and source records attributed to Y S Ding.

At least 37 records · Page 2Linked to original sources
PubMed1999

Methylphenidate and cocaine have a similar in vivo potency to block dopamine transporters in the human brain.

The reinforcing effects of cocaine and methylphenidate have been linked to their ability to block dopamine transporters (DAT). Though cocaine and methylphenidate have similar in vitro affinities for DAT the abuse of methylphenidate in humans is substantially lower than of cocaine. To test if differences in in vivo potency at the DAT between these two drugs could account for the differences in their abuse liability we compared the levels of DAT occupancies that we had previously reported separately for intravenous methylphenidate in controls and for intravenous cocaine in cocaine abusers. DAT occupancies were measured with Positron Emission Tomography using [11C]cocaine, as a DAT ligand, in 8 normal controls for the methylphenidate study and in 17 active cocaine abusers for the cocaine study. The ratio of the distribution volume of [11C]cocaine in striatum to that in cerebellum, which corresponds to Bmax/Kd +1, was used as measure of DAT availability. Parallel measures were obtained to assess the cardiovascular effects of these two drugs. Methylphenidate and cocaine produced comparable dose-dependent blockade of DAT with an estimated ED50 (dose required to block 50% of the DAT) for methylphenidate of 0.07 mg/kg and for cocaine of 0.13 mg/kg. Both drugs induced similar increases in heart rate and blood pressure but the duration of the effects were significantly longer for methylphenidate than for cocaine. The similar in vivo potencies at the DAT for methylphenidate than for cocaine are in agreement with their reported relative in vitro affinities (Ki 390 nM and 640 nM respectively), which is likely to reflect the similar degree of uptake (8-10% of the injected dose) and regional distribution of these two drugs in the human brain. Thus, differences in the in vivo potency of these two drugs at the DAT cannot be responsible for the differences in their rate of abuse in humans. Other variables i.e. longer duration of methylphenidate's side effects may counterbalance its reinforcing effects.

Adult↗
PubMed1999

Comparative studies of epibatidine derivatives [18F]NFEP and [18F]N-methyl-NFEP: kinetics, nicotine effect, and toxicity.

We have previously shown that [18F]norchlorofluoroepibatidine ([18F]NFEP) would be an ideal radiotracer for positron emission tomography (PET) imaging of nicotinic acetylcholine receptors (nAChR); however, its high toxicity is a limiting factor for human studies. We, therefore, synthesized its N-methyl derivative ([18F]N-Me-NFEP) and carried out comparative studies. The distribution volumes for different brain regions were higher for [18F]N-Me-NFEP than those for [18F]NFEP (average: 52.5+/-0.9 vs. 36.4+/-0.7 for thalamus), though the distribution volume (DV) ratios were similar (3.93+/-0.27 vs. 3.65+/-0.19 for thalamus to cerebellum). Treatment with nicotine reduced the binding of both radiotracers. Toxicology studies in awake rats showed that N-methyl-NFEP has a lower mortality (0 vs. 30%) and smaller effect on plasma catecholamines than NFEP at a dose of 1.5 microg/kg. However, marked alterations in cardiorespiratory parameters were observed after injection of N-methyl-NFEP (0.5 microg/kg, IV) to an awake dog. Our results suggest that although the binding characteristics of [18F]NFEP and [18F]N-Me-NFEP appear to be ideally suited for PET imaging studies of the human brain, their relatively small safety margin will limit their use in humans.

Animals↗
PubMed1999

Imaging the neurochemistry of nicotine actions: studies with positron emission tomography.

Although the effects of nicotine in the brains of laboratory animals have been investigated extensively, very little is known about its effects in the human brain. With positron emission tomography (PET), a non-invasive imaging technology that allows measurement of the concentration of positron-labeled compounds that are of physiological and pharmacological relevance, it has become possible to investigate the effects of nicotine in the human brain. These imaging studies have shown that nicotine has very fast pharmacokinetics in the human brain, that it changes cerebral blood flow (CBF) and brain metabolism, and that at least some of these effects show acute tolerance. PET studies have also shown that, in addition to nicotine, cigarettes possess other pharmacological actions that may contribute to their reinforcing effects, that cigarettes inhibit monoamine oxidase (MAO) A and B in the brain, and that this inhibition recovers with cigarette discontinuation. Although the nicotine receptors have not yet been imaged in the living human brain, PET studies in the primate brain have shown very high concentration of receptors in the thalamus and a high rate of blockade by doses of nicotine that approximate plasma levels achieved by humans when smoking cigarettes. However, further studies are required to determine the levels of nicotine receptor occupancies achieved when smoking a cigarette and those required for the nicotine patch to be therapeutically effective, to measure the half-life for MAO inhibition by cigarettes and the mechanisms underlying this inhibition, and to evaluate the effects of smoking on nicotine receptors and on other neurotransmitter systems in the human brain.

