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Caroline Vandeputte, Cindy Casteels,
Tom Struys,
Michel Koole,
Daisy van Veghel,
Nele Evens,
Anneleen Gerits,
Tom Dresselaers,
Ivo Lambrichts,
Uwe Himmelreich,
Guy Bormans,
Koen Van Laere
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ABSTRACT: Recent ex vivo and pharmacological evidence suggests involvement of the endocannabinoid system in the pathophysiology of stroke, but conflicting roles for type 1 and 2 cannabinoid receptors (CB(1) and CB(2)) have been suggested. The purpose of this study was to evaluate CB(1) and CB(2) receptor binding over time in vivo in a rat photothrombotic stroke model using PET.
CB(1) and CB(2) microPET imaging was performed at regular time-points up to 2 weeks after stroke using [(18)F]MK-9470 and [(11)C]NE40. Stroke size was measured using MRI at 9.4 T. Ex vivo validation was performed via immunostaining for CB(1) and CB(2). Immunofluorescent double stainings were also performed with markers for astrocytes (GFAP) and macrophages/microglia (CD68).
[(18)F]MK-9470 PET showed a strong increase in CB(1) binding 24 h and 72 h after stroke in the cortex surrounding the lesion, extending to the insular cortex 24 h after surgery. These alterations were consistently confirmed by CB(1) immunohistochemical staining. [(11)C]NE40 did not show any significant differences between stroke and sham-operated animals, although staining for CB(2) revealed minor immunoreactivity at 1 and 2 weeks after stroke in this model. Both CB (1) (+) and CB (2) (+) cells showed minor immunoreactivity for CD68.
Time-dependent and regionally strongly increased CB(1), but not CB(2), binding are early consequences of photothrombotic stroke. Pharmacological interventions should primarily aim at CB(1) signalling as the role of CB(2) seems minor in the acute and subacute phases of stroke.
European Journal of Nuclear Medicine 08/2012; 39(11):1796-806. · 4.53 Impact Factor
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ABSTRACT: [(18)F]MK-9470 is an inverse agonist for the type 1 cannabinoid (CB1) receptor allowing its use in PET imaging. We characterized the kinetics of [(18)F]MK-9470 and evaluated its ability to quantify CB1 receptor availability in the rat brain.
Dynamic small-animal PET scans with [(18)F]MK-9470 were performed in Wistar rats on a FOCUS-220 system for up to 10 h. Both plasma and perfused brain homogenates were analysed using HPLC to quantify radiometabolites. Displacement and blocking experiments were done using cold MK-9470 and another inverse agonist, SR141716A. The distribution volume (V(T)) of [(18)F]MK-9470 was used as a quantitative measure and compared to the use of brain uptake, expressed as SUV, a simplified method of quantification.
The percentage of intact [(18)F]MK-9470 in arterial plasma samples was 80 ± 23 % at 10 min, 38 ± 30 % at 40 min and 13 ± 14 % at 210 min. A polar radiometabolite fraction was detected in plasma and brain tissue. The brain radiometabolite concentration was uniform across the whole brain. Displacement and pretreatment studies showed that 56 % of the tracer binding was specific and reversible. V (T) values obtained with a one-tissue compartment model plus constrained radiometabolite input had good identifiability (≤10 %). Ignoring the radiometabolite contribution using a one-tissue compartment model alone, i.e. without constrained radiometabolite input, overestimated the [(18)F]MK-9470 V(T), but was correlated. A correlation between [(18)F]MK-9470 V(T) and SUV in the brain was also found (R(2) = 0.26-0.33; p ≤ 0.03).
While the presence of a brain-penetrating radiometabolite fraction complicates the quantification of [(18)F]MK-9470 in the rat brain, its tracer kinetics can be modelled using a one-tissue compartment model with and without constrained radiometabolite input.
