Showing papers by "Nora D. Volkow published in 1999"

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

Abstract: 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.

Reinforcing effects of psychostimulants in humans are associated with increases in brain dopamine and occupancy of D(2) receptors.

Abstract: Increases in dopamine concentration in limbic brain regions have been postulated to underlie the reinforcing effects of psychostimulant drugs in laboratory animals. However, neither the qualitative nor the quantitative relationship between drug-induced increases in brain dopamine and the reinforcing effects of psychostimulant drugs have been investigated in humans. Positron emission tomograph and [(11)C]raclopride, a dopamine D(2) receptor radioligand that competes with endogenous dopamine for occupancy of the D(2) receptors, were used to measure changes in brain dopamine after different doses of i.v. methylphenidate in 14 healthy controls. In parallel, measures for self-reports of drug effects were obtained to assess their relationship to methylphenidate-induced changes in brain dopamine. The intensity of the "high" induced by methylphenidate was significantly correlated with the levels of released dopamine (r = 0.78, p <.001); subjects having the greatest increases were those who perceived the most intense high. This relationship remained significant after partialing out for dose and concentration of methylphenidate in plasma. Furthermore, subjects for whom methylphenidate did not increase dopamine did not perceive a high. These results represent the first clear demonstration that stimulant-induced high, a mood descriptor that reflects reinforcing effects of drugs in humans, is associated with increases in brain dopamine, and also that there is a quantitative relationship between levels of D(2) receptor occupancy by dopamine and the intensity of the high.

Association of Methylphenidate-Induced Craving With Changes in Right Striato-orbitofrontal Metabolism in Cocaine Abusers: Implications in Addiction

Abstract: 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 ci...

Reinforcing Effects of Psychostimulants in Humans Are Associated with Increases in Brain Dopamine and Occupancy

Abstract: Increases in dopamine concentration in limbic brain regions have been postulated to underlie the reinforcing effects of psychostimulant drugs in laboratory animals. However, neither the qualitative nor the quantitative relationship between druginduced increases in brain dopamine and the reinforcing effects of psychostimulant drugs have been investigated in humans. Positron emission tomograph and [ 11 C]raclopride, a dopamine D2 receptor radioligand that competes with endogenous dopamine for occupancy of the D2 receptors, were used to measure changes in brain dopamine after different doses of i.v. methylphenidate in 14 healthy controls. In parallel, measures for selfreports of drug effects were obtained to assess their relationship to methylphenidate-induced changes in brain dopamine. The intensity of the “high” induced by methylphenidate was significantly correlated with the levels of released dopamine (r 5 0.78, p , .001); subjects having the greatest increases were those who perceived the most intense high. This relationship remained significant after partialing out for dose and concentration of methylphenidate in plasma. Furthermore, subjects for whom methylphenidate did not increase dopamine did not perceive a high. These results represent the first clear demonstration that stimulant-induced high, a mood descriptor that reflects reinforcing effects of drugs in humans, is associated with increases in brain dopamine, and also that there is a quantitative relationship between levels of D2 receptor occupancy by dopamine and the intensity of the high.

Imaging studies on the role of dopamine in cocaine reinforcement and addiction in humans

Abstract: We summarize our studies with positron emission tomography investigating the role of dopamine (DA) in the reinforcing effects of cocaine and methylphenidate in humans and its involvement in cocaine addiction. These studies have shown that the rate at which cocaine and methylphenidate enter the brain and block the dopamine transporters (DAT) is the variable associated with the 'high', rather than the presence per se of the drug in the brain. Our studies also show that, while the level of DAT blockade is important in predicting the intensity of the 'high' induced by these drugs (DAT blockade > 50% is required for these drugs to induce a 'high'), the rate at which DAT are blocked determines whether the 'high' is perceived or not. Thus, oral methylphenidate, which leads to slow DAT blockade, does not induce a 'high', even at doses which block DAT more than 60%. In cocaine abusers, we have shown significant reductions in DA D2 receptors that are associated with decreased metabolism in cingulate gyrus and in orbitofrontal cortex. We suggest that this is one of the mechanisms by which DA disruption leads to compulsive drug administration in cocaine addiction. Cocaine abusers also show significant decreases in DA release, which coupled with the reduction in D2 receptors may result in decreased activation of reward circuits by physiological reinforcers and may perpetuate cocaine use as a means to compensate for this deficit. Thus, strategies to enhance DA brain function in ways that mimic physiological DA activity may be of help in overcoming cocaine addiction.