Brain↗
PubMed1999

Association of methylphenidate-induced craving with changes in right striato-orbitofrontal metabolism in cocaine abusers: implications in addiction.

OBJECTIVE: The authors have shown that decreases in dopamine D2 receptors in cocaine abusers were associated with decreased metabolism in the cingulate and prefrontal and orbitofrontal cortices. To assess whether increasing dopamine would reverse these metabolic decrements, they measured the effects of methylphenidate, a drug that increases dopamine, on brain glucose metabolism in 20 cocaine abusers. METHOD: The subjects underwent two [18F]fluorodeoxyglucose positron emission tomography scans, one after two sequential placebo injections and one after two intravenous doses of methylphenidate. D2 receptors were measured with [11C]raclopride to evaluate their relation to methylphenidate-induced metabolic changes. RESULTS: Methylphenidate induced variable changes in brain metabolism: subjects with the higher D2 measures tended to increase metabolism, whereas those with the lower D2 measures tended to decrease metabolism. Methylphenidate's effects were significant for increases in metabolism in the superior cingulate, right thalamus, and cerebellum. Methylphenidate-induced changes in the right orbitofrontal cortex and right striatum were associated with craving, and those in the prefrontal cortex were associated with mood. CONCLUSIONS: Although methylphenidate increased metabolism in the superior cingulate, it only increased metabolism in orbitofrontal or prefrontal cortices in the subjects in whom it enhanced craving and mood, respectively. This indicates that dopamine enhancement is not sufficient per se to increase metabolism in these frontal regions. Activation of the right orbitofrontal cortex and right striatum (brain regions found to be abnormal in compulsive disorders) in the subjects reporting craving may be one of the mechanisms underlying compulsive drug administration in addicted persons. The predominant correlation of craving with right but not left brain regions suggests laterality of reinforcing and/or conditioned responses.

Adult↗
PubMed1999

Prediction of reinforcing responses to psychostimulants in humans by brain dopamine D2 receptor levels.

OBJECTIVE: This study assessed whether brain dopamine D2 receptor levels, which show significant intersubject variability, predict reinforcing responses to psychostimulants in humans. METHOD: [11C]Raclopride and positron emission tomography were used to measure D2 receptor levels in 23 healthy men (mean age = 34 years, SD = 7) who had no drug abuse histories in order to assess if there were differences between the subjects who liked and those who disliked the effects of intravenous methylphenidate (0.5 mg/kg). RESULTS: Subjects who liked the effects of methylphenidate had significantly lower D2 receptor levels (mean = 2.72 Bmax/Kd, SD = 0.3) than subjects who disliked its effects (mean = 3.16, SD = 0.3). Moreover, the higher the D2 levels found, the more intense were methylphenidate's unpleasant effects. CONCLUSIONS: These results provide preliminary evidence that D2 receptor levels predict response to psychostimulants in humans and that low D2 receptors may contribute to psychostimulant abuse by favoring pleasant response.

Adult↗
PubMed1999

PET and drug research and development.

The use of PET to examine the behavioral, therapeutic and toxic properties of drugs and substances of abuse is emerging as a powerful new scientific tool. PET provides a new perspective on drug research by virtue of its ability to directly assess both pharmacokinetic and pharmacodynamic events in humans and in animals. These parameters can be assessed directly in the human body both in healthy volunteers and in patients. Moreover, the new generation of high-resolution, small-animal cameras hold the promise of introducing imaging in the early stages of drug development and make it possible to carry out longitudinal studies in animals and to study genetically altered animals. This places PET in a unique position to contribute significantly to the process of drug development through understanding the molecular mechanisms underlying drug action while addressing some very practical questions such as determining effective drug doses for clinical trials for new drugs, determining the duration of drug action and examining potential drug interactions.

