Showing papers by "Nora D. Volkow published in 2003"

The addicted human brain: insights from imaging studies

Abstract: Imaging studies have revealed neurochemical and functional changes in the brains of drug-addicted subjects that provide new insights into the mechanisms underlying addiction. Neurochemical studies have shown that large and fast increases in dopamine are associated with the reinforcing effects of drugs of abuse, but also that after chronic drug abuse and during withdrawal, brain dopamine function is markedly decreased and these decreases are associated with dysfunction of prefrontal regions (including orbitofrontal cortex and cingulate gyrus). The changes in brain dopamine function are likely to result in decreased sensitivity to natural reinforcers since dopamine also mediates the reinforcing effects of natural reinforcers and on disruption of frontal cortical functions, such as inhibitory control and salience attribution. Functional imaging studies have shown that during drug intoxication, or during craving, these frontal regions become activated as part of a complex pattern that includes brain circuits involved with reward (nucleus accumbens), motivation (orbitofrontal cortex), memory (amygdala and hippocampus), and cognitive control (prefrontal cortex and cingulate gyrus). Here, we integrate these findings and propose a model that attempts to explain the loss of control and compulsive drug intake that characterize addiction. Specifically, we propose that in drug addiction the value of the drug and drug-related stimuli is enhanced at the expense of other reinforcers. This is a consequence of conditioned learning and of the resetting of reward thresholds as an adaptation to the high levels of stimulation induced by drugs of abuse. In this model, during exposure to the drug or drug-related cues, the memory of the expected reward results in overactivation of the reward and motivation circuits while decreasing the activity in the cognitive control circuit. This contributes to an inability to inhibit the drive to seek and consume the drug and results in compulsive drug intake. This model has implications for therapy, for it suggests a multi-prong approach that targets strategies to decrease the rewarding properties of drugs, to enhance the rewarding properties of alternative reinforcers, to interfere with conditioned-learned associations, and to strengthen cognitive control in the treatment of drug addiction.

Variables that affect the clinical use and abuse of methylphenidate in the treatment of ADHD.

Abstract: OBJECTIVE: Methylphenidate, the most common treatment for attention deficit hyperactivity disorder (ADHD), increases extracellular dopamine in the brain, which is associated with its reinforcing as well as its therapeutic effects. The authors evaluated variables that distinguish these two properties. METHOD: The brain imaging and clinical literatures were analyzed to identify variables that contribute to the abuse liability as well as to the clinical efficacy of methylphenidate. RESULTS: Four variables were identified. 1) Dose—there is a threshold for methylphenidate-induced dopamine increases to be perceived as reinforcing and to produce therapeutic effects. 2) Pharmacokinetics—the reinforcing effects of methylphenidate are associated with rapid changes in serum concentrations and presumably fast dopamine increases (as achieved with intravenous injection or insufflation), whereas the therapeutic effects are associated with slowly ascending serum concentrations and presumably smoothly rising dopamine leve...

Expectation Enhances the Regional Brain Metabolic and the Reinforcing Effects of Stimulants in Cocaine Abusers

Abstract: The reinforcing effects of drugs of abuse result from the complex interaction between pharmacological effects and conditioned responses. Here we evaluate how expectation affects the response to the stimulant drug methylphenidate in 25 cocaine abusers. The effects of methylphenidate (0.5 mg/kg, i.v.) on brain glucose metabolism (measured by [18F]deoxyglucose-positron emission tomography) and on its reinforcing effects (self-reports of drug effects) were evaluated in four conditions: (1) expecting placebo and receiving placebo; (2) expecting placebo and receiving methylphenidate; (3) expecting methylphenidate and receiving methylphenidate; (4) expecting methylphenidate and receiving placebo. Methylphenidate increased brain glucose metabolism, and the largest changes were in cerebellum, occipital cortex, and thalamus. The increases in metabolism were approximately 50% larger when methylphenidate was expected than when it was not, and these differences were significant in cerebellum (vermis) and thalamus. In contrast, unexpected methylphenidate induced greater increases in left lateral orbitofrontal cortex than when it was expected. Methylphenidate-induced increases in self-reports of "high" were also approximately 50% greater when subjects expected to receive it than when they did not and were significantly correlated with the metabolic increases in thalamus but not in cerebellum. These findings provide evidence that expectation amplifies the effects of methylphenidate in brain and its reinforcing effects. They also suggest that the thalamus, a region involved with conditioned responses, may mediate the enhancement of the reinforcing effects of methylphenidate by expectation and that the orbitofrontal cortex mediates the response to unexpected reinforcement. The enhanced cerebellar activation with expectation may reflect conditioned responses that are not linked to conscious responses.

