Alfred Buck

University Hospital Zürich, Zürich, Zurich, Switzerland

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Publications (164)727.35 Total impact

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    ABSTRACT: Lactate has been shown to offer neuroprotection in several pathologic conditions. This beneficial effect has been attributed to its use as an alternative energy substrate. However, recent description of the expression of the HCA1 receptor for lactate in the central nervous system calls for reassessment of the mechanism by which lactate exerts its neuroprotective effects. Here, we show that HCA1 receptor expression is enhanced 24 hours after reperfusion in an middle cerebral artery occlusion stroke model, in the ischemic cortex. Interestingly, intravenous injection of L-lactate at reperfusion led to further enhancement of HCA1 receptor expression in the cortex and striatum. Using an in vitro oxygen-glucose deprivation model, we show that the HCA1 receptor agonist 3,5-dihydroxybenzoic acid reduces cell death. We also observed that D-lactate, a reputedly non-metabolizable substrate but partial HCA1 receptor agonist, also provided neuroprotection in both in vitro and in vivo ischemia models. Quite unexpectedly, we show D-lactate to be partly extracted and oxidized by the rodent brain. Finally, pyruvate offered neuroprotection in vitro whereas acetate was ineffective. Our data suggest that L- and D-lactate offer neuroprotection in ischemia most likely by acting as both an HCA1 receptor agonist for non-astrocytic (most likely neuronal) cells as well as an energy substrate.Journal of Cerebral Blood Flow & Metabolism advance online publication, 3 June 2015; doi:10.1038/jcbfm.2015.115.
    Journal of cerebral blood flow and metabolism: official journal of the International Society of Cerebral Blood Flow and Metabolism 06/2015; DOI:10.1038/jcbfm.2015.115 · 5.34 Impact Factor
  • European Journal of Paediatric Neurology 05/2015; 19. DOI:10.1016/S1090-3798(15)30028-3 · 1.93 Impact Factor
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    ABSTRACT: Moyamoya disease (MMD) is an idiopathic intracranial angiopathy with a progressive spontaneous occlusion of the circle of Willis resulting in repeated ischemia if not diagnosed and treated early, especially in children. Prevention of stroke is achieved by revascularization of the affected cerebral regions. Functional imaging techniques such as H2[(15)O]-Positron emission tomography (PET) allow quantification of cerebral perfusion/blood flow (CBF) and in particular cerebrovascular response after acetazolamide (AZA) challenge. The cerebrovascular reserve (CVR) can then be calculated and used to identify regions at risk of infarct, hence allowing surgery to be specifically targeted and personalized. Pediatric patients with diagnosed MMD underwent initial H2[(15)O]-PET scans at baseline and after stimulation with AZA. Indication for surgery was then based collectively on the extent of disease observed clinically and on magnetic resonance imaging, on the arterial territories involved, as seen in angiography and the respective regional CVR observed in PET. Cerebral revascularization surgeries were subsequently performed, tailored to the individual patient. Postoperative assessment of clinical outcome was augmented with follow-up PET (median duration after surgery, 10.4 months). CBF at baseline, after AZA and CVR were compared between presurgery and postsurgery scans in the areas supplied by the major cerebral arteries. Parametric images reflecting CBF, response to AZA and CVR clearly showed deficits in cortical but not subcortical regions or cerebellum. AZA-CBF and CVR deficits were most clear in middle cerebral artery and anterior cerebral artery (ACA) regions. In addition to the clinical symptomatology, angiography, AZA-CBF, and CVR images allowed the laterality of deficits to be clearly visualized for tailored surgery and the indication for targeted ACA or posterior cerebral artery revascularization to be assessed. Comparison of baseline CBF, AZA-CBF, and CVR between presurgery and postsurgery scans in revascularized areas revealed a significant improvement in baseline and AZA-CBF after surgery. Although no significant differences in CVR after revascularization surgery were found, a clear improvement of the deficits apparent in AZA-CBF in revascularized regions was found. We demonstrate that quantitative H2[(15)O]-PET is a highly useful tool to direct surgical intervention in MMD. Detailed quantitative analysis of CBF changes and CVR after surgery supports a targeted surgical approach. Copyright © 2015 National Stroke Association. Published by Elsevier Inc. All rights reserved.
