Imaging Calorimeter for ACCESS (ICA) is a candidate of the calorimeter for the NASA's ACCESS program to be flown on the International Space Station. The ICA studies the origin and acceleration mechanism of cosmic rays by measuring the... more
Imaging Calorimeter for ACCESS (ICA) is a candidate of the calorimeter for the NASA's ACCESS program to be flown on the International Space Station. The ICA studies the origin and acceleration mechanism of cosmic rays by measuring the elemental composition of the cosmic rays in the energy up to 10^16 eV. For the past year, Monte Carlo simulation study for the ICA has been conducted using GEANT/FLUKA to predict the detector performance and to design the system for match the scientific objectives. Simulation results will be shown for the detector response and the energy resolution for various configurations.
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Research Interests: Psychopharmacology, Animal Studies, Anterior Cingulate, Experimental Design, Prefrontal Cortex, and 21 moreSerotonin, Dopamine, Primates, Humans, PET imaging, Animals, Laboratory Animals, Serotonin Transporter, Drug Addiction, Environmental Variables, Diagnostic Imaging, Integrated Approach, Cognitive impairment, Limbic System, Mechanism of action, Cerebral Blood Flow, Drug Interaction, Brain Chemistry, Treatment Response, Substance-Related Disorders, and Pharmaceutical preparations
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Page 1. &p.1:Abstract The behavioral effects of GBR 12909, a selec-tive dopamine uptake inhibitor, were determined in squirrel monkeys trained to respond under a fixed-inter-val (FI) schedule of stimulus termination and a... more
Page 1. &p.1:Abstract The behavioral effects of GBR 12909, a selec-tive dopamine uptake inhibitor, were determined in squirrel monkeys trained to respond under a fixed-inter-val (FI) schedule of stimulus termination and a second-order schedule of IV drug self-administration. ...
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The transition from infrequent and controlled cocaine use to dependence may involve enduring changes in neurobiology as a consequence of persistent drug use. The present study utilized an intravenous drug self-administration protocol of... more
The transition from infrequent and controlled cocaine use to dependence may involve enduring changes in neurobiology as a consequence of persistent drug use. The present study utilized an intravenous drug self-administration protocol of increasing cocaine access to evaluate potential changes in dopamine function in vivo, including changes in sensitivity to psychostimulants. Drug-naïve rhesus monkeys were provided limited access (1 h) to cocaine self-administration for 60 days followed by 60 days under an extended access condition (4 h). Basal levels of striatal extracellular dopamine and its metabolites, as well as the effectiveness of cocaine and amphetamine to elevate dopamine, were determined with in vivo microdialysis before the initiation of cocaine self-administration and during limited and extended access. The effect of cocaine and amphetamine on the acoustic startle response was also examined to assess complementary behavioral changes as a function of drug history. Extended access to cocaine self-administration lead to increased daily intake compared to limited access conditions but did not result in escalated intake over time. However, cocaine- and amphetamine-induced increases in striatal dopamine were diminished as a function of cocaine self-administration history. Surprisingly, there was no effect of drug-taking history on sensitivity to psychostimulant-induced enhancement of startle amplitude. The present experiments provide evidence of a hypofunctional dopamine system that is not associated with an escalation in drug intake or reflected in measures of acoustic startle.