PET and drug research and development.

Abstract: 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.

Dopamine-transporter occupancy after intravenous doses of cocaine and methylphenidate in mice and humans

Abstract: Objectives: Recent studies using positron emission tomography (PET) have established the relationship between an intravenous dose of cocaine and the percentage occupancy of the dopamine transporter in humans, and have documented the requirement of more than 50% occupancy for perception of the ”high”. The present experiments were conducted to examine dose–occupancy and dose–effect relationships in mice for cocaine and also for methylphenidate, a dopamine uptake blocker used in pediatric psychiatry. Methods: Percentage occupancies of the dopamine transporter by cocaine and methylphenidate were estimated after intravenous injection in mice from the displacement of in vivo binding of [3H]cocaine from the striatum. Locomotor activity was measured in a photocell apparatus. Results: The relationship between drug doses (milligrams of hydrochloride salt per kilogram body weight) and percentage occupancy of the dopamine transporter was indistinguishable for cocaine and methylphenidate, and corresponded to about 50% occupancy at 0.25 mg/kg and about 80% at 1 mg/kg. This was similar to the relationship between drug dose and transporter occupancy, previously measured in human and baboons using [11C]cocaine or [11C]d-threo-methylphenidate and PET. Methylphenidate increased locomotor activity in the mice substantially more than cocaine at the same dose and the same degree of dopamine-transporter receptor occupancy. Conclusions: The range of dopamine-transporter occupancy required for behavioral activation in the mice was thus similar to that previously reported for experience of a cocaine- or methylphenidate-induced ”high” in human subjects. Our results are consistent with other studies in which both cocaine and methylphenidate were evaluated in animal behavioral assays and were found to have very similar psychopharmacological properties.

Blockade of Striatal Dopamine Transporters by Intravenous Methylphenidate Is Not Sufficient to Induce Self-Reports of “High”

Abstract: 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 B max/ K d + 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”.

Large Receptor Reserve for Cannabinoid Actions in the Central Nervous System

Abstract: The receptor occupancy required to produce cannabinoid effects in the central nervous system was determined in both a neurochemical and a behavioral assay for cannabinoid actions. In the neurochemical experiments, performed on superfused rat hippocampal slices, electrically evoked [ 3 H]acetylcholine release was inhibited by the cannabinoid agonist, WIN 55212 to 2 with an EC 50 of 0.005 μM and maximum effect of 79%. In parallel experiments examining binding of the radiolabeled CB1 antagonist [ 131 I]AM 281 { N -(morpholin-4-yl)-5-(4-[ 131 I]iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1 H -pyrazole-3-carboxamide} to living hippocampal slices, WIN 55212 to 2 inhibited [ 131 I]AM 281 binding with an EC 50 of 1.3 μM. From these two sets of data it was determined that 50% of maximal inhibition of [ 3 H]acetylcholine release in hippocampal slices occurs at a receptor occupancy of only 0.13% and 95% of maximal inhibition at a receptor occupancy of 7.5%, suggesting the presence of a receptor reserve that is large compared with other G protein-coupled receptor systems in the central nervous system. In behavioral experiments, WIN 55212 to 2 inhibited spontaneous locomotor activity in mice with an ED 50 of 0.3 mg/kg, i.v.. In in vivo binding experiments using [ 131 I]AM 281, WIN 55212 to 2 failed to produce significant inhibition of radiotracer binding in the mouse brains, except at very high doses (10 mg/kg or greater, i.v.). By contrast, the CB1 antagonist SR 141716A (10 mg/kg, i.p.), completely abolished specific [ 131 I]AM 281 binding. These experiments suggest that behavioral effects of cannabinoids, like neurochemical effects, are produced at very low receptor occupancy.