Monoamine oxidase and cigarette smoking.

Abstract: Current cigarette smokers have reduced monoamine oxidase (MAO) and there is evidence that this is a pharmacological effect of tobacco smoke exposure rather than a biological characteristic of smokers. This article summarizes human and animal studies documenting the inhibitory effects of tobacco smoke on MAO and discusses MAO inhibition in the context of smoking epidemiology, MAO inhibitor compounds in tobacco, reinvestigations of low platelet MAO in psychiatric disorders and smoking cessation.

Brain dopamine is associated with eating behaviors in humans

Abstract: Objective Eating behavior in humans is influenced by variables other than just hunger-satiety including cognitive restraint, emotional distress, and sensitivity to food stimuli. We investigate the role of dopamine (DA), a neurotransmitter involved with food motivation, in these variables. Methods We used the Dutch Eating Behavior Questionnaire (DEBQ) to measure Restraint, Emotionality, and Externality in 10 subjects. We correlated DEBQ scores with brain DA levels. Positron emission tomography and {11C}raclopride uptake were used to measure baseline D2 receptors (neutral stimulation) and to assess changes in extracellular DA to food stimulation (display of food). Results Restraint was correlated with DA changes with food stimulation (higher restraint, greater responsivity), emotionality was negatively correlated with baseline D2 receptors (higher emotionality, lower D2 receptors), whereas externality was not. These correlations were significant in the dorsal but not in the ventral striatum. Discussion These results provide evidence that DA in the dorsal striatum is involved with the restraint and emotionality components regulating eating behavior and that these two dimensions reflect different neurobiologic processes. © 2003 by Wiley Periodicals, Inc.Int J Eat Disord 33: 136–142, 2003.

RatCAP: miniaturized head-mounted PET for conscious rodent brain imaging

Abstract: Anesthesia is currently required for positron emission tomography (PET) studies of the animal brain in order to eliminate motion artifacts. However, anesthesia profoundly affects the neurological state of the animal, complicating the interpretation of PET data. Furthermore, it precludes the use of PET to study the brain during normal behavior. The rat conscious animal PET tomograph (RatCAP) is designed to eliminate the need for anesthesia in rat brain studies. It is a miniaturized full-ring PET scanner that is attached directly to the head, imaging nearly the entire brain. RatCAP utilizes arrays of 2 mm /spl times/ 2 mm LSO crystals coupled to matching avalanche photodiode arrays, which are in turn read out by full custom integrated circuits. Principal challenges have been addressed considering the physical constraints on size, weight, and heat generation in addition to the usual requirements of small-animal PET, such as high spatial resolution in the presence of parallax error. A partial prototype has been constructed and preliminary measurements and optimization completed. Realistic Monte Carlo simulations have also been carried out to optimize system performance, which is predicted to be competitive with existing microPET systems.

Cardiovascular effects of methylphenidate in humans are associated with increases of dopamine in brain and of epinephrine in plasma

Abstract: Rationale The cardiovascular effects of psychostimulant drugs (methylphenidate, amphetamine, cocaine) have been mostly associated with their noradrenergic effects. However, there is some evidence that dopaminergic effects are involved in the cardiovascular actions of these drugs. Here, we evaluated this association in humans.