    Journal of stroke and cerebrovascular diseases: the official journal of National Stroke Association 03/2015; 24(5). DOI:10.1016/j.jstrokecerebrovasdis.2014.12.017 · 1.99 Impact Factor
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    ABSTRACT: Nicotine addiction is a major public health problem and is associated with primary glutamatergic dysfunction. We recently showed marked global reductions in metabotropic glutamate receptor type 5 (mGluR5) binding in smokers and recent ex-smokers (average abstinence duration of 25 weeks). The goal of this study was to examine the role of mGluR5 downregulation in nicotine addiction by investigating a group of long-term ex-smokers (abstinence >1.5 years), and to explore associations between mGluR5 binding and relapse in recent ex-smokers. Images of mGluR5 receptor binding were acquired in 14 long-term ex-smokers, using positron emission tomography with radiolabeled [11C]ABP688, which binds to an allosteric site with high specificity. Long-term ex-smokers and individuals who had never smoked showed no differences in mGluR5 binding in any of the brain regions examined. Long-term ex-smokers showed significantly higher mGluR5 binding than recent ex-smokers, most prominently in the frontal cortex (42%) and thalamus (57%). Our findings suggest that downregulation of mGluR5 is a pathogenetic mechanism underlying nicotine dependence and the high relapse rate in individuals previously exposed to nicotine. Therefore, mGluR5 receptor binding appears to be an effective biomarker in smoking and a promising target for the discovery of novel medication for nicotine dependence and other substance-related disorders. Copyright © 2015 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.
    Biological psychiatry 02/2015; DOI:10.1016/j.biopsych.2015.02.027 · 9.47 Impact Factor
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    ABSTRACT: Early uptake of [(11)C]-Pittsburgh Compound B (ePiB, 0-6 minutes) estimates cerebral blood flow. We studied ePiB in 13 PiB-negative and 10 PiB-positive subjects with mild cognitive impairment (MCI, n = 23) and 11 PiB-positive and 74 PiB-negative cognitively healthy elderly control subjects (HCS, n = 85) in 6 bilateral volumes of interest: posterior cingulate cortex (PCC), hippocampus (hipp), temporoparietal region, superior parietal gyrus, parahippocampal gyrus (parahipp), and inferior frontal gyrus (IFG) for the associations with cognitive status, age, amyloid deposition, and apolipoprotein E ε4-allele. We observed no difference in ePiB between PiB-positive and -negative subjects and carriers and noncarriers. EPiB decreased with age in PiB-positive subjects in bilateral superior parietal gyrus, bilateral temporoparietal region, right IFG, right PCC, and left parahippocampal gyrus but not in PiB-negative subjects. MCI had lower ePiB than HCS (left PCC, left IFG, and left and right hipp). Lowest ePiB values were found in MCI of 70 years and older, who also displayed high cortical PiB binding. This suggests that lowered regional cerebral blood flow indicated by ePiB is associated with age in the presence but not in the absence of amyloid pathology. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
    Neurobiology of Aging 01/2015; 32(4). DOI:10.1016/j.neurobiolaging.2014.12.036 · 4.85 Impact Factor
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    ABSTRACT: Accumulation of amyloid beta (Aβ) may occur during healthy aging and is a risk factor for Alzheimer Disease (AD). While individual Aβ-accumulation can be measured non-invasively using Pittsburgh Compund-B positron emission tomography (PiB-PET), Fluid-attenuated inversion recovery (FLAIR) is a Magnetic Resonance Imaging (MRI) sequence, capable of indicating heterogeneous age-related brain pathologies associated with tissue-edema. In the current study cognitively normal elderly subjects were investigated for regional correlation of PiB- and FLAIR intensity.