Research Interests: Psychopharmacology, Animal Behavior, Psychoacoustics, Drug Use, Dopamine, and 15 moreStartle Reflex, Female, Animals, Cocaine, Male, Behavior change, Self-administration, High Pressure Liquid Chromatography, Microdialysis, Phenols, Rhesus Monkey, Analysis of Variance, Time Factors, Operant Conditioning, and Macaca Mulatta
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In order to investigate the potential modulatory role of serotonin on the discriminative-stimulus effects of cocaine, two groups of squirrel monkeys were trained to discriminate 0.3 mg/kg or 1.0 mg/kg cocaine and saline under a two-lever... more
In order to investigate the potential modulatory role of serotonin on the discriminative-stimulus effects of cocaine, two groups of squirrel monkeys were trained to discriminate 0.3 mg/kg or 1.0 mg/kg cocaine and saline under a two-lever drug-discrimination procedure. Substitution of a range of cocaine doses (0.03-1.7 mg/kg) occasioned orderly, dose-dependent increases in cocaine-lever responding. When administered alone, the non-selective serotonin direct agonist, quipazine, also occasioned increases in cocaine-lever responding which were more pronounced in subjects trained with the lower cocaine dose. When quipazine was administered in combination with cocaine, there was an increase in cocaine-lever responding, indicating an additive effect. The serotonin uptake inhibitor, fluoxetine, occasioned saline-lever responding when administered alone. However, in combination with cocaine, fluoxetine enhanced the discriminative effects of cocaine in subjects trained at the lower cocaine dose. The 5-HT2-selective antagonists, ketanserin and ritanserin, did not occasion cocaine-lever responding when administered alone. In combination with cocaine, ketanserin attenuated the discriminative effects of cocaine in most subjects, and ritanserin attenuated the discriminative effects of cocaine in subjects trained at the higher dose. These results indicate that the discriminative-stimulus effects of cocaine may be increased by direct- and indirect-acting serotonin agonists and attenuated by serotonin antagonists in squirrel monkeys.
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... The cutoff energies for gamma rays and electrons in the GEANT simulation program were set as 10 MeV (the simulation results with a lower cutoff energy, for example, 100 keV, will be presented in the forthcoming paper [15]). ...
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The objective of the present study was to further elucidate the mechanisms involved in the wake-promoting effects of psychomotor stimulants. Many previous studies have tightly linked the effects of stimulants to dopamine... more
The objective of the present study was to further elucidate the mechanisms involved in the wake-promoting effects of psychomotor stimulants. Many previous studies have tightly linked the effects of stimulants to dopamine neurotransmission, and some studies indicate that serotonin 2A receptors modulate these effects. However, the role of dopamine in arousal is controversial, most notably because dopamine neurons do not change firing rates across arousal states. In the present study, we examined the wake-promoting effects of the dopamine-releaser amphetamine using non-invasive telemetric monitoring. These effects were evaluated in rhesus monkeys as a laboratory animal model with high translational relevance for human disorders of sleep and arousal. To evaluate the role of dopamine in the wake-promoting effects of amphetamine, we used in vivo microdialysis targeting the caudate nucleus, as this approach provides clearly interpretable measures of presynaptic dopamine release. This is beneficial in the present context because some of the inconsistencies between previous studies examining the role of dopamine in arousal may be related to differences between postsynaptic dopamine receptors. We found that amphetamine significantly and dose-dependently increased arousal at doses that engendered higher extracellular dopamine levels. Moreover, antagonism of serotonin 2A receptors attenuated the effects of amphetamine on both wakefulness and dopamine overflow. These findings further elucidate the role of dopamine and serotonin 2A receptors in arousal, and they suggest that increased dopamine neurotransmission may be necessary for the wake-promoting effects of amphetamine, and possibly other stimulants.
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Research Interests: Cognitive Science, Anterior Cingulate, Magnetic Resonance Imaging, Consciousness, Prefrontal Cortex, and 14 moreCortisol, Female, Animals, Feasibility Studies, Cocaine, Data Collection, Oxygen, Rhesus Monkey, Macaca Mulatta, Physiological Stress Markers, Human Subjects, Statistical Methods for Neuroscience, Conscious, and Neurosciences
... F. Ivy Carroll,* Leonard L. Howell, and Michael J. Kuhar . Chemistry and Life Sciences, Research Triangle Institute, Research Triangle Park, North Carolina 27709, and Yerkes Regional Primate Research Center, Emory University,... more
... F. Ivy Carroll,* Leonard L. Howell, and Michael J. Kuhar . Chemistry and Life Sciences, Research Triangle Institute, Research Triangle Park, North Carolina 27709, and Yerkes Regional Primate Research Center, Emory University, Atlanta, Georgia 30322. J. Med. Chem. ...