Animals↗
PubMed1999

Blockade of striatal dopamine transporters by intravenous methylphenidate is not sufficient to induce self-reports of "high".

The reinforcing effects of cocaine and methylphenidate have been linked to their ability to block dopamine transporters (DAT). Using positron emission tomography (PET), we previously showed that intravenous cocaine induced a significant level of DAT blockade, which was associated with the intensity for self-reports of "high" in cocaine abusers. In this study, we measured DAT occupancies after intravenous methylphenidate and assessed whether they also were associated with the "high". Occupation of DAT by intravenous MP was measured with PET using [11C]cocaine, as a DAT ligand, in eight normal control subjects tested with different methylphenidate doses. The ratio of the distribution volume of [11C]cocaine in striatum to that in cerebellum, which corresponds to Bmax/Kd + 1, was used as measure of DAT availability. In parallel, self-reports of "high" were measured. Methylphenidate produced a dose-dependent blockade of DAT with an estimated ED50 of 0.075 mg/kg. DAT occupancies were significantly correlated with the "high" (p <.03). However, four of the eight subjects, despite having significant levels of DAT blockade, did not perceive the "high". Methylphenidate is as effective as cocaine in blocking DAT in the human brain (cocaine ED50 = 0.13 mg/kg), and DAT blockade, as for cocaine, was also associated with the "high". However, the fact that there were subjects who despite significant DAT blockade did not experience the "high" suggests that DAT blockade, although necessary, is not sufficient to produce the "high".

Adult↗
PubMed1998

Substrates and inhibitors of human T-cell leukemia virus type I protease.

HTLV-I is an oncogenic retrovirus that is associated with adult T-cell leukemia. HTLV-I protease and HTLV-I protease fused to a deca-histidine containing leader peptide (His-protease) have been cloned, expressed, and purified. The refolded proteases were active and exhibited nearly identical enzymatic activities. To begin to characterize the specificity of HTLV-I, we measured protease cleavage of peptide substrates and inhibition by protease inhibitors. HTLV-I protease cleavage of a peptide representing the HTLV-I retroviral processing site P19/24 (APQVLPVMHPHG) yielded Km and kcat values of 470 microM and 0.184 s-1 while cleavage of a peptide representing the processing site P24/15 (KTKVLVVQPK) yielded Km and kcat values of 310 microM and 0.0060 s-1. When the P1' proline of P19/24 was replaced with p-nitro-phenylalanine (Nph), the ability of HTLV-I protease to cleave the substrate (APQVLNphVMHPL) was improved. Inhibition of HTLV-I protease and His-protease by a series of protease inhibitors was also tested. It was found that the Ki values for inhibition of HTLV-I protease and His-protease by a series of pepsin inhibitors ranged from 7 nM to 10 microM, while the Ki values of a series of HIV-1 protease inhibitors ranged from 6 nM to 127 microM. In comparison, the Ki values for inhibition of pepsin by the pepsin inhibitors ranged from 0.72 to 19.2 nM, and the Ki values for inhibition of HIV-1 protease by the HIV protease inhibitors ranged from 0.24 nM to 1.0 microM. The data suggested that the substrate binding site of HTLV-I protease is different from the substrate binding sites of pepsin and HIV-1 protease, and that currently employed HIV-1 protease inhibitors would not be effective for the treatment of HTLV-I infections.

Amino Acid Sequence↗
PubMed1998

Differences in regional brain metabolic responses between single and repeated doses of methylphenidate.

Studies investigating the acute effects of drugs of abuse on human brain metabolism have measured single doses whereas these drugs are mostly taken repeatedly. Here we compared the brain metabolic response to intravenous methylphenidate when given after a single dose to that when given after two sequential doses. Methylphenidate-induced changes in metabolism differed; whereas single doses tended to decrease metabolism, repeated doses tended to increase it, and these differences were significant in frontal, parietal and occipital cortices and hippocampus. This indicates that methylphenidate's metabolic effects vary with acute previous exposure and highlights the importance of studying drugs after single and repeated administration.

Adult↗
PubMed1998

Measuring dopamine transporter occupancy by cocaine in vivo: radiotracer considerations.

