Publications by authors named "Stephen L Dewey"

46 Publications

Design and Mechanism of (S)-3-Amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic Acid, a Highly Potent γ-Aminobutyric Acid Aminotransferase Inactivator for the Treatment of Addiction.

J Am Chem Soc 2018 02 30;140(6):2151-2164. Epub 2018 Jan 30.

Departments of Chemistry and Molecular Biosciences, Chemistry of Life Processes Institute, Center for Molecular Innovation and Drug Discovery, and Center for Developmental Therapeutics, Northwestern University , Evanston, Illinois 60208, United States.

γ-Aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the central nervous system. Inhibition of GABA aminotransferase (GABA-AT), a pyridoxal 5'-phosphate (PLP)-dependent enzyme that degrades GABA, has been established as a possible strategy for the treatment of substance abuse. The raised GABA levels that occur as a consequence of this inhibition have been found to antagonize the rapid release of dopamine in the ventral striatum (nucleus accumbens) that follows an acute challenge by an addictive substance. In addition, increased GABA levels are also known to elicit an anticonvulsant effect in patients with epilepsy. We previously designed the mechanism-based inactivator (1S,3S)-3-amino-4-difluoromethylenyl-1-cyclopentanoic acid (2), now called CPP-115, that is 186 times more efficient in inactivating GABA-AT than vigabatrin, the only FDA-approved drug that is an inactivator of GABA-AT. CPP-115 was found to have high therapeutic potential for the treatment of cocaine addiction and for a variety of epilepsies, has successfully completed a Phase I safety clinical trial, and was found to be effective in the treatment of infantile spasms (West syndrome). Herein we report the design, using molecular dynamics simulations, synthesis, and biological evaluation of a new mechanism-based inactivator, (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid (5), which was found to be almost 10 times more efficient as an inactivator of GABA-AT than CPP-115. We also present the unexpected crystal structure of 5 bound to GABA-AT, as well as computational analyses used to assist the structure elucidation process. Furthermore, 5 was found to have favorable pharmacokinetic properties and low off-target activities. In vivo studies in freely moving rats showed that 5 was dramatically superior to CPP-115 in suppressing the release of dopamine in the corpus striatum, which occurs subsequent to either an acute cocaine or nicotine challenge. Compound 5 also attenuated increased metabolic demands (neuronal glucose metabolism) in the hippocampus, a brain region that encodes spatial information concerning the environment in which an animal receives a reinforcing or aversive drug. This multidisciplinary computational design to preclinical efficacy approach should be applicable to the design and improvement of mechanism-based inhibitors of other enzymes whose crystal structures and inactivation mechanisms are known.
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http://dx.doi.org/10.1021/jacs.7b10965DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5812813PMC
February 2018

Levodopa-induced abnormal involuntary movements correlate with altered permeability of the blood-brain-barrier in the basal ganglia.

Sci Rep 2017 11 22;7(1):16005. Epub 2017 Nov 22.

Center for Neurosciences, The Feinstein Institute for Medical Research, Manhasset, NY, 11030, USA.

Chronic levodopa treatment leads to the appearance of dyskinesia in the majority of Parkinson's disease patients. Neurovascular dysregulation in putaminal and pallidal regions is thought to be an underlying feature of this complication of treatment. We used microPET to study unilaterally lesioned 6-hydroxydopamine rats that developed levodopa-induced abnormal involuntary movements (AIMs) after three weeks of drug treatment. Animals were scanned with [O]-labeled water and [F]-fluorodeoxyglucose, to map regional cerebral blood flow and glucose metabolism, and with [C]-isoaminobutyric acid (AIB), to assess blood-brain-barrier (BBB) permeability, following separate injections of levodopa or saline. Multitracer scan data were acquired in each animal before initiating levodopa treatment, and again following the period of daily drug administration. Significant dissociation of vasomotor and metabolic levodopa responses was seen in the striatum/globus pallidus (GP) of the lesioned hemisphere. These changes were accompanied by nearby increases in [C]-AIB uptake in the ipsilateral GP, which correlated with AIMs scores. Histopathological analysis revealed high levels of microvascular nestin immunoreactivity in the same region. The findings demonstrate that regional flow-metabolism dissociation and increased BBB permeability are simultaneously induced by levodopa within areas of active microvascular remodeling, and that such changes correlate with the severity of dyskinesia.
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http://dx.doi.org/10.1038/s41598-017-16228-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5700135PMC
November 2017

Imaging Sex Differences in Regional Brain Metabolism during Acute Opioid Withdrawal.

J Alcohol Drug Depend 2017 Apr 6;5(2). Epub 2017 Apr 6.

Center for Neurosciences, Laboratory for Molecular and Behavioral Neuroimaging, Feinstein Institute for Medical Research, Manhasset, NY, USA.

The rate of opioid overdose continues to rise, necessitating improved treatment options. Current therapeutic approaches rely on administration of either a blocking agent, such as naloxone, or chronic treatment with replacement drugs, including methadone and/or buprenorphine. Recent findings suggest that males and females respond to these treatments uniquely. In an effort to better understand this sex-specific variation in treatment efficacy, we investigated the effects of acute opioid withdrawal in male and female rats using 18FDG and microPET. These data demonstrate that acute opioid withdrawal produces metabolic alterations in brain regions associated with reward and drug dependence, namely corpus striatum, thalamic nuclei, septum, and frontal cortex. Furthermore, certain changes are unique to males. Specifically, males demonstrated increased metabolism in the anterior cingulate cortex and the ventral hippocampus (CA3) following acute opioid withdrawal. If males and females exhibit sex-specific changes in regional brain metabolism following acute opioid withdrawal, then perhaps it is not surprising that they respond to treatment differently.
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http://dx.doi.org/10.4172/2329-6488.1000262DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5642926PMC
April 2017

Sex Differences in Regional Brain Glucose Metabolism Following Opioid Withdrawal and Replacement.

Neuropsychopharmacology 2017 Aug 10;42(9):1841-1849. Epub 2017 Apr 10.

Center for Neurosciences, Laboratory for Molecular and Behavioral Neuroimaging, Feinstein Institute for Medical Research, Manhasset, NY, USA.