Design and synthesis of the CB1 selective cannabinoid antagonist AM281: a potential human SPECT ligand.

Abstract: In the search for a radioligand capable of imaging cannabinoid CB1 receptors in the living human brain by SPECT (single photon emission computed tomography), N-(morpholin-4-yl)-1-(2,4-dichlorophenyl)-5-(4-iodophenyl)-4-methyl-1H-pyrazole-3-carboxamide (AM281) was synthesized. This compound is an analog of the potent, CB1 receptor selective antagonist SR141716A [N-(piperidin-1-yl)-1-(2,4-dichlorophenyl)-5-(4-chlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide]. AM281 bound to brain and spleen membrane preparations (CB1 and CB2 receptors, respectively) with Ki values of 12 nM and 4200 nM, respectively. AM281 also inhibited the response of guinea-pig small intestine preparation to a cannabinoid receptor agonist. Thus, AM281 behaves as a CB1 receptor selective antagonist. Methods for the rapid, high-yield synthesis and purification of [123I]AM281 were developed, and transaxially reconstructed brain SPECT images obtained after continuous infusion of [123I]AM281 in baboons. Thus [123I]AM281 may be suitable for imaging CB1 receptors in humans.

Comparable changes in synaptic dopamine induced by methylphenidate and by cocaine in the baboon brain.

Abstract: Though the blockade of dopamine transporters (DAT) is associated with cocaine's and methylphenidate's reinforcing effects, it is the stimulation of dopamine (DA) receptors, achieved by increases in synaptic DA, that enables these effects to occur. Positron emission tomography (PET) and [11C]raclopride were used to assess the levels of occupancy of DA D2 receptors by dopamine achieved by doses of cocaine or methylphenidate previously documented to block over 70% of DAT. Studies were performed in five baboons using a paired scan protocol designed to measure DA D2 receptor availability (Bmax/Kd) at baseline conditions and after intravenous administration of either cocaine or methylphenidate. Cocaine (1-2 mg/kg) or methylphenidate (0.5 mg/kg) administered 5 min prior to [11C]raclopride decreased Bmax/Kd by 29+/-3% and 32 + 4%, respectively. Smaller reductions in Bmax/Kd (13% for cocaine given 30 min before [11C]raclopride and 25+/-10% for methylphenidate given 40 min before [11C]raclopride) were seen with longer periods between drug and radioligand. These observations are consistent with the slower striatal clearance kinetics of [11C]methylphenidate than [1C]cocaine observed in previous PET experiments and with the approximately twofold higher potency of methylphenidate than cocaine in in vitro experiments. Though the elevation of synaptic DA induced by >70% occupancy of DAT by these drugs lead to a modest increase in occupancy of D2 receptors (25-30%), further studies are required to assess if this is an underestimation because of differences in D2 receptor binding kinetics between raclopride and DA.

Reproducibility of repeated measures of endogenous dopamine competition with [11C]raclopride in the human brain in response to methylphenidate

Abstract: The measureof changesin synapticdopamine(DA)concentra tion in responseto the psychostimulantdrug methylphenidate (MP)hasbeenusedas an indicatorof responsiveness of the DA system.Thepurposeofthis studywasto assessthe reproducibil ity of thesemeasures. Methods:Sevenhealthysubjects were scannedwith PETand [11C]raclopride twice in the sameday: 7 mmafterplaceboor methylphenidate (0.5mg/kg)administration. In parallel we also measuredthe physiologicand behavioral responsesto placeboandto methylphenidate. Thesameproce dureswererepeated1—2 wk laterto assesstest-retestreproduc ibility. Results: Measuresof plasmato brain transferconstant (Ki), striataldistribution volume(DV@)and DA D2 receptor availability(Bmax/Kd),for the placeboconditionweresimilarfor thefirst (El) andsecond(E2)evaluations(Bmax/Kd,El : 2.77 ± 0.44; E2: 2.97 ±0.44). MP administration did notchange , but itsignificantlydecreasedDV@(El: —25.9% ± 8.7%,P @ 0.0002; E2:—20.7% ± 11.7%,P 0.007)andBmaxlKd (El: —18.4% ± 8.7%,P

Smoking a single cigarette does not produce a measurable reduction in brain MAO B in non-smokers.