Several recent neuroimaging studies in humans and in monkeys using different radiotracers have reported widely differing values of dopamine transporter (DAT) occupancy by doses of cocaine which are perceived as reinforcing by humans. Here we tested the hypothesis that the measurement of DAT occupancies by drugs with fast pharmacokinetics such as cocaine requires a radioligand with similar kinetics in order to effectively compete with the drug. We measured DAT occupancy by four different doses of cocaine (1.0, 0.5, 0.25, and 0.1 mg/kg) using [11C]d-threo-methylphenidate (a radiotracer which binds rapidly to the DAT in vivo) and compared them to estimates reported previously using [11C]cocaine in the same two baboons and with the same four doses of cocaine [Volkow et al. (1996b) Synapse 24:399-402). Cocaine reduced [11C]d-threo-methylphenidate binding in striatum in a dose-dependent manner, and values were significantly correlated with those obtained previously with [11C]cocaine (r = 0.9, F = 37, P < 0.001). The ED50s (50% occupancy of DAT by cocaine) were 0.27 and 0.17 mg/kg for [11C]d-threo-methylphenidate and [11C]cocaine, respectively. This is significantly lower than values obtained with labeled beta-CIT and other similar radiotracers with a slow uptake and clearance (ED50s: 3-7 mg/kg). We conclude that in vivo measurements of DAT occupancy by rapidly clearing drugs like cocaine requires the use of radiotracers having similar kinetics to the drug itself.

Animals↗
PubMed1998

Parallel loss of presynaptic and postsynaptic dopamine markers in normal aging.

Aging of the human brain is associated with a decline in dopamine (DA) function, generally interpreted as reflecting DA cell loss. Positron emission tomography studies revealed that in healthy individuals, the age-related losses in DA transporters (presynaptic marker) were associated with losses in D2 receptors (postsynaptic marker) rather than with increases as is known to occur with DA cell loss. This association was specific for DA synaptic markers, because they were not correlated with striatal metabolism. Furthermore, the association was independent of age, suggesting that a common mechanism regulates the expression of receptors and transporters irrespective of age.

Adult↗
PubMed1998

PET studies of peripheral catechol-O-methyltransferase in non-human primates using [18F]Ro41-0960.

We previously reported the results of PET (positron emission tomography) studies of [18F]Ro41-0960, a potent COMT inhibitor, in baboon brain. Here we report an evaluation of the pharmacokinetics and specificity of binding of [18F]Ro41-0960 in the peripheral organs of baboon. We observed a rapid clearance of the tracer from the heart and no significant uptake in the lung. In contrast, there was a high uptake and slow clearance in both kidney and liver, consistent with a high level of COMT in these peripheral organs. We also observed a dose-dependent inhibition of [18F]Ro41-0960 uptake by unlabeled Ro41-0960 (ED50 was 0.5 mg/kg in liver, and <0.01 mg/kg in kidney), with a halftime for recovery of COMT of about 25 h at the dose of 2 mg/kg of unlabeled Ro41-0960. This indicates a reversible tight binding interaction between COMT and Ro41-0960 in both liver and kidney and suggests that [18F]Ro41-0960 may be a useful radiotracer for future examination of the functional activity of COMT in the human body.

Animals↗
PubMed1998

In vitro and ex vivo autoradiographic studies of nicotinic acetylcholine receptors using [18F]fluoronochloroepibatidine in rodent and human brain.

A fluorine-18-labeled analog of the potent nicotinic agonist epibatidine is a candidate radioligand for positron emission tomographic (PET) studies of nicotinic acetylcholine receptors (nAcChR). Following intravenous administration of [18F]exo-2-(2'-fluoro-5'-pyridinyl)-7-azabicyclo[2.2.1]heptane (NFEP), high uptake in thalamus was visualized in sections of mouse and rat brain by autoradiography using a phosphor imaging device. Binding of [18F]NFEP to rat thalamic homogenate was consistent with a single class of binding site with a Kd value of 71 pM. In vitro autoradiography of thaw-mounted sections of human thalamus revealed a heterogeneous pattern of binding; Bmax values for ventrolateral nucleus, insular cortex and dorsomedial nucleus, and internal capsule were 20, 8, and 3 pmol/cc of tissue, respectively. However, similar Kd values close to 50 pM were calculated for all regions. These studies support the suitability of [18F]NFEP as a radioligand for PET studies of nAcChR in the living human brain.