Methadone and buprenorphine are currently the most common pharmacological treatments for opioid dependence. Interestingly, the clinical response to these drugs appears to be sex specific. That is, females exhibit superior therapeutic efficacy, defined as extended periods of abstinence and longer time to relapse, compared with males. However, the underlying metabolic effects of opioid withdrawal and replacement have not been examined. Therefore, using FDG and microPET, we measured differences in regional brain glucose metabolism in males and females following morphine withdrawal and subsequent methadone or buprenorphine replacement. In both males and females, spontaneous opioid withdrawal altered glucose metabolism in regions associated with reward and drug dependence. Specifically, metabolic increases in the thalamus, as well as metabolic decreases in insular cortex and the periaqueductal gray, were noted. However, compared with males, females exhibited increased metabolism in the preoptic area, primary motor cortex, and the amygdala, and decreased metabolism in the caudate/putamen and medial geniculate nucleus. Methadone and buprenorphine initially abolished these changes uniformly, but subsequently produced their own regional metabolic alterations that varied by treatment and sex. Compared with sex-matched control animals undergoing spontaneous opioid withdrawal, male animals treated with methadone exhibited increased caudate/putamen metabolism, whereas buprenorphine produced increased ventral striatum and motor cortex metabolism in females, and increased ventral striatum and somatosensory cortex metabolism in males. Notably, when treatment effects were compared between sexes, methadone-treated females showed increased cingulate cortex metabolism, whereas buprenorphine-treated females showed decreased metabolism in cingulate cortex and increased metabolism in the globus pallidus. Perhaps the initial similarities in males and females underlie early therapeutic efficacy, whereas these posttreatment sex differences contribute to clinical treatment failure more commonly experienced by the former.
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http://dx.doi.org/10.1038/npp.2017.69DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5520789PMC
August 2017

In vivo evaluation of IGF1R/IR PET ligand [F]BMS-754807 in rodents.

Bioorg Med Chem Lett 2017 02 7;27(4):941-943. Epub 2017 Jan 7.

Molecular Imaging and Neuropathology Division, New York State Psychiatric Institute, New York, USA. Electronic address:

In vivo evaluation of [F]BMS-754807 binding in mice and rats using microPET and biodistribution methods is described herein. The radioligand shows consistent binding characteristics, in vivo, in both species. Early time frames of the microPET images and time activity curves of brain indicate poor penetration of the tracer across the blood brain barrier (BBB) in both species. However, microPET experiments in mice and rats show high binding of the radioligand outside the brain to heart, pancreas and muscle, the organs known for higher expression of IGF1R/1R. Biodistribution analysis 2h after injection of [F]BMS-754807 in rats show negligible [F]defluorination as reflected by the low bone uptake and clearance from blood. Overall, the data indicate that [F]BMS-754807 can potentially be a radiotracer for the quantification of IGF1R/IR outside the brain using PET.
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http://dx.doi.org/10.1016/j.bmcl.2016.12.086DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5846678PMC
February 2017

A Novel Strategy for Attenuating Opioid Withdrawal in Neonates.

J Addict Res Ther 2016 08 11;7(4). Epub 2016 Aug 11.

Center for Neurosciences, Laboratory for Molecular and Behavioural Neuroimaging, Feinstein Institute for Medical Research, Manhasset, NY, USA; Department of Molecular Medicine, Hofstra North Shore-LIJ School of Medicine, Hempstead, NY, USA; Psychiatry Department, New York University School of Medicine, NY, USA.

The rate of Neonatal Abstinence Syndrome (NAS) has drastically increased over the past decade. The average hospital expense per NAS patient has tripled, while the number of babies born to opioid-dependent mothers has increased to 5 in 1000 births. Current treatment options are limited to opioid replacement and tapering. Consequently, we examined the efficacy of prenatal, low-dose and short-term vigabatrin (γ-vinyl GABA, GVG) exposure for attenuating these symptoms as well as the metabolic changes observed in the brains of these animals upon reaching adolescence. Pregnant Sprague-Dawley rats were treated in one of four ways: 1) saline; 2) morphine alone; 3) morphine+GVG at 25 mg/kg; 4) morphine+GVG at 50 mg/kg. Morphine was administered throughout gestation, while GVG administration occurred only during the last 5 days of gestation. On post-natal day 1, naloxone-induced withdrawal behaviours were recorded in order to obtain a gross behaviour score. Approximately 28 days following birth, FDG microPET scans were obtained on these same animals (Groups 1, 2, and 4). Morphine-treated neonates demonstrated significantly higher withdrawal scores than saline controls. However, GVG at 50 but not 25 mg/kg/day significantly attenuated them. Upon reaching adolescence, morphine treated animals showed regionally specific changes in FDG uptake. Again, prenatal GVG exposure blocked them. These data demonstrate that low-dose, short-term prenatal GVG administration blocks naloxone-induced withdrawal in neonates. Taken together, these preliminary findings suggest that GVG may provide an alternative and long-lasting pharmacologic approach for the management of neonatal and adolescent symptoms associated with NAS.
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http://dx.doi.org/10.4172/2155-6105.1000291DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5222617PMC
August 2016

Dissociation of metabolic and hemodynamic levodopa responses in the 6-hydroxydopamine rat model.

Neurobiol Dis 2016 Dec 17;96:31-37. Epub 2016 Aug 17.

Center for Neurosciences, The Feinstein Institute for Medical Research, Manhasset, NY 11030, USA. Electronic address:

Dissociation of vasomotor and metabolic responses to levodopa has been observed in human subjects with Parkinson's disease (PD) studied with PET and in autoradiograms from 6-hydroxydopamine (6-OHDA) rat. In both species, acute levodopa administration was associated with increases in basal ganglia cerebral blood flow (CBF) with concurrent reductions in cerebral metabolic rate (CMR) for glucose in the same brain regions. In this study, we used a novel dual-tracer microPET technique to measure CBF and CMR levodopa responses in the same animal. Rats with unilateral 6-OHDA or sham lesion underwent sequential O-water (HO) and F-fluorodeoxyglucose (FDG) microPET to map CBF and CMR following the injection of levodopa or saline. A subset of animals was separately scanned under ketamine/xylazine and isoflurane to compare the effects of these anesthetics. Regardless of anesthetic agent, 6-OHDA animals exhibited significant dissociation of vasomotor (ΔCBF) and metabolic (ΔCMR) responses to levodopa, with stereotyped increases in CBF and reductions in CMR in the basal ganglia ipsilateral to the dopamine lesion. No significant changes were seen in sham-lesioned animals. These data faithfully recapitulate analogous dissociation effects observed previously in human PD subjects scanned sequentially during levodopa infusion. This approach may have utility in the assessment of new drugs targeting the exaggerated regional vasomotor responses seen in human PD and in experimental models of levodopa-induced dyskinesia.
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http://dx.doi.org/10.1016/j.nbd.2016.08.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5102795PMC
December 2016

18FDG-microPET and MR DTI findings in Tor1a+/- heterozygous knock-out mice.