    Frontiers in Aging Neuroscience 09/2014; 6(240). DOI:10.3389/fnagi.2014.00240 · 2.84 Impact Factor
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    ABSTRACT: The biomarker potential of the inhibitory neurotransmitter γ-aminobutyric acid (GABA) for the in vivo characterization of preclinical stages in Alzheimer's disease has not yet been explored. We measured GABA, glutamate + glutamine (Glx), and N-acetyl-aspartate (NAA) levels by single-voxel MEGA-PRESS magnetic resonance spectroscopy in the posterior cingulate cortex of 21 elderly subjects and 15 patients with amnestic mild cognitive impairment. Participants underwent Pittsburgh Compound B positron emission tomography, apolipoprotein E (APOE) genotyping, and neuropsychological examination. GABA, Glx, and NAA levels were significantly lower in patients. NAA was lower in Pittsburgh Compound B-positive subjects and APOE ε4 allele carriers. GABA, Glx, and NAA levels were positively correlated to CERAD word learning scores. Reductions in GABA, Glx, and NAA levels may serve as metabolic biomarkers for cognitive impairment in amnestic mild cognitive impairment. Because GABA and Glx do not seem to reflect amyloid β deposition or APOE genotype, they are less likely biomarker candidates for preclinical Alzheimer's disease.
    Neurobiology of Aging 07/2014; 36(1). DOI:10.1016/j.neurobiolaging.2014.07.030 · 4.85 Impact Factor
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    ABSTRACT: Obsessive-compulsive disorder (OCD) is a disabling, mostly chronic, psychiatric condition with significant social and economic impairments and is a major public health issue. However, numerous patients are resistant to currently available pharmacological and psychological interventions. Given that recent animal studies and magnetic resonance spectroscopy research points to glutamate dysfunction in OCD, we investigated the metabotropic glutamate receptor 5 (mGluR5) in patients with OCD and healthy controls. We determined mGluR5 distribution volume ratio (DVR) in the brain of ten patients with OCD and ten healthy controls by using [11C]ABP688 positron-emission tomography. As a clinical measure of OCD severity, the Yale-Brown Obsessive Compulsive Scale (Y-BOCS) was employed. We found no significant global difference in mGluR5 DVR between patients with OCD and healthy controls. We did, however, observe significant positive correlations between the Y-BOCS obsession sub-score and mGluR5 DVR in the cortico-striatal-thalamo-cortical brain circuit, including regions of the amygdala, anterior cingulate cortex, and medial orbitofrontal cortex (Spearman's ρ's⩾ = 0.68, p < 0.05). These results suggest that obsessions in particular might have an underlying glutamatergic pathology related to mGluR5. The research indicates that the development of metabotropic glutamate agents would be useful as a new treatment for OCD.
    The International Journal of Neuropsychopharmacology 05/2014; 17(12):1-8. DOI:10.1017/S1461145714000716 · 5.26 Impact Factor
  • Joint Congress of European Neurology; 05/2014
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    ABSTRACT: Background: Deposition of cortical amyloid beta (Aβ) is a correlate of aging and a risk factor for Alzheimer disease (AD). While several higher order cognitive processes involve functional interactions between cortex and cerebellum, this study aims to investigate effects of cortical Aβ deposition on coupling within the cerebro-cerebellar system. Methods: We included 15 healthy elderly subjects with normal cognitive performance as assessed by neuropsychological testing. Cortical Aβ was quantified using (11)carbon-labeled Pittsburgh compound B positron-emission-tomography late frame signals. Volumes of brain structures were assessed by applying an automated parcelation algorithm to three dimensional magnetization-prepared rapid gradient-echo T1-weighted images. Basal functional network activity within the cerebro-cerebellar system was assessed using blood-oxygen-level dependent resting state functional magnetic resonance imaging at the high field strength of 7 T for measuring coupling between cerebellar seeds and cerebral gray matter. A bivariate regression approach was applied for identification of brain regions with significant effects of individual cortical Aβ load on coupling. Results: Consistent with earlier reports, a significant degree of positive and negative coupling could be observed between cerebellar seeds and cerebral voxels. Significant positive effects of cortical Aβ load on cerebro-cerebellar coupling resulted for cerebral brain regions located in inferior temporal lobe, prefrontal cortex, hippocampus, parahippocampal gyrus, and thalamus. Conclusion: Our findings indicate that brain amyloidosis in cognitively normal elderly subjects is associated with decreased network efficiency within the cerebro-cerebellar system. While the identified cerebral regions are consistent with established patterns of increased sensitivity for Aβ-associated neurodegeneration, additional studies are needed to elucidate the relationship between dysfunction of the cerebro-cerebellar system and risk for AD.