Reproducibility of 11C-Raclopride Binding in the Rat Brain Measured with the MicroPET R4: Effects of Scatter Correction and Tracer Specific Activity

Abstract: A new generation of commercial animal PET cameras may accelerate drug development by streamlining preclinical testing in laboratory animals. However, little information on the feasibility of using these machines for quantitative PET in small animals is available. Here we investigate the reproducibility of microPET imaging of 11C-raclopride in the rat brain and the effects of tracer-specific activity and photon scatter correction on measures of D2 receptor (D2R) availability. Methods: Sprague-Dawley rats (422 ± 29 g; n = 7) were anesthetized with ketamine/xylazine and catheterized for tail vein injection of 11C-raclopride. Each animal was positioned prone in the microPET, centering the head in the field of view. MicroPET data was collected for 60 min—starting at 11C-raclopride injection—and binned into 24 time frames (6 × 10 s, 3 × 20 s, 8 × 60 s, 4 × 200 s, 3 × 600 s). In 3 studies, 11C-raclopride was administered a second time in the same animal, with 2–4 h between injections. In a fourth animal, raclopride (1 mg/kg) was coinjected with 11C-raclopride for the second injection. Three rats received a single dose of 11C-raclopride. The range of doses for all studies was 6.11–18.54 MBq (165–501 μCi). The specific activity at injection was 4.07–48.1 GBq/μmol (0.11–1.3 Ci/μmol). Region-of-interest analysis was performed and the distribution volume ratio (DVR) was computed for striatum/cerebellum using sinograms uncorrected and corrected for scatter using a tail-fit method. Results: Test-retest results showed that the 11C-raclopride microPET DVR was reproducible (change in DVR = −8.3% ± 4.4%). The average DVR from 6 rats injected with high specific activity ( 1.5 nmol/kg. Scatter fractions within the rat head were ∼25%–45% resulting in an average increase of DVR of 3.5% (range, 0%–10%) after correction. Conclusion: This study shows that the 11C-raclopride microPET-derived DVR is reproducible and suitable for studying D2R availability in the rat brain. MicroPET sensitivity was sufficient to determine reproducible DVRs from 11C-raclopride injections of 9.25 MBq (∼250 μCi). However, the effect of tracer mass on the DVR should be considered for studies using more than ∼1–2 nmol/kg raclopride, and scatter correction has a measurable impact on the results.

Low monoamine oxidase B in peripheral organs in smokers.

Abstract: One of the major mechanisms for terminating the actions of catecholamines and vasoactive dietary amines is oxidation by monoamine oxidase (MAO). Smokers have been shown to have reduced levels of brain MAO, leading to speculation that MAO inhibition by tobacco smoke may underlie some of the behavioral and epidemiological features of smoking. Because smoking exposes peripheral organs as well as the brain to MAO-inhibitory compounds, we questioned whether smokers would also have reduced MAO levels in peripheral organs. Here we compared MAO B in peripheral organs in nonsmokers and smokers by using positron emission tomography and serial scans with the MAO B-specific radiotracers,l-[11C]deprenyl and deuterium-substituted l-[11C]deprenyl (l-[11C]deprenyl-D2). Binding specificity was assessed by using the deuterium isotope effect. We found that smokers have significantly reduced MAO B in peripheral organs, particularly in the heart, lungs, and kidneys, when compared with nonsmokers. Reductions ranged from 33% to 46%. Because MAO B breaks down catecholamines and other physiologically active amines, including those released by nicotine, its inhibition may alter sympathetic tone as well as central neurotransmitter activity, which could contribute to the medical consequences of smoking. In addition, although most of the emphases on the carcinogenic properties of smoke have been placed on the lungs and the upper airways, this finding highlights the fact that multiple organs in the body are also exposed to pharmacologically significant quantities of chemical compounds in tobacco smoke.