Abstract: Positron emission tomography (PET) studies with [11C]L-deprenyl-D2 have shown that brain monoamine oxidase (MAO) B is 40% lower in smokers than in non-smokers. Here we investigated whether MAO B inhibition can be detected after smoking a single cigarette. Eight normal healthy non-smokers (35 +/- 11 years) received two PET studies 2 h apart with [11C]L-deprenyl-D2, one at baseline and the second 5-10 min after the subject had smoked a single cigarette. Plasma nicotine and expired carbon monoxide (CO) were measured prior to smoking and 10 min after smoking completion as an index of tobacco smoke exposure. A three-compartment model was used to calculate lambda k3, a model term which is proportional to MAO B activity and which is derived from the time course of carbon-11 in the brain and the time course of the radiotracer in the plasma and K1, the plasma-to-brain transfer constant (for [11C]L-deprenyl-D2) which is related to brain blood flow. Subjects experienced difficulty inhaling and became dizzy and/or nauseous after smoking. Plasma nicotine averaged 11.6 +/- 5.5 ng/ml and expired CO averaged 8 +/- 10 ppm after smoking. The average lambda k3 and K1 for 11 different brain regions did not differ significantly between baseline and smoking. These results indicate that the reduction in MAO B in smokers probably occurs gradually and requires chronic tobacco smoke exposure.

Distribution of tracer levels of cocaine in the human brain as assessed with averaged [11C]cocaine images.

Abstract: The Ability of cocaine to block the dopamine transporter (DAT) in the nucleus accumbens, as well as its non-striatal and non-DAT actions, appears to be crucial for its reinforcing/rewardig effects. However, we have been unable to use PET and [11C]cocaine to map small regions with greater sensitivity due in part to the low specific to non-specific binding ration of [11C]cocaine. In order to increase the signal to noise ratio of the individual [11]cocaine images, we averaged the distribution volume (DV) PET images of 17 normal controls. In addition we also obtained averaged images for the dynamic set (14 time frames) and for the K1 values. The dynamic images were used to generate the average time activity curves from which we obtained the time required to half maximum clearance (T50). Twenty-nine ROIs were identified in the Talarach-Tournoux atlas and were then projected to the corregistered average PET image. The brain regions clustered in 3 groups according to their DV values. The highest activity (Group DV.1, 4.6-3.7) included putamen > accumbens > caudate. Intermediate DVs (Group DV.2, 3.2-2.8) included thalamus (mediodorsal and ventrolateral nucleus) > precuneus and posterior cingulate gyrus > amygdala, hippocampus, and temporal pole. Group DV.3 with low DVs (2.6-2.1) included the orbital cortex, precentral gyrus, and cerebellum. The brain regions clustered in 3 groups according to their T50 values. Regions with the faster clearance rates (15-20 minutes) included the orbital cortex, posterior cingulate, dorsomedial thalamus, precuneus, and cerebellum. Intermediate clearance rates (20-25 minutes) included caudate, putamen and accumbens regions with the slowest clearance rates (25-30 minuters) included caudate, putamen, and accumbens. In addition to the previously documented high binding of cocaine in striatum and moderate binding in thalamus in the living human brain this study also documents binding of cocaine in limbic and paralimbic brain regions. Further work is required to characterize the binding properties of cocaine in these brain areas and to elucidate their role in the reinforcing and addictive properties of cocaine.