European Journal of Nuclear Medicine 06/2012; 39(9):1467-77. · 4.53 Impact Factor
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ABSTRACT: Using (18)F-fluorodeoxyglucose microPET imaging, we investigated the neurocircuitry of contextual anxiety versus control in awake, conditioned rats (n = 7-10 per group). In addition, we imaged a group expressing cued fear. Simultaneous measurements of startle amplitude and freezing time were used to assess conditioning. To the best of our knowledge, no neuroimaging studies in conditioned rats have been conducted thus far, although visualizing and quantifying the metabolism of the intact brain in behaving animals is clearly of interest. In addition, more insight into the neurocircuitry involved in contextual anxiety may stimulate the development of new treatments for anxiety disorders. Our main finding was hypermetabolism in a cluster comprising the bed nucleus of the stria terminalis (BST) in rats expressing contextual anxiety compared with controls. Analysis of a subset of rats showing the best behavioral results (n = 5 per subgroup) confirmed this finding. We also observed hypermetabolism in the same cluster in rats expressing contextual anxiety compared with rats expressing cued fear. Our results provide novel evidence for a role of the BST in the expression of contextual anxiety.
Journal of Neuroscience 01/2012; 32(1):254-63. · 7.11 Impact Factor
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ABSTRACT: The type 1 cannabinoid receptor (CB1) is a crucial modulator of synaptic transmission in brain and has been proposed as a potential therapeutic target in Parkinson's disease (PD), especially for treatment of levodopa-induced dyskinesias (LID). Our aim was to measure CB1 levels in brains of PD patients in vivo and to investigate the relation between CB1 availability and LID. We studied 12 healthy controls and 29 PD patients (9 drug-naïve patients with early PD, 10 patients with advanced PD and LID, and 10 patients with advanced PD without LID). PD patients were examined using the Unified Parkinson's Disease Rating Scale (UPDRS) and the modified Abnormal Involuntary Movement Scale (mAIMS). All subjects underwent positron emission tomography (PET) with the CB1-selective radioligand [(18)F] MK-9470 and magnetic resonance imaging (MRI). PD patients showed an absolute decrease in CB1 availability in the substantia nigra. By contrast, CB1 availability was relatively increased in nigrostriatal, mesolimbic, and mesocortical dopaminergic projection areas. CB1 availability did not differ significantly between advanced PD patients with and without LID. Within the group of PD patients with LID, there was no significant correlation between CB1 availability and LID severity. These data demonstrate regional changes in CB1 availability in PD in vivo, but do not support a role for dysregulation of CB1 levels in the pathogenesis of LID.
Neurobiology of aging 04/2011; 33(3):620.e1-8. · 5.94 Impact Factor
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ABSTRACT: Several lines of evidence imply early alterations in metabolic, dopaminergic and endocannabinoid neurotransmission in Huntington's disease (HD). Using [18F]MK-9470 and small animal PET, we investigated cerebral changes in type 1 cannabinoid (CB1) receptor binding in the quinolinic acid (QA) rat model of HD in relation to glucose metabolism, dopamine D2 receptor availability and amphetamine-induced turning behaviour.
Twenty-one Wistar rats (11 QA and 10 shams) were investigated. Small animal PET acquisitions were conducted on a Focus 220 with approximately 18 MBq of [18F]MK-9470, [18F]FDG and [11C]raclopride. Relative glucose metabolism and parametric CB1 receptor and D2 binding images were anatomically standardized to Paxinos space and analysed voxel-wise using Statistical Parametric Mapping (SPM2).
In the QA model, [18F]MK-9470 uptake, glucose metabolism and D2 receptor binding were reduced in the ipsilateral caudate-putamen by 7, 35 and 77%, respectively (all p<2.10(-5)), while an increase for these markers was observed on the contralateral side (>5%, all p<7.10(-4)). [18F]MK-9470 binding was also increased in the cerebellum (p=2.10(-5)), where it was inversely correlated to the number of ipsiversive turnings (p=7.10(-6)), suggesting that CB1 receptor upregulation in the cerebellum is related to a better functional outcome. Additionally, glucose metabolism was relatively increased in the contralateral hippocampus, thalamus and sensorimotor cortex (p=1.10(-6)).
These data point to in vivo changes in endocannabinoid transmission, specifically for CB1 receptors in the QA model, with involvement of the caudate-putamen, but also distant regions of the motor circuitry, including the cerebellum. These data also indicate the occurrence of functional plasticity on metabolism, D2 and CB1 neurotransmission in the contralateral hemisphere.
European Journal of Nuclear Medicine 12/2010; 37(12):2354-63. · 4.53 Impact Factor
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ABSTRACT: The type 1 cannabinoid receptor (CB1) is a crucial modulator of synaptic transmission in the brain. Animal and postmortem human data suggest that mutant huntingtin represses CB1 transcription. Our aim was to measure CB1 levels in the brains of Huntington disease (HD) patients in vivo.