Neurobiol Dis 2015 Jan 4;73:399-406. Epub 2014 Nov 4.

Center for Neurosciences, The Feinstein Institute for Medical Research, NY 11030, USA; Department of Molecular Medicine, Hofstra University, NY 11549, USA; Department of Radiology, Albert Einstein College of Medicine, NY 10461, USA; Institute of Biomedical Engineering, Boğaziçi University, Istanbul, Turkey. Electronic address:

TorsinA is an important protein in brain development, and plays a role in the regulation of neurite outgrowth and synaptic function. Patients with the most common form of genetic dystonia carry a mutation (DYT1) in one copy of the Tor1a gene, a 3-bp deletion, causing removal of a single glutamic acid from torsinA. Previous imaging studies have shown that abnormal cerebellar metabolism and damaged cerebello-thalamo-cortical pathway contribute to the pathophysiology of DYT1 dystonia. However, how a mutation in one copy of the Tor1a gene causes these abnormalities is not known. We studied Tor1a heterozygous knock-out mice in vivo with FDG-PET and ex vivo with diffusion tensor imaging. We found metabolic abnormalities in cerebellum, caudate-putamen, globus pallidus, sensorimotor cortex and subthalamic nucleus. We also found that FA was increased in caudate-putamen, sensorimotor cortex and brainstem. We compared our findings with a previous imaging study of the Tor1a knock-in mice. Our study suggested that having only one normal copy of Tor1a gene may be responsible for the metabolic abnormalities observed; having a copy of mutant Tor1a, on the other hand, may be responsible for white matter pathway damages seen in DYT1 dystonia subjects.
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http://dx.doi.org/10.1016/j.nbd.2014.10.020DOI Listing
January 2015

Regional brain metabolism in a murine systemic lupus erythematosus model.

J Cereb Blood Flow Metab 2014 Aug 14;34(8):1315-20. Epub 2014 May 14.

Center for Autoimmune and Musculoskeletal Disease, The Feinstein Institute for Medical Research, Manhasset, New York, USA.

Systemic lupus erythematosus (SLE) is characterized by multiorgan inflammation, neuropsychiatric disorders (NPSLE), and anti-nuclear antibodies. We previously identified a subset of anti-DNA antibodies (DNRAb) cross-reactive with the N-methyl-D-aspartate receptor, present in 30% to 40% of patients, able to enhance excitatory post-synaptic potentials and trigger neuronal apoptosis. DNRAb+ mice exhibit memory impairment or altered fear response, depending on whether the antibody penetrates the hippocampus or amygdala. Here, we used 18F-fluorodeoxyglucose (FDG) microPET to plot changes in brain metabolism after regional blood-brain barrier (BBB) breach. In DNRAb+ mice, metabolism declined at the site of BBB breach in the first 2 weeks and increased over the next 2 weeks. In contrast, DNRAb- mice exhibited metabolic increases in these regions over the 4 weeks after the insult. Memory impairment was present in DNRAb+ animals with hippocampal BBB breach and altered fear conditioning in DNRAb+ mice with amygdala BBB breach. In DNRAb+ mice, we observed an inverse relationship between neuron number and regional metabolism, while a positive correlation was observed in DNRAb- mice. These findings suggest that local metabolic alterations in this model take place through different mechanisms with distinct time courses, with important implications for the interpretation of imaging data in SLE subjects.
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http://dx.doi.org/10.1038/jcbfm.2014.85DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4126091PMC
August 2014

(1S, 3S)-3-amino-4-difluoromethylenyl-1-cyclopentanoic acid (CPP-115), a potent γ-aminobutyric acid aminotransferase inactivator for the treatment of cocaine addiction.

J Med Chem 2012 Jan 30;55(1):357-66. Epub 2011 Dec 30.

Department of Chemistry, Chemistry of Life Processes Institute, Center for Molecular Innovation and Drug Discovery, Northwestern University, Evanston, Illinois 60208-3113, United States.

Vigabatrin, a GABA aminotransferase (GABA-AT) inactivator, is used to treat infantile spasms and refractory complex partial seizures and is in clinical trials to treat addiction. We evaluated a novel GABA-AT inactivator (1S, 3S)-3-amino-4-difluoromethylenyl-1-cyclopentanoic acid (CPP-115, compound 1) and observed that it does not exhibit other GABAergic or off-target activities and is rapidly and completely orally absorbed and eliminated. By use of in vivo microdialysis techniques in freely moving rats and microPET imaging techniques, 1 produced similar inhibition of cocaine-induced increases in extracellular dopamine and in synaptic dopamine in the nucleus accumbens at (1)/(300) to (1)/(600) the dose of vigabatrin. It also blocks expression of cocaine-induced conditioned place preference at a dose (1)/(300) that of vigabatrin. Electroretinographic (ERG) responses in rats treated with 1, at doses 20-40 times higher than those needed to treat addiction in rats, exhibited reductions in ERG responses, which were less than the reductions observed in rats treated with vigabatrin at the same dose needed to treat addiction in rats. In conclusion, 1 can be administered at significantly lower doses than vigabatrin, which suggests a potential new treatment for addiction with a significantly reduced risk of visual field defects.
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http://dx.doi.org/10.1021/jm201231wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3257419PMC
January 2012

PET imaging of thin objects: measuring the effects of positron range and partial-volume averaging in the leaf of Nicotiana tabacum.

Nucl Med Biol 2011 Feb 27;38(2):191-200. Epub 2010 Oct 27.

Medical Department, Brookhaven National Laboratory, Upton, New York, USA.

Introduction: PET imaging in plants is receiving increased interest as a new strategy to measure plant responses to environmental stimuli and as a tool for phenotyping genetically engineered plants. PET imaging in plants, however, poses new challenges. In particular, the leaves of most plants are so thin that a large fraction of positrons emitted from PET isotopes ((18)F, (11)C, (13)N) escape while even state-of-the-art PET cameras have significant partial-volume errors for such thin objects. Although these limitations are acknowledged by researchers, little data have been published on them.

Methods: Here we measured the magnitude and distribution of escaping positrons from the leaf of Nicotiana tabacum for the radionuclides (18)F, (11)C and (13)N using a commercial small-animal PET scanner. Imaging results were compared to radionuclide concentrations measured from dissection and counting and to a Monte Carlo simulation using GATE (Geant4 Application for Tomographic Emission).