    Frontiers in Aging Neuroscience 03/2014; 5:52. DOI:10.3389/fnagi.2014.00052 · 2.84 Impact Factor
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    ABSTRACT: Quantitative measures of 11C-raclopride receptor binding can be used as a correlate of postsynaptic D2 receptor density in the striatum, allowing 11C-raclopride positron emission tomography (PET) to be used for the differentiation of Parkinson's disease from atypical parkinsonian syndromes. Comparison with reference values is recommended to establish a reliable diagnosis. A PET template specific to raclopride may facilitate direct computation of parametric maps without the need for an additional MR scan, aiding automated image analysis. Sixteen healthy volunteers underwent a dynamic 11C-raclopride PET and a high-resolution T1-weighted MR scan of the brain. PET data from eight healthy subjects was processed to generate a raclopride-specific PET template normalized to standard space. Subsequently, the data processing based on the PET template was validated against the standard magnetic resonance imaging (MRI)-based method in 8 healthy subjects and 20 patients with suspected parkinsonian syndrome. Semi-quantitative image analysis was performed in Montreal Neurological Institute (MNI) and in original image space (OIS) using VOIs derived from a probabilistic brain atlas previously validated by Hammers et al. (Hum Brain Mapp, 15:165-174, 2002). The striatal-to-cerebellar ratio (SCR) of 11C-raclopride uptake obtained using the PET template was in good agreement with the MRI-based image processing method, yielding a Lin's concordance coefficient of 0.87. Bland-Altman analysis showed that all measurements were within the +/-1.96 standard deviation range. In all 20 patients, the PET template-based processing was successful and manual volume of interest optimization had no further impact on the diagnosis of PD in this patient group. A maximal difference of <5 % was found between the measured SCR in MNI space and OIS. The PET template-based method for automated quantification of postsynaptic D2 receptor density is simple to implement and facilitates rapid, robust and reliable image analysis. There was no significant difference between the SCR values obtained with either PET- or MRI-based image processing. The method presented alleviates the clinical workflow and facilitates automated image analysis.
    01/2014; 4(1):7. DOI:10.1186/2191-219X-4-7
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    ABSTRACT: BACKGROUND AND PURPOSE:Cerebral perfusion assessment is important in the preoperative evaluation and postoperative follow-up of patients with Moyamoya disease. The objective of this study was to evaluate the correlation of quantitative CBF measurements performed with arterial spin-labeling-MR imaging and H2[(15)O]-PET in children and young adults with Moyamoya disease.MATERIALS AND METHODS:Thirteen children and young adults (8 female patients; age, 9.7 ± 7.1 years; range, 1-23 years) with Moyamoya disease underwent cerebral perfusion imaging with H2[(15)O]-PET (Discovery STE PET/CT, 3D Fourier rebinning filtered back-projection, 128 × 128 × 47 matrix, 2.34 × 2.34 × 3.27 mm(3) voxel spacing) and arterial spin-labeling (3T scanner, 3D pulsed continuous arterial spin-labeling sequence, 32 axial sections, TR = 5.5 seconds, TE = 25 ms, FOV = 24 cm, 128 × 128 matrix, 1.875 × 1.875 × 5 mm(3) voxel spacing) within less than 2 weeks of each other. Perfusion of left and right anterior cerebral artery, MCA, and posterior cerebral artery territories was qualitatively assessed for arterial spin-labeling-MR imaging and H2[(15)O]-PET by 2 independent readers by use of a 3-point-Likert scale. Quantitative correlation of relative CBF with cerebellar normalization between arterial spin-labeling-MR imaging and H2[(15)O]-PET was evaluated in a volume-based approach for each vascular territory after 3D image coregistration.RESULTS:Interreader agreement was good (κ = 0.67-0.69), and strong and significant correlations were found between arterial spin-labeling-MR imaging and H2[(15)O]-PET for both qualitative perfusion scoring (ρ = 0.77; P < .001) and quantitative perfusion assessment of relative CBF with cerebellar normalization (r = 0.67, P < .001).CONCLUSIONS:In children and young adults with Moyamoya disease, quantitative evaluation of CBF is possible with the use of arterial spin-labeling-MR imaging without ionizing radiation or contrast injection with a good correlation to H2[(15)O]-PET after cerebellar normalization.