Maternal-Fetal In Vivo Imaging: A Combined PET and MRI Study

Abstract: An understanding of how drugs are transferred between mother and fetus during the gestational period is an important medical issue of relevance to both therapeutic drugs and drugs of abuse. Though there are several in vitro and in vivo methods to examine this issue, all have limitations. Furthermore, ethical and safety considerations generally preclude such studies in pregnant humans. PET and appropriately labeled compounds have the ability to provide information on both maternal-fetal drug pharmacokinetics and pharmacodynamics. We present here a nonhuman primate animal model and the methodology for combining PET and MRI to identify fetal organs and to measure maternal and fetal isotope distribution using 18F-FDG and a whole-body imaging protocol to demonstrate proof-of-principle. Methods: One nonpregnant nonhuman primate was used for determination of the anesthesia protocol and MRI methods and 3 pregnant nonhuman primates (Macaques radiata) weighing 4.5–7 kg were used for the imaging study and anesthetized with propofol (160–300 μg/kg/min). Anatomic T2-weighted MR images were acquired on a 4-T MR instrument. Subsequently, whole-body PET images were acquired 35 min after injection of 18F-FDG, and standardized uptake values (SUVs) were calculated. Image processing and coregistration were performed using commercial software. Results: All animals underwent uneventful general anesthesia for a period of up to 7 h. Coregistration of PET and MR images allowed identification of fetal organs and demonstrated that 18F-FDG readily crosses the placenta and that 18F accumulates in both maternal and fetal brain, heart, and bladder. Brain SUVs averaged 1.95 ± 0.08 (mean ± SD) and 1.58 ± 0.11 for mothers and fetuses, respectively. Monkeys delivered healthy babies after a normal gestational term of 170 d following the PET/MRI study. Conclusion: The pregnant macaque in combination with PET and MRI technology allows the measurement of radioisotope distribution in maternal and fetal organs. This demonstrates the potential for noninvasively measuring the transfer of drugs across the placenta and for measuring the fetal drug distribution. It also opens up the possibility for studying binding and elimination as well as the effects of a drug on specific cellular elements and physiologic processes during the gestational period in a primate model.

Alcohol Intoxication Induces Greater Reductions in Brain Metabolism in Male Than in Female Subjects

Abstract: Background: The mechanisms underlying the gender differences in alcohol drinking behavior and alcohol's effects are poorly understood and may reflect gender differences in brain neurochemistry. Alcohol decreases glucose metabolism in the human brain in a pattern that is consistent with its facilitation of GABAergic neurotransmission. We compared the regional changes in brain glucose metabolism during alcohol intoxication between female and male subjects. Methods: Ten female and 10 male healthy controls were scanned with positron emission tomography and 2-deoxy-2[18F]fluoro-d-glucose twice: 40 min after placebo (diet soda) or alcohol (0.75 g/kg mixed with diet soda). Results: Alcohol significantly and consistently decreased whole-brain metabolism. The magnitude of these changes was significantly larger in male (−25 ± 6%) than in female (−14 ± 11%;p < 0.005) subjects. Half of the female subjects had reductions in metabolism during intoxication that were significantly lower than those in male subjects. This blunted response in the female subjects was not due to differences in alcohol concentration in plasma, because these did not differ between the genders. In contrast, the self-reports for the perception of intoxication were significantly greater in female than in male subjects. The cognitive deterioration during alcohol intoxication, although not significant, tended to be worse in female subjects. Conclusions: This study shows a markedly blunted sensitivity to the effects of acute alcohol on brain glucose metabolism in female subjects that may reflect gender differences in alcohol's modulation of GABAergic neurotransmission. The greater behavioral effects of alcohol in female subjects despite the blunted metabolic responses could reflect other effects of alcohol, for which the regional metabolic signal may be hidden within the large decrements in metabolism that occur during alcohol intoxication.