Results: Simulated and experimentally determined escape fractions were consistent. The fractions of positrons (mean±S.D.) escaping the leaf parenchyma were measured to be 59±1.1%, 64±4.4% and 67±1.9% for (18)F, (11)C and (13)N, respectively. Escape fractions were lower in thicker leaf areas like the midrib. Partial-volume averaging underestimated activity concentrations in the leaf blade by a factor of 10 to 15.

Conclusions: The foregoing effects combine to yield PET images whose contrast does not reflect the actual activity concentrations. These errors can be largely corrected by integrating activity along the PET axis perpendicular to the leaf surface, including detection of escaped positrons, and calculating concentration using a measured leaf thickness.
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http://dx.doi.org/10.1016/j.nucmedbio.2010.08.004DOI Listing
February 2011

Microglial ablation and lipopolysaccharide preconditioning affects pilocarpine-induced seizures in mice.

Neurobiol Dis 2010 Jul 9;39(1):85-97. Epub 2010 Apr 9.

Department of Pharmacological Sciences, Molecular and Cellular Pharmacology, Stony Brook University, Stony Brook, NY 11794-8651, USA.

Activated microglia have been associated with neurodegeneration in patients and in animal models of Temporal Lobe Epilepsy (TLE), however their precise functions as neurotoxic or neuroprotective is a topic of significant investigation. To explore this, we examined the effects of pilocarpine-induced seizures in transgenic mice where microglia/macrophages were conditionally ablated. We found that unilateral ablation of microglia from the dorsal hippocampus did not alter acute seizure sensitivity. However, when this procedure was coupled with lipopolysaccharide (LPS) preconditioning (1 mg/kg given 24 h prior to acute seizure), we observed a significant pro-convulsant phenomenon. This effect was associated with lower metabolic activation in the ipsilateral hippocampus during acute seizures, and could be attributed to activity in the mossy fiber pathway. These findings reveal that preconditioning with LPS 24 h prior to seizure induction may have a protective effect which is abolished by unilateral hippocampal microglia/macrophage ablation.
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http://dx.doi.org/10.1016/j.nbd.2010.04.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2875881PMC
July 2010

Decreased serotonin levels associated with behavioral disinhibition in tissue plasminogen activator deficient (tPA-/-) mice.

Brain Res 2010 Apr 12;1326:135-42. Epub 2010 Feb 12.

Department of Pharmacological Sciences, Stony Brook University, Stony Brook, NY 11733, USA.

Tissue Plasminogen Activator (tPA) is a serine protease expressed in different areas of the mammalian brain. It has been used clinically to dissolve clots and shown to have a role in neurodegeneration. Early studies suggested that tPA plays an important role in the processes of learning and memory, demonstrated at the level of behavior and synaptic plasticity. Herein, we extend the behavioral characterization of these mice to the related dimension of exploratory-related behavior using an extensive battery of behavioral tests as well as the neurotransmitter metabolism associated with the behavioral measures. Our results indicate a behavior tendency in these mice consistent with "impulsivity" or reduced exploratory inhibition. These patterns are accompanied by decreased levels of serotonin in several brain regions important in behavioral regulation in the tPA(-/-) mice compared to control animals. Systemic administration of fluoxetine reversed the behavioral disinhibition of tPA(-/-) mice, further supporting an important alteration in behavior regulation mediated by serotonin systems as underappreciated but important element of the behavioral phenotype of these animals.
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http://dx.doi.org/10.1016/j.brainres.2009.12.095DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2853966PMC
April 2010

Randomized, double-blind, placebo-controlled trial of vigabatrin for the treatment of cocaine dependence in Mexican parolees.

Am J Psychiatry 2009 Nov 3;166(11):1269-77. Epub 2009 Aug 3.

Department of Psychiatry, New York University School of Medicine, New York, NY 10016, USA.

Objective: Cocaine dependence is associated with severe medical, psychiatric, and social morbidity, but no pharmacotherapy is approved for its treatment in the United States. The atypical antiepileptic vigabatrin (gamma-vinyl gamma-aminobutyric acid [GABA]) has shown promise in animal studies and open-label trials. The purpose of the present study was to assess the efficacy of vigabatrin for short-term cocaine abstinence in cocaine-dependent individuals.

Method: Participants were treatment seeking parolees who were actively using cocaine and had a history of cocaine dependence. Subjects were randomly assigned to a fixed titration of vigabatrin (N=50) or placebo (N=53) in a 9-week double-blind trial and 4-week follow-up assessment. Cocaine use was determined by directly observed urine toxicology testing twice weekly. The primary endpoint was full abstinence for the last 3 weeks of the trial.

Results: Full end-of-trial abstinence was achieved in 14 vigabatrin-treated subjects (28.0%) versus four subjects in the placebo arm (7.5%). Twelve subjects in the vigabatrin group and two subjects in the placebo group maintained abstinence through the follow-up period. The retention rate was 62.0% in the vigabatrin arm versus 41.5% in the placebo arm. Among subjects who reported prestudy alcohol use, vigabatrin, relative to placebo, was associated with superior self-reported full end-of-trial abstinence from alcohol (43.5% versus 6.3%). There were no differences between the two groups in drug craving, depressed mood, anxiety, or Clinical Global Impression scores, and no group differences in adverse effects emerged.

Conclusions: This first randomized, double-blind, placebo-controlled trial supports the safety and efficacy of short-term vigabatrin treatment of cocaine dependence.
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http://dx.doi.org/10.1176/appi.ajp.2009.08121811DOI Listing
November 2009

Cue-induced dopamine release predicts cocaine preference: positron emission tomography studies in freely moving rodents.

J Neurosci 2009 May;29(19):6176-85

Medical Department, Brookhaven National Laboratory, Upton, New York 11973, USA.