Twenty symptomatic HD patients and 14 healthy controls underwent PET with the novel CB1 ligand N-[2-(3-cyano-phenyl)-3-(4-(2-(18)F-fluorethoxy)phenyl)-1-methylpropyl]-2-(5-methyl-2-pyridyloxy)-2-methylproponamide.
We observed a profound decrease of CB1 availability throughout the gray matter of the cerebrum, cerebellum, and brain stem in HD patients, even in early disease stages. Disease burden ([number of CAG repeats in the HTT gene - 35.5] x age) was inversely correlated with CB1 availability in the prefrontal and premotor cortex.
The profound early and widespread reduction of CB1 availability in vivo is consistent with the hypothesis that mutant huntingtin represses CB1 transcription. This is the first, to our knowledge, in vivo demonstration of disturbance of the endocannabinoid system in a human neurologic disease.
Journal of Nuclear Medicine 09/2010; 51(9):1413-7. · 6.38 Impact Factor
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ABSTRACT: The endocannabinoid system is an important modulatory system in the brain. Complex interactions with brain dopaminergic circuits have been demonstrated. The aim of this study was to investigate the in vivo effect of the commonly used antiparkinsonian drugs, levodopa (L-DOPA) and bromocriptine, on type 1 cannabinoid (CB1) receptors, using the PET radioligand [(18)F]MK-9470.
Seventeen female Wistar rats were studied at baseline and after chronic exposure to either L-DOPA (6 mg/kg/day with 1.5 mg/kg/day carbidopa; n = 6), bromocriptine (4 mg/kg/day; n = 5), or saline (n = 6). [(18)F]MK-9470 binding was assessed in vivo using small animal PET imaging. [(18)F]MK-9470 parametric images were generated, anatomically standardized to Paxinos space and analyzed by voxel-based statistical parametric mapping (SPM2) and a predefined volume-of-interest (VOI) approach.
In a 2 x 2 analysis design (condition vs. treatment), no significant changes in absolute or relative [(18)F]MK-9470 binding were present upon chronic exposure to L-DOPA or bromocriptine as compared to saline treatment. The post hoc comparison of chronic scans to baseline within each treatment modality showed regional increases in relative [(18)F]MK-9470 binding in the thalamus (peak average value +6.3%) and in the sensorimotor cortex and hippocampus (peak average value +10.2%) after bromocriptine exposure, while no changes were found for L-DOPA.
Chronic administration of L-DOPA and bromocriptine at the applied doses does not produce major cerebral changes in in vivo cannabinoid CB1 receptor binding of [(18)F]MK-9470 in the rat brain. These results also suggest that similar chronic L-DOPA and bromocriptine usage is unlikely to interfere with human PET imaging in healthy conditions using this radioligand.
Synapse 03/2010; 64(8):617-23. · 2.94 Impact Factor
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Nadja Van Camp,
Ruth Vreys,
Koen Van Laere,
Erwin Lauwers,
Dirk Beque,
Marleen Verhoye, Cindy Casteels,
Alfons Verbruggen,
Zeger Debyser,
Luc Mortelmans,
Jan Sijbers,
Johan Nuyts,
Veerle Baekelandt,
Annemie Van der Linden
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ABSTRACT: In the present study, we aimed to evaluate the impact of neurodegeneration of the nigrostriatal tract in a rodent model of Parkinson's disease on the different MR contrasts (T(2), T(1), CBF and CBV) measured in the striatum.
Animals were injected with 6-hydroxydopamine (6OHDA) in the substantia nigra resulting in massive loss of nigrostriatal neurons and hence dopamine depletion in the ipsilateral striatum. Using 7T MRI imaging, we have quantified T(2), T(1), CBF and CBV in the striata of 6OHDA and control rats. To validate the lesion size, behavioral testing, dopamine transporter muSPECT and tyrosine hydroxylase staining were performed.
No significant differences were demonstrated in the absolute MRI values between 6OHDA animals and controls; however, 6OHDA animals showed significant striatal asymmetry for all MRI parameters in contrast to controls.
These PD-related asymmetry ratios might be the result of counteracting changes in both intact and affected striatum and allowed us to diagnose PD lesions. As lateralization is known to occur also in PD patients and might be expected in transgenic PD models as well, we propose that MR-derived asymmetry ratios in the striatum might be a useful tool for in vivo phenotyping of animal models of PD.