Neuroscience networks: data-sharing in an information age

Abstract: The completion of the human genome project has ushered in a new era in which biology has become an information science. In this new era, sharing of information is quickly becoming a critical aspect of scientific discovery. As directors of National Institutes of Health (NIH) institutes dedicated to neuroscience, we recognize several areas of research where sharing of primary data will be necessary for us to reach our scientific goals, including brain-mapping, genetics, and clinical trials. Progress in each of these areas will require not only new tools for sharing information but a change in our scientific culture. Here we describe some of the recent progress in efforts to map the brain as an example of the potential and the challenge of sharing data in an era when neurobiology, like genomics, is becoming an information science. In parallel to the worldwide effort to map the human genome, investigators in neuroscience have used a range of techniques to map the brain. The efforts share some superficial similarities: the genome has 3 × 109 bases and the human brain has roughly 100 × 109 neurons; both the genome and the brain have embedded modules of functional units (genes versus circuits) that can be mapped in space; and localization of both genes and circuits requires computational power that can be distributed across laboratories. But the analogy breaks down quickly. Whereas fundamental genome data can be addressed as unidimensional text of four letters in varying order, a comprehensive map of the brain includes molecular, cellular, system, and behavioral data—all of which are dynamic, interacting, and interdependent. For example, brain circuitry is organized in three-dimensional space constantly changing in time, with each neuron having 103–104 synapses and with many of those synapses capable of plasticity that may, in turn, have significant functional consequences. As we emerge from the “decade of the brain,” we are entering a decade for which data-sharing will be the currency for progress in neuroscience. As a testament to the complexity of brain data, a century after the classic age of neurohistology, there are continuing arguments about the taxonomy of neurons, depending on location, morphology, neurochemistry, or RNA profile. For instance, a population of neurons in a small region of the brain, the dorsal raphe, is the main source of the neurochemical serotonin that has been implicated in stress responsiveness and mood disorders. These serotonergic neurons can be subdivided according to rostralcaudal location, axon thickness, or projections (Mamounas et al. 1991; Lowry 2002). However, what we recognize by immunochemical stain as a single shared phenotype in an anatomically distinct region may consist of a heterogeneous population of cells with diverse RNA profiles. In this sense, the strategy for brain-mapping might borrow a page from astronomy, with its maps of galaxies with mixed elements, as well as from the experience of the genome project. Indeed, advances in human brain-mapping, like discoveries in astronomy, have until recently largely depended on the tools available. The postmortem studies of the early 20th century provided delineation of cortical areas through light microscopic histology and gross connectional information. Neurochemical techniques in the last three decades yielded maps with cellular and subcellular resolution, identifying populations of cells usually by one or two neurochemical phenotypes. During the same period, electrophysiological approaches revealed the exquisite distribution of function across the brain, within particular brain subdivisions, and within neurons themselves. In the past two decades, direct study of the intact, functioning human brain in healthy and disordered states has been made possible by a variety of neuroimaging modalities. These studies have provided both structural and functional topography at increasing resolution, as well as neurochemical data and, most recently, information regarding neural connectivity (Behrens et al. 2003). The advent of techniques for mapping RNA profiles now permits analysis of several thousand species of RNA even in a single neuron, resulting in exponential increases in information. As these approaches are combined with the experimental behavioral and clinical sciences, opportunities abound for understanding this complex organ and treating its pathologies. The challenge now is to integrate this information into a coherent, accessible form that permits hierarchical analysis from RNA to protein to morphology to connectivity to function in a universal language while preserving fidelity. While earlier comprehensive maps in simpler nervous systems, such as the classic lineage maps of invertebrates (Stern and Fraser 2001), could be completed by single labs, more ambitious projects like a transcriptional map of the mouse brain, the Human Genome Project, and other goal-directed or large-scale research endeavors (Nass and Stillman 2003) will require collaboration of scientists who add value to the enterprise by working in multidisciplinary teams; coordination of efforts to attain a goal; and computation through the use of informatics, models, and simulations. The keystone in this new paradigm is, of course, meaningful data-sharing. Several initiatives serving the brain and behavioral research communities are advancing cooperative research. The Gensat Project (www.gensat.org) will soon provide developmental and whole-brain maps of several hundred genes in the mouse nervous system using a bacterial artificial chromosome (BAC) transgenic strategy with fluorescent reporters to provide subcellular resolution. A digital atlas of the mouse brain and associated informatics tools have been developed to organize, visualize, and analyze such gene expression (and other spatial) data generated by researchers (http://www.loni.ucla.edu/MAP/index.html). We now have the capability to map the transcriptional expression of virtually the entire mouse genome in the adult and the developing mouse brain, registering these data to a common, digital atlas. Like the galaxy maps generated by the Hubble telescope, this transcriptional atlas will provide important temporal as well as spatial information, revealing genes that may be expressed only at critical stages of brain development. Similarly, the Human Brain Project (http://www.nimh.nih.gov/neuroinformatics/index.cfm) is an informatics effort funded through several federal agencies to develop databases, analytical and computational simulations, and other resources to assist human brain-mapping as well as other large-scale coordinated neuroscience programs. While there are several initiatives at NIH aimed at overcoming the informatics barriers to sharing data and facilitating collaboration, coordination, and computation, we recognize that not all of the impediments to data-sharing are technical. The advent of neurobiology as an information science also demonstrates that the academic culture in which our science develops and the publication culture in which our science is communicated will need to change. Promotion decisions at major universities largely depend on the quality and quantity of first-authored or senior-authored papers. Multidisciplinary studies require teams of investigators in which hierarchical schemes for authorship may fail to reflect accurately the magnitude of each individual's contributions. Similarly, contributions to a research database may represent important scientific and scholarly achievements, but generally are underrecognized by promotions committees counting peer-reviewed publications. Indeed, the nature of publication itself needs to change in an era when some of the most important contributions will emerge from comprehensive descriptions of new landscapes (analogous to new genomes and new galaxies) rather than tests of specific hypotheses. These cultural issues are not peculiar to brain and behavioral science, of course, and have recently been considered broadly at the NIH (http://www.becon.nih.gov/symposium2003.htm). Scientific publication, as we have known it in print, is slow and expensive, with access limited to those with either the funds to purchase an individual subscription or the proximity to a library with an institutional subscription. Data-sharing also means open-access publishing so that data, whether from mapping efforts or from hypothesis-driven experiments, become available quickly and freely to the scientific community. As we emerge from the “decade of the brain,” we are entering a decade for which data-sharing will be the currency for progress in neuroscience. Efforts driven by collaboration, coordination, and computation should yield the data, tools, and resources that neuroscientists will need in the coming decades. We hope that new electronic publications with open access will accelerate this change and provide the vehicle for disseminating the most exciting discoveries in neuroscience in a rapid, respected, and ready format. A Constellation of Neurons