Positron emission tomography studies in drug-addicted patients have shown that exposure to drug-related cues increases striatal dopamine, which displaces binding of the D(2) ligand, [(11)C]-raclopride. However, it is not known if animals will also show cue-induced displacement of [(11)C]-raclopride binding. In this study, we use [(11)C]-raclopride imaging in awake rodents to capture cue-induced changes in dopamine release associated with the conditioned place preference model of drug craving. Ten animals were conditioned to receive cocaine in a contextually distinct environment from where they received saline. Following conditioning, each animal was tested for preference and then received two separate [(11)C]-raclopride scans. For each scan, animals were confined to the cocaine and/or the saline-paired environment for the first 25 min of uptake, after which they were anesthetized and scanned. [(11)C]-raclopride uptake in the saline-paired environment served as a within-animal control for uptake in the cocaine-paired environment. Cocaine produced a significant place preference (p = 0.004) and exposure to the cocaine-paired environment decreased [(11)C]-raclopride binding relative to the saline-paired environment in both the dorsal (20%; p < 0.002) and ventral striatum (22%; p < 0.05). The change in [(11)C]-raclopride binding correlated with preference in the ventral striatum (R(2) = -0.87; p = 0.003). In this region, animals who showed little or no preference exhibited little or no change in [(11)C]-raclopride binding in the cocaine-paired environment. This noninvasive procedure of monitoring neurochemical events in freely moving, behaving animals advances preclinical molecular imaging by interrogating the degree to which animal models reflect the human condition on multiple dimensions, both biological and behavioral.
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http://dx.doi.org/10.1523/JNEUROSCI.5221-08.2009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6665516PMC
May 2009

Racemic gamma vinyl-GABA (R,S-GVG) blocks methamphetamine-triggered reinstatement of conditioned place preference.

Synapse 2009 Feb;63(2):87-94

Medical Department, Brookhaven National Laboratory, Upton, New York 11973, USA.

Preventing relapse poses a significant challenge to the successful management of methamphetamine (METH) dependence. Although no effective medication currently exists for its treatment, racemic gamma vinyl-GABA (R,S-GVG, vigabatrin) shows enormous potential as it blocks both the neurochemical and behavioral effects of a variety of drugs, including METH, heroin, morphine, ethanol, nicotine, and cocaine. Using the reinstatement of a conditioned place preference (CPP) as an animal model of relapse, the present study specifically investigated the ability of an acute dose of R,S-GVG to block METH-triggered reinstatement of a METH-induced CPP. Animals acquired a METH CPP following a 20-day-period of conditioning, in which they received 10 pairings of alternating METH and saline injections. During conditioning, rats were assigned to one of four METH dosage groups: 1.0, 2.5, 5.0, or 10.0 mg/kg (i.p., n = 8/group). Animals in all dosage groups demonstrated a robust and consistent CPP. This CPP was subsequently extinguished in each dosage group with repeated saline administration. Upon extinction, all groups reinstated following an acute METH challenge. On the following day, an acute dose of R,S-GVG (300 mg/kg, i.p.) was administered 2.5 h prior to an identical METH challenge. R,S-GVG blocked METH-triggered reinstatement in all four groups. Given that drug re-exposure may potentiate relapse to drug-seeking behavior, the ability of R,S-GVG to block METH-triggered reinstatement offers further support for its use in the successful management of METH dependence.
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http://dx.doi.org/10.1002/syn.20582DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5004629PMC
February 2009

Subchronic racemic gamma vinyl-GABA produces weight loss in Sprague Dawley and Zucker fatty rats.

Synapse 2008 Nov;62(11):870-2

Medical Department, Brookhaven National Laboratory, Upton, New York 11973, USA.

Given the growing obesity epidemic, pressure to develop an effective pharmacologic treatment is mounting. Following the completion of a randomized, double-blind, placebo controlled trial as well as two small open label trials, gamma vinyl-GABA (GVG) has been shown to be safe and effective for treating cocaine and/or methamphetamine dependence. In an extension of these findings, the present study examined whether GVG could produce weight loss in adolescent as well as genetically obese animals. Specifically, adolescent Sprague Dawley and adolescent and adult Zucker fatty rats received GVG at various doses (75-300 mg/kg, i.p., racemic) for treatment periods lasting no longer than 14 consecutive days. GVG produced significant weight loss in a dose dependent fashion in all groups. These effects were marked, as average decreases of 12-20% of original body weight were observed. These findings suggest that GVG may be useful as a treatment for obesity. Further, that these results occurred in genetically obese animals offers the possibility that GVG may even help manage severe obesity resulting from binge-eating, a disorder involving food consumption in a pattern similar to the compulsive drug-seeking behavior observed in cocaine and methamphetamine dependent subjects.
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http://dx.doi.org/10.1002/syn.20555DOI Listing
November 2008

Imaging dopamine release with Positron Emission Tomography (PET) and (11)C-raclopride in freely moving animals.

Neuroimage 2008 Jul 19;41(3):1051-66. Epub 2008 Mar 19.

Medical Department, Brookhaven National Laboratory, Upton NY 11973, USA.

We investigated an imaging strategy that provides simultaneous measurements of radiotracer binding and behavior in awake, freely moving animals. In this strategy, animals are injected intravenously (i.v.) through a catheterized line and permitted to move freely for 30 min during uptake of the imaging agent, in this case 11C-raclopride. After this Awake Uptake period, animals are anesthetized and scanned for 25 min. We tested the utility of this strategy for measuring changes in striatal 11C-raclopride binding under control conditions (awake and freely moving in the home cage) and with several drug challenges: a loading dose of unlabeled raclopride, pretreatment with methamphetamine (METH) or pretreatment with gamma-vinyl-GABA [S+-GVG] followed by METH. An additional group of animals underwent a stress paradigm that we have previously shown increases brain dopamine. For drug challenge experiments, the change in 11C-raclopride binding was compared to data from animals that were anesthetized for the uptake period ("Anesthetized Uptake") and full time activity curves were used to calculate 11C-raclopride binding. Regardless of the drug treatment protocol, there was no difference in 11C-raclopride striatum to cerebellum ratio between the Awake versus the Anesthetized Uptake conditions. Awake and Anesthetized groups demonstrated over 90% occupancy of dopamine receptors with a loading dose of cold raclopride, both groups demonstrated approximately 30% reduction in 11C-raclopride binding from METH pretreatment and this effect was modulated to the same degree by GVG under both uptake conditions. Restraint during Awake Uptake decreased 11C-raclopride binding by 29%. These studies support a unique molecular imaging strategy in which radiotracer uptake occurs in freely moving animals, after which they are anesthetized and scanned. This imaging strategy extends the applicability of small animal PET to include functional neurotransmitter imaging and the neurochemical correlates of behavioral tasks.
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http://dx.doi.org/10.1016/j.neuroimage.2008.02.065DOI Listing
July 2008

The effects of inhaled acetone on place conditioning in adolescent rats.

Pharmacol Biochem Behav 2008 Mar 22;89(1):101-5. Epub 2007 Nov 22.