Animals↗
PubMed1998

Efficient expression and rapid purification of human T-cell leukemia virus type 1 protease.

Human T-cell leukemia virus type 1 (HTLV-1) is an oncovirus that is clinically associated with adult T-cell leukemia. We report here the construction of a pET19-based expression clone containing HTLV-1 protease fused to a decahistidine-containing leader peptide. The recombinant protein is efficiently expressed in Escherichia coli, and the fusion protein can be easily purified by affinity chromatography. Active mature protease in yields in excess of 3 mg/liter of culture can then be obtained by a novel two-step refolding and autoprocessing procedure. The purified enzyme exhibited Km and Kcat, values of 0.3 mM and 0.143 sec(-1) at pH 5.3 and was inhibited by pepstatin A.

Amino Acid Sequence↗
PubMed1998

Dopamine transporter occupancies in the human brain induced by therapeutic doses of oral methylphenidate.

OBJECTIVE: The therapeutic effects of methylphenidate in the treatment of attention deficit disorder have been attributed to its ability to increase the synaptic concentration of dopamine by blocking the dopamine transporters. However, the levels of dopamine transporter blockade achieved by therapeutic doses of methylphenidate are not known. This study measured, for the first time, dopamine transporter occupancy by orally administered methylphenidate in the human brain and its rate of uptake in the brain. METHOD: Positron emission tomography (PET) and [11C]cocaine were used to estimate dopamine transporter occupancies after different doses of oral methylphenidate in seven normal subjects (mean age=24 years, SD=7). In addition, the pharmacokinetics of oral methylphenidate were measured in the baboon brain through use of PET and [11C]methylphenidate administered through an orogastric tube. RESULTS: At 120 minutes after administration, oral methylphenidate produced a dose-dependent blockade of dopamine transporter; means=12% (SD= 4%) for 5 mg, 40% (SD=12%) for 10 mg, 54% (SD=5%) for 20 mg, 72% (SD=3%) for 40 mg, and 74% (SD=2%) for 60 mg. The estimated dose of oral methylphenidate required to block 50% of the dopamine transporter corresponded to 0.25 mg/kg. Oral methylphenidate did not reach peak concentration in brain until 60 minutes after its administration. CONCLUSIONS: Oral methylphenidate is very effective in blocking dopamine transporters, and at the weight-adjusted doses used therapeutically (0.3 to 0.6 mg/kg), it is likely to occupy more than 50% of the dopamine transporters. The time to reach peak brain uptake for oral methylphenidate in brain corresponds well with the reported time course to reach peak behavioral effects.

Administration, Oral↗
PubMed1998

Association between decline in brain dopamine activity with age and cognitive and motor impairment in healthy individuals.

OBJECTIVE: Although it is documented that brain dopamine activity declines with age, the functional significance of this is not known. This study assessed the relation between measures of brain dopamine activity and indexes of motor and cognitive function in healthy individuals. METHOD: Thirty healthy volunteers aged 24-86 years were studied with positron emission tomography and [11C]raclopride to assess dopamine D2 receptors. All subjects underwent a neuropsychological test battery that included tasks found to be sensitive to dopamine alterations in patients with neurodegenerative disease and control tasks. RESULTS: Transfer of [11C]raclopride from plasma to brain in the striatum and cerebellum was not affected by age. In contrast, D2 receptor availability in the caudate and putamen declined with age. Correlations between D2 receptors and neuropsychological test performance were strongest for the motor task (Finger Tapping Test) and were also significant for most tasks involving frontal brain regions, including measures of abstraction and mental flexibility (Wisconsin Card Sorting Test) and attention and response inhibition (Stroop Color-Word Test, interference score). These relationships remained significant after control for age effects. CONCLUSIONS: Age-related decreases in brain dopamine activity are associated with a decline in motor function and may also contribute to impaired performance on tasks that involve frontal brain regions. Interventions that enhance dopamine activity may improve performance and quality of life for the elderly. The fact that correlations remained significant after age effects were partialed out suggests that dopamine activity may influence motor and cognitive performance irrespective of age.

Adult↗