Monoamine Oxidase: Radiotracer Development and Human Studies

Abstract: In 1928, Mary Hare isolated a new enzyme which catalyzed the oxidative deamination of tyramine (Hare 1928). She called it tyramine oxidase and speculated that it “may be protective and present for the purpose of rapid detoxification of excessive amounts of tyramine absorbed from the intestine.” Later Blashko and coworkers showed that this same enzyme also oxidized catecholamines (Blaschko et al. 1937). To reflect this more general reactivity, Zeller (1938) proposed the general name monoamine oxidase (MAO). In the years that followed its discovery, MAO was further characterized along with its role in the regulation of chemical neurotransmitters and as a target for therapeutic drugs and toxic substances. More recently its genetics have been studied. This chapter will focus on general aspects of MAO, on the development of radiotracers for imaging MAO A and MAO B, and on PET studies of MAO in the human brain.

Monoamine oxidase A imaging in peripheral organs in healthy human subjects.

Abstract: Monoamine oxidase (MAO) catalyzes the oxidative deamination of many biogenic and dietary amines. Though studies of MAO have focused mainly on its regulatory role in the brain, MAO in peripheral organs also represents a vast mechanism for detoxifying vasoactive compounds as well as for terminating the action of physiologically active amines, which can cross the blood brain barrier. Indeed, robust central and peripheral MAO activity is a major requirement in the safe use of many CNS drugs, particularly antidepressants, and thus an awareness of the MAO inhibitory potential of drugs is essential in therapeutics. In this study, we examined the feasibility of quantifying MAO A in peripheral organs in healthy human subjects using comparative positron emission tomography (PET) imaging with carbon-11 (t1/2: 20.4 min) labeled clorgyline ([11C]clorgyline) a suicide inactivator of MAO A and its deuterium labeled counterpart ([11C]clorgyline-D2). Heart, lungs, kidneys, thyroid, and spleen showed a robust deuterium isotope effect characteristic of MAO and the magnitude of the effect was similar to that of trancylcypromine, an irreversible MAO inhibitor used in the treatment of depression. Liver time-activity curves were not affected by deuterium substitution precluding the estimation of liver MAO in vivo. In organs showing an isotope effect, MAO A is greatest in the lungs and kidneys followed by the thyroid and heart. This method, which has been previously applied in the human brain, opens the possibility to also directly assess the effects of different variables including smoking, dietary substances, drugs, disease, and genetics on peripheral MAO A in humans. Synapse 49:178–187, 2003. Published 2003 Wiley-Liss, Inc.