Medical Department, Brookhaven National Laboratory, Upton, NY 11973, USA.

Introduction: Acetone is an ubiquitous ingredient in many household products (e.g., glue solvents, air fresheners, adhesives, nail polish, and paint) that is putatively abused; however, there is little empirical evidence to suggest that acetone alone has any abuse liability. Therefore, we systematically investigated the conditioned response to inhaled acetone in a place conditioning apparatus.

Method: Three groups of male, Sprague-Dawley rats were exposed to acetone concentrations of 5000, 10,000 or 20,000 ppm for 1 h in a conditioned place preference apparatus alternating with air for 6 pairing sessions. A place preference test ensued in an acetone-free environment. To test the preference of acetone as a function of pairings sessions, the 10,000 ppm group received an additional 6 pairings and an additional group received 3 pairings. The control group received air in both compartments. Locomotor activity was recorded by infrared photocells during each pairing session.

Results: We noted a dose response relationship to acetone at levels 5000-20,000 ppm. However, there was no correlation of place preference as a function of pairing sessions at the 10,000 ppm level. Locomotor activity was markedly decreased in animals on acetone-paired days as compared to air-paired days.

Conclusion: The acetone concentrations we tested for these experiments produced a markedly decreased locomotor activity profile that resemble CNS depressants. Furthermore, a dose response relationship was observed at these pharmacologically active concentrations, however, animals did not exhibit a positive place preference.
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http://dx.doi.org/10.1016/j.pbb.2007.11.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5394741PMC
March 2008

Gamma-vinyl GABA inhibits cocaine-triggered reinstatement of drug-seeking behavior in rats by a non-dopaminergic mechanism.

Drug Alcohol Depend 2008 Oct 11;97(3):216-25. Epub 2007 Dec 11.

Neuropsychopharmacology Section, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, DHHS, Baltimore, MD 21224, United States.

Relapse to drug use is a core feature of addiction. Previous studies demonstrate that gamma-vinyl GABA (GVG), an irreversible GABA transaminase inhibitor, attenuates the acute rewarding effects of cocaine and other addictive drugs. We here report that systemic administration of GVG (25-300 mg/kg) dose-dependently inhibits cocaine- or sucrose-induced reinstatement of reward-seeking behavior in rats. In vivo microdialysis data indicated that the same doses of GVG dose-dependently elevate extracellular GABA levels in the nucleus accumbens (NAc). However, GVG, when administered systemically or locally into the NAc, failed to inhibit either basal or cocaine-priming enhanced NAc dopamine in either naïve rats or cocaine extinction rats. These data suggest that: (1) GVG significantly inhibits cocaine- or sucrose-triggered reinstatement of reward-seeking behavior; and (2) a GABAergic-, but not dopaminergic-, dependent mechanism may underlie the antagonism by GVG of cocaine-triggered reinstatement of drug-seeking behavior, at least with respect to GVG's action on the NAc.
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http://dx.doi.org/10.1016/j.drugalcdep.2007.10.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2574671PMC
October 2008

Targeting the treatment of drug abuse with molecular imaging.

Nucl Med Biol 2007 Oct 9;34(7):833-47. Epub 2007 Aug 9.

Medical Department, Brookhaven National Laboratory, Upton, NY 11973, USA.

Although imaging studies in and of themselves have significant contributions to the study of human behavior, imaging in drug abuse has a much broader agenda. Drugs of abuse bind to molecules in specific parts of the brain in order to produce their effects. Positron emission tomography (PET) provides a unique opportunity to track this process, capturing the kinetics with which an abused compound is transported to its site of action. The specific examples discussed here were chosen to illustrate how PET can be used to map the regional distribution and kinetics of compounds that may or may not have abuse liability. We also discussed some morphological and functional changes associated with drug abuse and different stages of recovery following abstinence. PET measurements of functional changes in the brain have also led to the development of several treatment strategies, one of which is discussed in detail here. Information such as this becomes more than a matter of academic interest. Such knowledge can provide the bases for anticipating which compounds may be abused and which may not. It can also be used to identify biological markers or changes in brain function that are associated with progression from drug use to drug abuse and also to stage the recovery process. This new knowledge can guide legislative initiatives on the optimal duration of mandatory treatment stays, promoting long-lasting abstinence and greatly reducing the societal burden of drug abuse. Imaging can also give some insights into potential pharmacotherapeutic targets to manage the reinforcing effects of addictive compounds, as well as into protective strategies to minimize their toxic consequences.
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http://dx.doi.org/10.1016/j.nucmedbio.2007.05.004DOI Listing
October 2007

PET studies of d-methamphetamine pharmacokinetics in primates: comparison with l-methamphetamine and ( --)-cocaine.

J Nucl Med 2007 Oct 14;48(10):1724-32. Epub 2007 Sep 14.

Brookhaven National Laboratory, Upton, New York, USA.

Unlabelled: The methamphetamine molecule has a chiral center and exists as 2 enantiomers, d-methamphetamine (the more active enantiomer) and l-methamphetamine (the less active enantiomer). d-Methamphetamine is associated with more intense stimulant effects and higher abuse liability. The objective of this study was to measure the pharmacokinetics of d-methamphetamine for comparison with both l-methamphetamine and (-)-cocaine in the baboon brain and peripheral organs and to assess the saturability and pharmacologic specificity of binding.

Methods: d- and l-methamphetamine and (-)-cocaine were labeled with (11)C via alkylation of the norprecursors with (11)C-methyl iodide using literature methods. Six different baboons were studied in 11 PET sessions at which 2 radiotracer injections were administered 2-3 h apart to determine the distribution and kinetics of (11)C-d-methamphetamine in brain and peripheral organs. Saturability and pharmacologic specificity were assessed using pretreatment with d-methamphetamine, methylphenidate, and tetrabenazine. (11)C-d-Methamphetamine pharmacokinetics were compared with (11)C-l-methamphetamine and (11)C-(-)-cocaine in both brain and peripheral organs in the same animal.

Results: (11)C-d- and l-methamphetamine both showed high uptake and widespread distribution in the brain. Pharmacokinetics did not differ between enantiomers, and the cerebellum peaked earlier and cleared more quickly than the striatum for both. (11)C-d-Methamphetamine distribution volume ratio was not substantially affected by pretreatment with methamphetamine, methylphenidate, or tetrabenazine. Both enantiomers showed rapid, high uptake and clearance in the heart and lungs and slower uptake and clearance in the liver and kidneys. A comparison of (11)C-d-methamphetamine and (11)C-(-)-cocaine showed that (11)C-d-methamphetamine peaked later in the brain than did (11)C-(-)-cocaine and cleared more slowly. The 2 drugs showed similar behavior in all peripheral organs examined except the kidneys and pancreas, which showed higher uptake for (11)C-d-methamphetamine.