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

Abstract: 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.

Spectroscopic imaging of the uptake kinetics of human brain ethanol.

Abstract: Previous measurements of the ratio of brain to venous blood alcohol have ranged from 21-100%, depending on the experimental model, pulse sequence, and the concentration reference used. The goal of this study was to evaluate the uptake kinetics and visibility of brain ethanol in comparison to venous blood levels using a pulse sequence that minimizes uncertainties due to differences in J-modulation, T(1), and T(2) between ethanol and the concentration standard. This was achieved using a short TE (24 msec) spin echo sequence with a semiselective refocusing pulse to minimize J-modulation losses of the ethanol. Brain ethanol levels were measured with 10-min time resolution using a 16 x 16 spectroscopic imaging matrix with nominal voxels of 1.44 cc. During the course of the study, the brain/blood alcohol ratio declined from a value of 1.54 +/- 0.74 at 35 min after drinking to a final value of 0.93 +/- 0.16 at 85 min postdrinking. Magn Reson Med 42:1019-1026, 1999.

Measuring reproducibility of regional brain metabolic responses to lorazepam using statistical parametric maps.

Abstract: Statistical parametric mapping (SPM) is a method for localizing differences in brain activation patterns without the need for anatomic predefined constraints. The purpose of this study was to assess the reproducibility of the patterns of activation obtained with SPM for baseline measures and for metabolic changes in response to lorazepam on a test-retest design. The results were compared with those we previously published using region-of-interest (ROI) methods. Methods: Sixteen healthy right-handed men were scanned twice with PET and [18F]fluorodeoxyglucose (FDG): before placebo and before lorazepam (30 µg/kg). The same double FDG procedure was repeated 6–8 wk later to assess test-retest reproducibility. Image datasets were analyzed by using SPM95 software. Difference images between baseline and lorazepam were compared for the first and second evaluations, both for relative decreases as well as increases in metabolism. Significance level was systematically varied to P

Intimate combination of low‐ and high‐resolution image data: I. real‐space PET and 1H2O MRI, PETAMRI

Abstract: Two different types of (co-registered) images of the same slice of tissue will generally have different spatial resolutions. The judicious pixel-by-pixel combination of their data can be accomplished to yield a single image exhibiting properties of both. Here, axial (18)FDG PET and (1)H(2)O MR images of the human brain are used as the low- and high-resolution members of the pair. A color scale is necessary in order to provide for separate intensity parameters from the two image types. However, not all color scales can accommodate this separability. The HSV color model allows one to choose a color scale in which the intensity of the low-resolution image type is coded as hue, while that of the high-resolution type is coded as value, a reasonably independent parameter. Furthermore, the high-resolution image must have high contrast and be quantitative in the same sense as the low-resolution image almost always is. Here, relaxographic MR images (naturally segmented quantitative (1)H(2)O spin-density components) are used. Their essentially complete contrast serves to effect an apparent editing function when encoded as the value of the color scale. Thus, the combination of (18)FDG PET images with gray-matter (GM) relaxographic (1)H(2)O images produces visually "GM-edited" (18)FDG PETAMR (positron emission tomography and magnetic resonance) images. These exhibit the high sensitivity to tracer amounts characteristic of PET along with the high spatial resolution of (1)H(2)O MRI. At the same time, however, they retain the complete quantitative measures of each of their basis images. Magn Reson Med 42:345-360, 1999. Published 1999 Wiley-Liss, Inc.

Positron emission tomography studies of dopamine-enhancing drugs.

Abstract: Although PET is technologically complex because the restricted time scale requires that radioisotope production, radiotracer synthesis, and PET imaging be carried out in the same place, the payoff is that compounds labeled with these isotopes can be used to track the distribution and movement of drugs in the brain and also measure drug effects on specific molecular targets in the human brain. Provided that appropriate radiotracers are available, one can determine the amount of a drug that gets into the brain, the minimum effective dose, the duration of action, or the binding site occupancy required to elicit a particular therapeutic or behavioral effect with a relatively small number of PET studies. Because studies are carried out directly in humans, the relationship of these parameters to behavior and to therapeutic efficacy can be evaluated. The possibilities are enormous and are largely driven by advances in PET technology (including radiotracer chemistry and instrumentation) that synergize with advances in neuropharmacology.