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Dopamine transporter (DAT) inhibitors have been developed as a promising treatment approach for cocaine dependence. However, the stimulant effects of DAT inhibitors have the potential to disrupt sleep patterns, and the influence of... more
Dopamine transporter (DAT) inhibitors have been developed as a promising treatment approach for cocaine dependence. However, the stimulant effects of DAT inhibitors have the potential to disrupt sleep patterns, and the influence of long-term treatment on dopamine neurochemistry is still unknown. The objectives of this study were to (1) explore the stimulant-related effects of chronic DAT inhibitor (RTI-336) treatment on motor activity and sleep-like measures in male rhesus monkeys (Macaca mulatta; n = 4) and (2) to determine the effect of drug treatment on prolactin and cortisol levels. Subjects were fitted with a collar-mounted activity monitor to evaluate their motor activity, with 4 days of baseline recording preceding 21 days of daily saline or RTI-336 (1 mg/kg/day; intramuscular) injections. Blood samples were collected immediately prior to and following chronic treatment to assess hormone levels. RTI-336 produced a significant increase in locomotor activity at the end of the daytime period compared to saline administration. During the 3-week treatment period, sleep efficiency was decreased and the fragmentation index and latency to sleep onset were significantly increased. Hormone levels were not changed throughout the study. Chronic treatment with RTI-336 has a mild but significant stimulant effect, as evidenced by the significant increase in activity during the evening period which may cause minor disruptions in sleep measures.
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A consistent observation in drug abuse research is that males and females show differences in their response to drugs of abuse. In order to understand the neurobiology underlying cocaine abuse and effective treatments, it is important to... more
A consistent observation in drug abuse research is that males and females show differences in their response to drugs of abuse. In order to understand the neurobiology underlying cocaine abuse and effective treatments, it is important to consider the role of sex differences. Sex hormones have been investigated in both behavioral and molecular studies, but further evidence addressing drug abuse and dependence in both sexes would expand our knowledge of sex differences in response to drugs of abuse. Neuroimaging is a powerful tool that can offer insight into the biological bases of these differences and meet the challenges of directly examining drug-induced changes in brain function. As such, neuroimaging has drawn much interest in recent years. Specifically, positron emission tomography (PET), single photon emission computed tomography (SPECT), and magnetic resonance imaging (MRI) technology have emerged as effective noninvasive approaches for human and animal models. Studies have revealed sex-specific changes in patterns of brain activity in response to acute cocaine injection and after prolonged cocaine use. SPECT and PET studies have demonstrated changes in the dopamine transporter but are less clear on other components of the dopaminergic system. This review highlights contributions of neuroimaging toward understanding the role of sex differences in the drug abuse field, specifically regarding cocaine, and identifies relevant questions that neuroimaging can effectively address.
Research Interests: Psychology, Neuroimaging, Magnetic Resonance Imaging, Sex Hormones, Positron Emission Tomography, and 13 moreBrain, Humans, Sex Difference, Female, Animals, Male, Animal Model, Drug abuse, Single Photon Emission Computed Tomography, Dopamine Transporter, Drugs of Abuse, Clinical and Experimental Hypnosis, and Brain Function
Psychostimulants are a broadly defined class of drugs that stimulate the central and peripheral nervous systems as their primary pharmacological effect. The abuse liability of psychostimulants is well established and represents a... more
Psychostimulants are a broadly defined class of drugs that stimulate the central and peripheral nervous systems as their primary pharmacological effect. The abuse liability of psychostimulants is well established and represents a significant public health concern. An extensive literature documents the critical importance of monoamines (dopamine, serotonin and norepinephrine) in the behavioral pharmacology and addictive properties of psychostimulants. In particular, the dopamine transporter plays a primary role in the reinforcing and behavioral-stimulant effects of psychostimulants in animals and humans. Moreover, both serotonin and norepinephrine systems can reliably modulate the neurochemical and behavioral effects of psychostimulants. However, there is a growing body of evidence that highlights complex interactions among additional neurotransmitter systems. Cortical glutamatergic systems provide important regulation of dopamine function, and inhibitory amino acid gamma-aminobutyric acid (GABA) systems can modulate basal dopamine and glutamate release. Repeated exposure to psychostimulants can lead to robust and enduring changes in neurobiological substrates, including monoamines, and corresponding changes in sensitivity to acute drug effects on neurochemistry and behavior. Significant advances in the understanding of neurobiological mechanisms underlying psychostimulant abuse and dependence have guided pharmacological treatment strategies to improve clinical outcome. In particular, functional agonist treatments may be used effectively to stabilize monoamine neurochemistry, influence behavior and lead to long-term abstinence. However, additional clinical studies are required in order to identify safe and efficacious pharmacotherapies.