Conclusion: Brain pharmacokinetics did not differ between d-and l-methamphetamine and thus cannot account for the more intense stimulant effects of d-methamphetamine. Lack of pharmacologic blockade by methamphetamine indicates that the PET image represents nonspecific binding, though the fact that methamphetamine is both a transporter substrate and an inhibitor may also play a role. A comparison of (11)C-d-methamphetamine and (11)C-(-)-cocaine in the same animal showed that the slower clearance of methamphetamine is likely to contribute to its previously reported longer-lasting stimulant effects relative to those of (-)-cocaine. High kidney uptake of d-methamphetamine or its labeled metabolites may account for the reported renal toxicity of d-methamphetamine in humans.
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http://dx.doi.org/10.2967/jnumed.107.040279DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2732342PMC
October 2007

A novel approach for imaging brain-behavior relationships in mice reveals unexpected metabolic patterns during seizures in the absence of tissue plasminogen activator.

Neuroimage 2007 Oct 18;38(1):34-42. Epub 2007 Jul 18.

Graduate Program in Molecular and Cellular Pharmacology, State University of New York at Stony Brook, Stony Brook, NY 11794, USA.

Medically refractory seizures cause inflammation and neurodegeneration. Seizure initiation thresholds have been linked in mice to the serine protease tissue plasminogen activator (tPA); mice lacking tPA exhibit resistance to seizure induction, and the ensuing inflammation and neurodegeneration are similarly suppressed. Seizure foci in humans can be examined using PET employing 2-deoxy-2[(18)F]fluoro-d-glucose ((18)FDG) as a tracer to visualize metabolic dysfunction. However, there currently exist no such methods in mice to correlate measures of brain activation with behavior. Using a novel method for small animal PET data analysis, we examine patterns of (18)FDG uptake in wild-type and tPA(-/-) mice and find that they correlate with the severity of drug-induced seizure initiation. Furthermore, we report unexpected activations that may underlie the tPA modulation of seizure susceptibility. The methods described here should be applicable to other mouse models of human neurological disease.
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http://dx.doi.org/10.1016/j.neuroimage.2007.06.032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2084071PMC
October 2007

Brain metabolic changes following 4-week citalopram infusion: increased 18FDG uptake and gamma-amino butyric acid levels.

Synapse 2007 Nov;61(11):877-81

Graduate Program in Molecular and Cellular Pharmacology, SUNY Stony Brook, Stony Brook, New York 11794, USA.

We used 2-week and 4-week citalopram infusion (10 mg/kg/day) to determine how this selective serotonin reuptake inhibitor (SSRI) would alter 2-deoxy-2-[18F]-fluoro-D-glucose (18FDG) uptake and neurotransmitter tissue levels in male Sprague-Dawley rodents. A weekly time course of 18FDG uptake altered by chronic citalopram treatment was determined in vivo with small animal positron emission tomography (microPET). Additionally, end of study monoamine levels were measured ex vivo using high pressure liquid chromatography (HPLC) and amino acid levels were determined ex vivo with proton nuclear magnetic resonance spectroscopy (1H-NMRS). We found increased striatal 18FDG uptake, reduced tissue levels of noradrenaline and serotonin in the striatum and prefrontal cortex, and increased striatal gamma-amino-butyric acid following 4-week citalopram infusion.
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http://dx.doi.org/10.1002/syn.20428DOI Listing
November 2007

Optimizing experimental protocols for quantitative behavioral imaging with 18F-FDG in rodents.

J Nucl Med 2007 Feb;48(2):277-87

Medical Department, Brookhaven National Laboratory, Upton, New York, New York 11973, USA.

Unlabelled: Small-animal PET provides the opportunity to image brain activation during behavioral tasks in animal models of human conditions. The present studies aimed to simplify behavioral imaging procedures without a loss of quantitation by using an intraperitoneal route of administration (no cannulation, no anesthesia) and using a standardized uptake value (SUV) to reduce scan duration.

Methods: Sixteen animals with carotid artery cannulations were studied with 18F-FDG small-animal PET accompanied by serial arterial blood sampling. Ten of these animals were anesthetized and were inside the tomograph during 18F-FDG uptake, whereas 6 animals were awake in their home cages and scanned after 60 min of uptake. Of the 10 anesthetized animals, 6 received intraperitoneal 18F-FDG, whereas 4 received intravenous 18F-FDG, and all 6 awake animals received intraperitoneal 18F-FDG. Intravenously injected animals were positioned far enough inside the tomograph to obtain region-of-interest-based measures from the heart and the brain. In all animals, a full arterial input function and plasma glucose levels were obtained. To establish the optimal time during 18F-FDG uptake for blood sampling when using an SUV, a Patlak kinetic model was used to derive absolute rates of glucose metabolism and compared with SUVs calculated using different plasma points from the arterial input function.

Results: A single plasma point taken at 60 min after injection for intraperitoneal injections or 45 min after injection for intravenous injections provides a sensitive index of glucose metabolic rate with the highest correlation with data obtained from a fully quantitative input function.

Conclusion: These studies support an experimental protocol in which animals can receive the 18F-FDG tracer injection intraperitoneally, away from the small-animal tomograph and with minimal impact on behavior. Further, animals can occupy the tomograph bed for a 10- to 30-min scan with a consequent increase in animal throughput.
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February 2007

Short-term treatment of cocaine and/or methamphetamine abuse with vigabatrin: ocular safety pilot results.

Arch Ophthalmol 2006 Sep;124(9):1257-62

Institute of Ophthalmology and Visual Science, University of Medicine and Dentistry of New Jersey-New Jersey Medical School, 90 Bergen Street, Newark, NJ 07103, USA.

Objective: To evaluate the ocular safety of short-term use of vigabatrin to treat cocaine and/or methamphetamine addiction.