Selegiline potentiates cocaine-induced increases in rodent nucleus accumbens dopamine

Abstract: Selegiline has been proposed as a treatment for cocaine addiction and studies in humans suggest that it attenuates cocaine's reinforcing effects. Here we assessed the effects of selegiline treatment on cocaine-induced increases in nucleus accumbens (NAc) dopamine (DA) in freely moving rodents. Chronic treatment with selegiline (L-deprenyl, 0.25/mg/kg, 24 days) potentiated cocaine-induced increases in NAc DA from 350-600%. However, this enhanced response was abolished when animals were treated chronically with both cocaine and selegiline. Inasmuch as increases in NAc DA are associated with the reinforcing effects of cocaine, these results obtained in rodents suggest that MAO-A and -B inhibition may not be a suitable strategy to antagonize cocaine's reinforcing effects during cocaine detoxification. On the other hand, chronic selegiline treatment may improve DA deficits, which are thought to contribute to relapse through a decreased response to natural rewards.

Compact conscious animal positron emission tomography scanner

Abstract: A method of serially transferring annihilation information in a compact positron emission tomography (PET) scanner includes generating a time signal for an event, generating an address signal representing a detecting channel, generating a detector channel signal including the time and address signals, and generating a composite signal including the channel signal and similarly generated signals. The composite signal includes events from detectors in a block and is serially output. An apparatus that serially transfers annihilation information from a block includes time signal generators for detectors in a block and an address and channel signal generator. The PET scanner includes a ring tomograph that mounts onto a portion of an animal, which includes opposing block pairs. Each of the blocks in a block pair includes a scintillator layer, detection array, front-end array, and a serial encoder. The serial encoder includes time signal generators and an address signal and channel signal generator.

System performance simulations of the RatCAP awake rat brain scanner

Abstract: The capability to create high quality images from data acquired by the Rat Conscious Animal PET tomograph (RatCAP) has been evaluated using modified versions of the PET Monte Carlo code Simulation System for Emission Tomography (SimSET). The proposed tomograph consists of lutetium oxyorthosilicate (LSO) crystals arranged in 12 4 /spl times/ 8 blocks. The effects of the RatCAPs small ring diameter (/spl sim/40 mm) and its block detector geometry on image quality for small animal studies have been investigated. Since the field of view will be almost as large as the ring diameter, radial elongation artifacts due to parallax error are expected to degrade the spatial resolution and thus the image quality at the edge of the field of view. In addition to Monte Carlo simulations, some preliminary results of experimentally acquired images in both two-dimensional (2-D) and 3-D modes are presented.

Spatial resolution of a noninvasive measurement of the arterial and venous input function using a wrist monitor

Abstract: The current method for measuring the input function of a PET tomograph is by withdrawing arterial blood from a patient's wrist In this study, the possibility of making a noninvasive measurement of the arterial blood is explored to determine the feasibility of using a planar set of detectors situated around the wrist. The arterial measurement was simulated using a peristaltic pump and an anatomically correct wrist phantom with attenuation. A step function was used to measure the activity flowing through arterial and venous tubing in the phantom. The detector was tested for spatial resolution and counting efficiency. The results showed the detector was able to discriminate the arterial and venous flows from noise when using planar coincidence images.