    American Journal of Neuroradiology 12/2013; 35(5). DOI:10.3174/ajnr.A3799 · 3.68 Impact Factor
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    European Neuropsychopharmacology 10/2013; 23(2):354. DOI:10.1016/S0924-977X(13)70558-3 · 5.40 Impact Factor
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    ABSTRACT: Background and Purpose—Arterial hypertension is an important risk factor for cerebrovascular diseases, such as transient ischemic attacks or stroke, and represents a major global health issue. The effects of hypertension on cerebral blood flow, particularly at the microvascular level, remain unknown. Methods—Using the spontaneously hypertensive rat (SHR) model, we examined cortical hemodynamic responses on whisker stimulation applying a multimodal imaging approach (multiwavelength spectroscopy, laser speckle imaging, and 2-photon microscopy). We assessed the effects of hypertension in 10-, 20-, and 40-week-old male SHRs and age-matched male Wistar Kyoto rats (CTRL) on hemodynamic responses, histology, and biochemical parameters. In 40-week-old animals, losartan or verapamil was administered for 10 weeks to test the reversibility of hypertension-induced impairments. Results—Increased arterial blood pressure was associated with a progressive impairment in functional hyperemia in 20- and 40-week-old SHRs; baseline capillary red blood cell velocity was increased in 40-week-old SHRs compared with age-matched CTRLs. Antihypertensive treatment reduced baseline capillary cerebral blood flow almost to CTRL values, whereas functional hyperemic signals did not improve after 10 weeks of drug therapy. Structural analyses of the microvascular network revealed no differences between normo- and hypertensive animals, whereas expression analyses of cerebral lysates showed signs of increased oxidative stress and signs of impaired endothelial homeostasis upon early hypertension. Conclusions—Impaired neurovascular coupling in the SHR evolves upon sustained hypertension. Antihypertensive monotherapy using verapamil or losartan is not sufficient to abolish this functional impairment. These deficits in neurovascular coupling in response to sustained hypertension might contribute to accelerate progression of neurodegenerative diseases in chronic hypertension.
    Stroke 06/2013; · 6.02 Impact Factor
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    ABSTRACT: BACKGROUND AND PURPOSE: Arterial hypertension is an important risk factor for cerebrovascular diseases, such as transient ischemic attacks or stroke, and represents a major global health issue. The effects of hypertension on cerebral blood flow, particularly at the microvascular level, remain unknown. METHODS: Using the spontaneously hypertensive rat (SHR) model, we examined cortical hemodynamic responses on whisker stimulation applying a multimodal imaging approach (multiwavelength spectroscopy, laser speckle imaging, and 2-photon microscopy). We assessed the effects of hypertension in 10-, 20-, and 40-week-old male SHRs and age-matched male Wistar Kyoto rats (CTRL) on hemodynamic responses, histology, and biochemical parameters. In 40-week-old animals, losartan or verapamil was administered for 10 weeks to test the reversibility of hypertension-induced impairments. RESULTS: Increased arterial blood pressure was associated with a progressive impairment in functional hyperemia in 20- and 40-week-old SHRs; baseline capillary red blood cell velocity was increased in 40-week-old SHRs compared with age-matched CTRLs. Antihypertensive treatment reduced baseline capillary cerebral blood flow almost to CTRL values, whereas functional hyperemic signals did not improve after 10 weeks of drug therapy. Structural analyses of the microvascular network revealed no differences between normo- and hypertensive animals, whereas expression analyses of cerebral lysates showed signs of increased oxidative stress and signs of impaired endothelial homeostasis upon early hypertension. CONCLUSIONS: Impaired neurovascular coupling in the SHR evolves upon sustained hypertension. Antihypertensive monotherapy using verapamil or losartan is not sufficient to abolish this functional impairment. These deficits in neurovascular coupling in response to sustained hypertension might contribute to accelerate progression of neurodegenerative diseases in chronic hypertension.