Imaging the functioning human brain

Abstract: One of the most exciting methodological advances for brain research field arises in functional brain imaging, which enables us to localize and characterize neural activity and biochemical events in the living human brain. Recently developed event-related functional MRI makes it possible to visualize the brain activity associated with cognitive processes with the temporal resolution of the hemodynamic response. In addition, the high sensitivity and selectivity of positron-emission tomography allow us to probe the neurochemical processes at the molecular level. Positron-emission tomography also has been applied to investigate the effects of therapeutic drugs as well as the effects of drugs of abuse.

Comparison of Brain Glucose Metabolism and Monoamine Oxidase B (MAO B) in Traumatic Brain Injury.

Abstract: Objective: Positron emission tomography (PET) studies in patients with temporal lobe epilepsy have reported that hypometabolism in temporal regions is associated with elevated monoamine oxidase B (MAO B) probably reflecting gliosis. The purpose of this study was to examine a group of head trauma patients suffering from seizures and memory loss to determine whether hypometabolic regions show correspondingly elevated MAO B. Methods: Seven patients with traumatic brain injury received PET scans with 18FDG and [11C] l -deprenyl-D2 to measure regional glucose metabolism (LCMRglu) and MAO B respectively. Results were compared to a group of nine age-matched healthy controls. Hypometabolic regions were identified and MAO B values corresponding to these brain regions were determined. Averaged brain images for temporal regions for LCMRglu and MAO were also compared. Results: LCMRglu values for temporal regions were reduced in patients relative to normal subjects. Of the 13 hypometabolic brain regions, 6 (46%) showed a corresponding elevation in MAO B. There was a trend for a significant inverse relationship between normalized LCMRglu and normalized MAO B values for medial temporal cortex. Glucose metabolism was significantly higher in lateral than medial temporal regions whereas the pattern was reversed for MAO B. Conclusion: MAO B images provide a markedly better delineation of the medial temporal regions than LCMRglu. There was not a consistent inverse relationship between metabolism and MAO B as had been reported in PET studies of epileptogenic temporal lobes with [11C] l -deprenyl-D2 and 18FDG indicating that prospective studies are needed to determine the pathophysiology of hypometabolic lesions in head trauma.

Attempts to replicate the claim of James' at NSLS beam line X12B

Abstract: (1999). Attempts to replicate the claim of James' at NSLS beam line X12B. Synchrotron Radiation News: Vol. 12, No. 5, pp. 34-36.

PET Studies of the Effect of the Antidepressant Drugs Nefazodone or Paroxetine on [11C]Raclopride Binding in Human Brain.

Abstract: Serotonin modulates dopamine release in the striatum. In this study we set out to determine whether nefazodone and paroxetine, two antidepressant drugs that interact with the brain serotonin system, produce detectable changes in synaptic dopamine in vivo in the human brain using positron emission tomography (PET) and [11C]raclopride, a dopamine D-2 receptor specific radiotracer that is sensitive to changes in synaptic dopamine. Three normal healthy human volunteers had 4 PET/[11C]raclopride scans each in 2 sessions. In the first session, subjects had a baseline [11C]raclopride scan and a second scan 1 hour following the oral administration of either nefazodone (200 mg PO) or paroxetine (20 mg PO). Four to 6 weeks later, in a second PET/[11C]raclopride session, the same subjects received the other drug for comparison. Neither nefazodone nor paroxetine produced significant changes in [11C]raclopride binding. This and other reports in the literature indicate that different drugs that affect the serotonin system do not produce consistent and predictable changes in [11C]raclopride binding and that a full understanding of their actions on serotonin and the associated changes in dopamine requires further investigation.