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Early life stress has effects on behavior and stress reactivity, which are linked to enhanced sensitivity to stimulants in rodents. This study investigated whether rhesus monkeys that experienced early life stress would show altered... more
Early life stress has effects on behavior and stress reactivity, which are linked to enhanced sensitivity to stimulants in rodents. This study investigated whether rhesus monkeys that experienced early life stress would show altered sensitivity to the reinforcing effects of stimulants as compared with controls. Control (n=5) and maternally separated (n=4) monkeys were trained to self-administer cocaine (0.1 mg/kg/injection) under a second-order schedule of intravenous drug delivery. The rate of acquisition and subsequent dose-effect determinations for cocaine (0.01-1.0 mg/kg/injection) and amphetamine (0.003-0.3 mg/kg/injection) provided complementary measures of reinforcing effectiveness. In addition, stimulant-induced increases in home cage activity and dopamine D2 receptor binding potential were quantified with positron emission tomography neuroimaging. Compared with controls, maternally separated monkeys showed lower responding during the acquisition of self-administration and in the dose-response curves for both stimulants, and significantly lower response rates during maintenance of cocaine self-administration. Maternally separated monkeys also failed to exhibit stimulant-induced increases in motor activity. Groups did not differ in dopamine D2 receptor binding potential in the caudate nucleus or the putamen. Taken together, the results of this study do not provide support for early life stress leading to enhanced vulnerability to stimulant use in the nonhuman primate model employed.
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There is significant interest in the NMDA receptor antagonist ketamine due to its efficacy in treating depressive disorders and its induction of psychotic-like symptoms that make it a useful tool for modeling psychosis. The present study... more
There is significant interest in the NMDA receptor antagonist ketamine due to its efficacy in treating depressive disorders and its induction of psychotic-like symptoms that make it a useful tool for modeling psychosis. The present study extends the successful development of an apparatus and methodology to conduct pharmacological MRI studies in awake rhesus monkeys in order to evaluate the CNS effects of ketamine. Functional MRI scans were conducted in four awake adult female rhesus monkeys during sub-anesthetic intravenous (i.v.) infusions of ketamine (0.345 mg/kg bolus followed by 0.256 mg/kg/h constant infusion) with and without risperidone pretreatment (0.06 mg/kg). Statistical parametric maps of ketamine-induced blood oxygenation level-dependent (BOLD) activation were obtained with appropriate general linear regression models (GLMs) incorporating motion and hemodynamics of ketamine infusion. Ketamine infusion induced and sustained robust BOLD activation in a number of cortical ...
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Research Interests: Psychology, Brain Imaging, Kinetics, Positron Emission Tomography, Dopamine, and 21 moreBrain, PET imaging, Female, Animals, Animal Model, Substantia nigra, Tyrosine Hydroxylase, Clinical Sciences, Experimental, Rhesus Monkey, Time Factors, Dopamine Transporter, Autoradiography, Reproducibility of Results, Transporter, Macaca Mulatta, Experimental Neurology, Ligands, Neurosciences, Mono, and Behavioral symptoms
Despite intensive medication development efforts, no effective pharmacotherapy for cocaine abuse has demonstrated efficacy for long-term use. Given the obvious importance of the dopamine transporter in the addictive properties of cocaine,... more
Despite intensive medication development efforts, no effective pharmacotherapy for cocaine abuse has demonstrated efficacy for long-term use. Given the obvious importance of the dopamine transporter in the addictive properties of cocaine, the development and use of compounds that target the dopamine transporter represents a reasonable approach for the pharmacological treatment of cocaine abuse. The therapeutic approach of replacement or substitute agonist medication has been successful, as shown with methadone maintenance for heroin dependence and nicotine replacement for tobacco use. A number of preclinical studies with dopamine transporter inhibitors provide evidence that substitute agonists may be used effectively to reduce cocaine use. Nonhuman primate models of drug self-administration provide a rigorous, systematic approach to characterize medication effectiveness in subjects with a documented history of drug use. Several cocaine analogs and other dopamine transporter inhibito...