Methods: Individuals who were actively using cocaine and/or methamphetamine were eligible for enrollment. Enrolled subjects were scheduled for comprehensive eye examinations at the beginning and end of the study. Visual field testing was performed at baseline and 1 week, 4 weeks, 8 weeks, and 1 month or more after discontinuing vigabatrin. Twenty-eight subjects received at least 1 dose of vigabatrin; however, only 20 subjects continued beyond the initial escalating vigabatrin dose phase to the treatment phase. Of these 20 subjects, 18 completed the study with full follow-up. Visual fields were evaluated subjectively by 2 glaucoma specialists and analyzed objectively for group and individual changes in quadrant mean sensitivity. The objective analysis was also repeated for superior field quadrants after excluding the uppermost peripheral points to minimize the eyelid effect. The main outcome measures were change of visual field, visual acuity, and ocular adverse effects.

Results: Vigabatrin seemed to help treat cocaine and/or methamphetamine addiction. Of 18 subjects, 16 had negative test results for cocaine and methamphetamine use during the last 6 weeks of the trial. No ocular adverse events were detected. The subjective evaluation did not reveal visual field constriction in any of the 18 evaluable participants. Objective group and individual analyses for quadrant mean sensitivity did not show any change from baseline in any quadrant. No changes in visual acuity were noted.

Conclusions: In this short-term pilot study, vigabatrin seemed to help treat cocaine and/or methamphetamine abuse. There was no evidence of ocular or visual field adverse effects.
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http://dx.doi.org/10.1001/archopht.124.9.1257DOI Listing
September 2006

Metabolic correlates of toluene abuse: decline and recovery of function in adolescent animals.

Psychopharmacology (Berl) 2006 Jun 22;186(2):159-67. Epub 2006 Apr 22.

Chemistry Department, Brookhaven National Laboratory, Upton, NY 11973, USA.

Rationale: Children and adolescents will readily abuse household products that contain solvents such as toluene. It is likely that reinforcing exposures to toluene alter brain glucose metabolism.

Objective: Using an animal model of drug reinforcement, we sought to identify a metabolic signature of toluene abuse in the adolescent rodent brain. Small animal PET (microPET), in combination with the glucose analog radiotracer, (18)FDG, were used to evaluate the metabolic consequences of inhaled toluene.

Methods: The exposure protocol paralleled our previously established method for assessing the conditioned reinforcing effects of toluene (5,000 ppm) using the conditioned place preference (CPP) paradigm. Animals were scanned at baseline and 2 h after the last exposure. Follow-up (18)FDG scans occurred 1 day, 3 weeks, and 2 months later.

Results: After six pairings, 38% of the animals preferred the toluene paired chamber and 25% were averse. The immediate metabolic effect in toluene-exposed animals was a 20% decline in whole brain (18)FDG uptake. Twenty-four hours following the last exposure, the whole brain decline was 40%, and 2 months later, the decline was 30% of pretoluene levels. A region-by-region analysis demonstrated significant additional decreases in the pons, cerebellum, striatum, midbrain, temporal cortex, and hippocampus. Two months after toluene cessation, regions of complete metabolic recovery were the thalamus and cerebellum; however, the temporal cortex did not recover.

Conclusions: Brain uptake of (18)FDG appears to be a useful tool for examining the metabolic impact of toluene abuse, which include a profound decline followed by region-specific recovery after cessation.
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http://dx.doi.org/10.1007/s00213-006-0359-6DOI Listing
June 2006

Serial microPET measures of the metabolic reaction to a microdialysis probe implant.

J Neurosci Methods 2006 Sep 7;155(2):272-84. Epub 2006 Mar 7.

Graduate Program in Neuroscience, Department of Neurobiology & Behavior, Stony Brook University, Stony Brook, NY 11794-5230, USA.

Despite the widespread use of chronic brain implants in experimental and clinical settings, the effects of these long-term procedures on brain metabolism and receptor expression remain largely unknown. Under the hypothesis that intracerebral microdialysis transiently alters tissue metabolism, we performed a series of 18FDG microPET scans prior to and following surgical implantation of microdialysis cannulae. Parallel microPET measures using the competitive dopamine (DA) D2 receptor antagonist, 11C-raclopride, provided an assay of DA stability in these same animals. 18FDG scans were performed prior to microdialysis cannulation and again at 2, 12, 24, 48, 120, 168, 360 and 500 h (0.2, 0.5, 1, 2, 5, 7, 15 and 25 days). Separate animals received a sham surgery and the control group had no surgical intervention. For the first 24 h (scans at 2, 12 and 24 h post-surgery) uptake was reduced in both hemispheres. However, by 48 h, contralateral uptake had returned to pre-surgical levels. The striking finding was that from 48 to 500 h, the microdialysis cannulation produced widespread ipsilateral reductions in 18FDG uptake that encompassed the entire hemisphere. Despite the extent and persistence of these reductions, 11C-raclopride binding and ECF DA concentrations remained stable.
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http://dx.doi.org/10.1016/j.jneumeth.2006.01.027DOI Listing
September 2006

Reproducibility of intraperitoneal 2-deoxy-2-[18F]-fluoro-D-glucose cerebral uptake in rodents through time.

Nucl Med Biol 2006 Jan;33(1):71-9

Graduate Program in Molecular and Cellular Pharmacology, SUNY Stony Brook, NY 11794-8651, USA.

Introduction: One strength of small animal imaging is the ability to obtain longitudinal measurements within the same animal, effectively reducing the number of animals needed and increasing statistical power. However, the variability of within-rodent brain glucose uptake after an intraperitoneal injection across an extended time has not been measured.

Methods: Small animal imaging with 2-deoxy-2-[(18)F]-fluoro-D-glucose ((18)FDG) was used to determine the variability of a 50-min brain (18)FDG uptake following an intraperitoneal injection over time in awake male and female Sprague-Dawley rodents.

Results: After determining the variability of an intraperitoneal injection in the awake rat, we found that normalization of brain (18)FDG uptake for (1) injected dose and body weight or (2) body weight, plasma glucose concentration and injected dose resulted in a coefficient of variation (CV) of 15%. However, if we normalized regional uptake to whole brain to compare relative regional changes, the CV was less than 5%. Normalized cerebral (18)FDG uptake values were reproducible for a 2-week period in young adult animals. After 1 year, both male and female animals had reduced whole-brain uptake, as well as reduced regional hippocampal and striatal (18)FDG uptake.

Conclusion: Overall, our results were similar to findings in previous rodent and human clinical populations; thus, using a high throughput study with intraperitoneal (18)FDG is a promising preclinical model for clinical populations. This is particularly relevant for measuring changes in brain function after experimental manipulation, such as long-term pharmacological administration.
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http://dx.doi.org/10.1016/j.nucmedbio.2005.09.003DOI Listing
January 2006