Positron emission tomography and its use to image the occupancy of drug binding sites

Abstract: The development of positron emission tomography (PET) and the ability to synthesize compounds labeled with the short-lived positron emitters 11C and 18F has made possible the imaging and quantification of drug binding sites in the human body. By conducting PET studies with an appropriate radioligand before and after treatment with a drug, the fraction of the total number of binding sites that is occupied by the drug (the “occupancy” of the site) can often be determined. To the extent that occupancy is a good indicator of pharmacological activity, such PET experiments can aid the development of drug dosage regimens. Some of the general issues involved in PET studies of drug occupancy are discussed. There have been many such studies involving antipsychotic drugs and dopamine D2 receptor radioligands. Since neuroleptics have been extensively reviewed elsewhere, only the major findings are discussed here. Other binding sites (and drug classes) in the dopamine system to which this methodology has been applied include: the dopamine transporter (stimulant drugs) and monoamine oxidase A and B (antidepressant drugs). Occupancy studies are also possible for many drug targets beyond the dopamine system. Drug Dev. Res. 59:194–207, 2003. © 2003 Wiley-Liss, Inc.

Low Level of Brain Dopamine D2 Receptors in Methamphetamine Abusers: Association With Metabolism in the Orbitofrontal Cortex

Abstract: Objective: The role of dopamine in the addictive process (loss of control and compulsive drug intake) is poorly understood. A consistent finding in drug-addicted subjects is a lower level of dopamine D2 receptors. In cocaine abusers, low levels of D2 receptors are associated with a lower level of metabolism in the orbitofrontal cortex. Because the orbitofrontal cortex is associated with compulsive behaviors, its disruption may contribute to compulsive drug intake in addicted subjects. This study explored whether a similar association occurs in methamphetamine abusers. Method: Fifteen methamphetamine abusers and 20 non-drug-abusing comparison subjects were studied with positron emission tomography (PET) and [11C]raclopride to assess the availability of dopamine D2 receptors and with [18F]fluorodeoxyglucose to assess regional brain glucose metabolism, a marker of brain function. Results: Methamphetamine abusers had a significantly lower level of D2 receptor availability than comparison subjects (a differenc...

Neuroimaging in drug abuse.

Abstract: Neuroimaging techniques, including positron emission tomography (PET), are ideally suited for studies of addiction. These minimally invasive modalities yield information about acute and long-term drug-induced structural and functional changes in the brain over time. Changes can be observed in the brains of human and animal subjects during drug self-administration. Neuroimaging with PET allows precise quantification and visualization of the drug and its rates of movement in the body. In addition, imaging reveals recovery of function and reappearance of neuronal markers in abstinent drug users. Evidence that suggests that PET may have use in identifying individuals predisposed to become addicted is emerging. Finally, candidate pharmacotherapies for drug addiction can be critically evaluated. These unique assets clearly point to the use of these strategies for addiction studies.

Blending practice and research: a potent catalyst for progress.

Abstract: As this issue of Science & Practice Perspectives goes to press, NIDA’s third “Blending Clinical Practice and Research”conference is about to begin in Denver. Hundreds of producers of recovery and creators of new knowledge on drug abuse are gathering to share and combine their expertise in plenary sessions, topic discussions, and skills-building workshops on a wide range of critically important topics. “Blending” is NIDA’s short name for some of its most important work. By blending, we mean the integrated research-practice partnership so necessary to achieve our full potential to relieve the suffering and waste of human life caused by drug abuse and addiction. In “Blending” meetings, researchers, clinicians, other care providers, social workers, criminal justice officers, and community leaders bring their observations, insights, viewpoints, and priorities collectively to bear in advancing our understanding of drug abuse and addiction and our ability to treat and prevent it. Experience has shown that these collegial discussions are a potent catalyst for progress. NIDA initiatives that focus directly on facilitating and improving research-practice dialogue take many forms. The fullest expression of blending in action is the Clinical Trials Network. In this nationwide consortium, researchers and providers work together to set research priorities and plan studies specifically to resolve issues that community treatment and prevention programs identify as top-priority. They conduct the studies together in community settings, ensuring that the results are readily adaptable for rapid implementation in a variety of treatment settings. Science & Practice Perspectives brings the robust research-practice exchanges that are the essence of blending to the page (and the Web), and to research centers and treatment programs nationwide and around the world. We hope S&PP will stimulate and inspire you, and that you too join in the growing research-practice dialogue. Only in this way can we realize the full power of rapidly advancing science and current clinical experience to improve the health and well-being of everyone affected by substance abuse.