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Diffusion-weighted imaging (DWI) and perfusion MRI were used to examine the spatiotemporal evolution of stroke lesions in adult macaques with ischemic occlusion. Permanent MCA occlusion was induced with silk sutures through an... more
Diffusion-weighted imaging (DWI) and perfusion MRI were used to examine the spatiotemporal evolution of stroke lesions in adult macaques with ischemic occlusion. Permanent MCA occlusion was induced with silk sutures through an interventional approach via the femoral artery in adult rhesus monkeys (n = 8, 10-21 years old). The stroke lesions were examined with high-resolution DWI and perfusion MRI, and T2-weighted imaging (T2W) on a clinical 3T scanner at 1-6, 48, and 96 hours post occlusion and validated with H&E staining. The stroke infarct evolved via a natural logarithmic pattern with the mean infarct growth rate = 1.38 ± 1.32 ml per logarithmic time scale (hours) (n = 7) in the hyperacute phase (1-6 hours). The mean infarct volume after 6 hours post occlusion was 3.6±2.8 ml (n = 7, by DWI) and increased to 3.9±2.9 ml (n = 5, by T2W) after 48 hours, and to 4.7±2.2ml (n = 3, by T2W) after 96 hours post occlusion. The infarct volumes predicted by the natural logarithmic function were correlated significantly with the T2W-derived lesion volumes (n = 5, r = 0.92, p = 0.01) at 48 hours post occlusion. The final infarct volumes derived from T2W were correlated significantly with those from H&E staining (r = 0.999, p < 0.0001, n = 4). In addition, the diffusion-perfusion mismatch was visible generally at 6 hours but nearly diminished at 48 hours post occlusion. The infarct evolution follows a natural logarithmic pattern in the hyperacute phase of stroke. The logarithmic pattern of evolution could last up to 48 hours after stroke onset and may be used to predict the infarct volume growth during the acute phase of ischemic stroke. The nonhuman primate model, MRI protocols, and post data processing strategy may provide an excellent platform for characterizing the evolution of acute stroke lesion in mechanistic studies and therapeutic interventions of stroke disease.
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Research Interests: Psychopharmacology, Animal Behavior, Drug interactions, Magnetic Resonance Spectroscopy, Positron Emission Tomography, and 16 moreSerotonin, Dopamine, Brain, Female, Animals, Methamphetamine, Male, Hallucinogens, Microdialysis, Rhesus Monkey, Analysis of Variance, Dopamine Transporter, Operant Conditioning, Macaca Mulatta, Serotonin antagonists, and Piperidines
Acute re-exposure to cocaine or drug cues associated with cocaine use can elicit drug craving and relapse. Neuroimaging studies have begun to define neurobiological substrates underlying the acute effects of cocaine or cocaine cues in... more
Acute re-exposure to cocaine or drug cues associated with cocaine use can elicit drug craving and relapse. Neuroimaging studies have begun to define neurobiological substrates underlying the acute effects of cocaine or cocaine cues in cocaine-dependent subjects. The present study was the first to use functional brain imaging to document acute cocaine-induced changes in brain activity during active drug use in nonhuman primates. Positron emission tomography imaging with O15-labeled water was used to measure drug-induced changes in cerebral blood flow. The acute effects of cocaine administered noncontingently were characterized in four drug-naïve rhesus monkeys. The same subjects were trained to self-administer cocaine under a fixed ratio schedule during image acquisition. Subsequently, three subjects with an extensive history of cocaine use were trained to self-administer cocaine under a second-order schedule. The same subjects also underwent extinction sessions during which saline was substituted for cocaine under the second-order schedule. Noncontingent administration of cocaine in drug-naïve subjects induced robust activation of prefrontal cortex localized primarily to the dorsolateral regions. In contrast, the pattern of brain activation induced by self-administered cocaine differed qualitatively and included anterior cingulate cortex. Moreover, drug-associated stimuli during extinction also induced robust activation of prefrontal cortex. The effects of cocaine and associated cues extend beyond the limbic system to engage brain areas involved in cognitive processes. The identification of neural circuits underlying the direct pharmacological and conditioned stimulus effects of cocaine may be highly relevant toward efforts to develop treatments for cocaine addiction.