    Stroke 06/2013; 44(7). DOI:10.1161/STROKEAHA.111.000185 · 6.02 Impact Factor
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    ABSTRACT: Long-lasting neuroadaptations in the glutamatergic corticostriatal circuitry have been suggested to be responsible for the persisting nature of drug addiction. In particular, animal models have linked the metabotropic glutamate receptor 5 (mGluR5) to drug-seeking behavior and extinction learning. Accordingly, blocking mGluR5s attenuated self-administration of cocaine and other addictive drugs in rats. How these animal findings extend to humans remains unclear. Therefore, we investigated if human cocaine users (CU) exhibit altered mGluR5 availability compared with drug-naïve control subjects. Seventeen male controls (11 smokers) and 18 male cocaine users (13 smokers) underwent positron emission tomography with (11)C-ABP688 to quantify mGluR5 availability in 12 volumes of interest in addiction-related brain areas. Drug use was assessed by self-report and quantitative hair toxicology. CU and controls did not significantly differ in regional mGluR5 availability. In contrast, smokers (n=24) showed significantly lower mGluR5 density throughout the brain (mean 20%) compared with non-smokers (n=11). In terms of effect sizes, lower mGluR5 availability was most pronounced in the caudate nucleus (d=1.50, 21%), insula (d=1.47, 20%), and putamen (d=1.46, 18%). Duration of smoking abstinence was positively associated with mGluR5 density in all brain regions of interest, indicating that lower mGluR5 availability was particularly pronounced in individuals who had smoked very recently. Specifically tobacco smoking was associated with lower mGluR5 availability in both CU and controls, while cocaine use was not linked to detectable mGluR5 alterations. These findings have important implications regarding the development of novel pharmacotherapies aimed at facilitating smoking cessation.Molecular Psychiatry advance online publication, 30 April 2013; doi:10.1038/mp.2013.51.
    Molecular Psychiatry 04/2013; DOI:10.1038/mp.2013.51 · 15.15 Impact Factor
  • Neuropediatrics 03/2013; 44(02). DOI:10.1055/s-0033-1337729 · 1.10 Impact Factor
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    ABSTRACT: Nicotine addiction is a major public health problem, resulting in primary glutamatergic dysfunction. We measured the glutamate receptor binding in the human brain and provided direct evidence for the abnormal glutamate system in smokers. Because antagonism of the metabotropic glutamate receptor 5 (mGluR5) reduced nicotine self-administration in rats and mice, mGluR5 is suggested to be involved in nicotine addiction. mGluR5 receptor binding specifically to an allosteric site was observed by using positron emission tomography with [(11)C]ABP688. We found a marked global reduction (20.6%; P < 0.0001) in the mGluR5 distribution volume ratio (DVR) in the gray matter of 14 smokers. The most prominent reductions were found in the bilateral medial orbitofrontal cortex. Compared with 14 nonsmokers, 14 ex-smokers had global reductions in the average gray matter mGluR5 DVR (11.5%; P < 0.005), and there was a significant difference in average gray matter mGluR5 DVR between smokers and ex-smokers (9.2%; P < 0.01). Clinical variables reflecting current nicotine consumption, dependence and abstinence were not correlated with mGluR5 DVR. This decrease in mGluR5 receptor binding may be an adaptation to chronic increases in glutamate induced by chronic nicotine administration, and the decreased down-regulation seen in the ex-smokers could be due to incomplete recovery of the receptors, especially because the ex-smokers were abstinent for only 25 wk on average. These results encourage the development and testing of drugs against addiction that directly target the glutamatergic system.
    Proceedings of the National Academy of Sciences 12/2012; 110(2). DOI:10.1073/pnas.1210984110 · 9.81 Impact Factor

Publication Stats

6k Citations
727.35 Total Impact Points

Institutions

  • 1995–2015
    • University Hospital Zürich
      Zürich, Zurich, Switzerland
  • 1993–2015
    • University of Zurich
      • • Center for Integrative Human Physiology
      • • Institute of Veterinary Pharmacology and Toxicology
      • • Psychiatry Research
      • • Division of Neuropsychology
      Zürich, Zurich, Switzerland
  • 2011
    • University of Mississippi
      Mississippi, United States
    • Department of Nuclear Medicine
      Nyitra, Nitriansky, Slovakia
  • 2005
    • University of Toronto
      Toronto, Ontario, Canada
  • 1999
    • Universität Bern
      • Department of Geriatric Psychiatry
      Bern, BE, Switzerland
  • 1994
    • University of Michigan
      • Department of Internal Medicine
      Ann Arbor, MI, United States
  • 1991
    • Concordia University–Ann Arbor
      Ann Arbor, Michigan, United States