MAGMA Magnetic Resonance Materials in Physics Biology and Medicine 02/2010; 23(2):65-75. · 1.88 Impact Factor
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ABSTRACT: Small animal PET can be applied to study molecular processes in animal models of a variety of human diseases. In order to keep the animals in a restricted position during imaging, anaesthesia is in many instances inevitable. Using small animal PET and ex vivo autoradiography, we examined the influence of pentobarbital and isoflurane anaesthesia on the rat brain uptake of [(18)F]MK-9470, a radioligand for the type 1 cannabinoid receptor.
PET imaging was performed on adult Wistar rats under pentobarbital (n = 6) and isoflurane anaesthesia (n = 7), and under control conditions (free moving during tracer uptake, n = 8). Parametric PET images were generated, anatomically standardized and analysed by voxel-based Statistical Parametric Mapping and a predefined volume of interest approach. Immediately after in vivo PET, brains were processed for ex vivo autoradiography using manually placed regions of interest. An extra group (n = 6) was included ex vivo, in which animals were intravenously injected without the use of anaesthetics.
Using in vivo and ex vivo molecular imaging techniques, no significant changes in absolute [(18)F]MK-9470 uptake were present in the brain of pentobarbital and isoflurane rats as compared to control conditions. Relative [(18)F]MK-9470 uptake PET values obtained applying global scaling were, however, decreased in the cortex under both anaesthetics (pentobarbital: -13.3+/-1.4%; isoflurane -8.7 +/- 3.1%), while an increase was seen in the cerebellum by 13.5 +/- 4.0% and 13.9 +/- 4.1% under pentobarbital and isoflurane, respectively. Ex vivo results were in agreement with in vivo findings.
These findings suggest a similar, regionally specific interference of pentobarbital and isoflurane anaesthesia with in vivo CB1 receptor imaging using [(18)F]MK-9470.
European Journal of Nuclear Medicine 02/2010; 37(6):1164-73. · 4.53 Impact Factor
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ABSTRACT: Several lines of evidence suggest a functional interaction between central nicotinic and endocannabinoid systems. Furthermore, type 1 cannabinoid receptor (CB1R) antagonism is evaluated as antismoking therapy, and nicotine usage can be an important confound in positron emission tomography (PET) imaging studies of the CB1R. We evaluated CB1R binding in the rat brain using the PET radioligand [(18)F]MK-9470 after chronic administration of nicotine. Twelve female Wistar rats were scanned at baseline and after chronic administration of either nicotine (1 mg/kg; 2 weeks daily intraperitoneal (IP)) or saline as control. In vivo micro-PET images of CB1R binding were anatomically standardized and analyzed by voxel-based statistical parametric mapping and a predefined volume-of-interest approach. We did not observe changes in [(18)F]MK-9470 binding (p (height) < 0.001 level; uncorrected) on a group basis in either condition. Only at a less stringent threshold of p (height) < 0.005 (uncorrected) was a modest increase observed in tracer binding in the cerebellum for nicotine (peak voxel value + 6.8%, p (cluster) = 0.002 corrected). In conclusion, chronic IP administration of nicotine does not produce major cerebral changes in CB1R binding of [(18)F]MK-9470 in the rat. These results also suggest that chronic nicotine usage is unlikely to interfere with human PET imaging using this radioligand.
Journal of Molecular Neuroscience 02/2010; 42(2):162-7. · 2.50 Impact Factor
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ABSTRACT: Accurate and reproducible behavioral tests in animal models are of major importance in the development and evaluation of new therapies for central nervous system disease. In this study we investigated for the first time gait parameters of rat models for Parkinson's disease (PD), Huntington's disease (HD) and stroke using the Catwalk method, a novel automated gait analysis test. Static and dynamic gait parameters were measured in all animal models, and these data were compared to readouts of established behavioral tests, such as the cylinder test in the PD and stroke rats and the rotarod tests for the HD group.
Hemiparkinsonian rats were generated by unilateral injection of the neurotoxin 6-hydroxydopamine in the striatum or in the medial forebrain bundle. For Huntington's disease, a transgenic rat model expressing a truncated huntingtin fragment with multiple CAG repeats was used. Thirdly, a stroke model was generated by a photothrombotic induced infarct in the right sensorimotor cortex. We found that multiple gait parameters were significantly altered in all three disease models compared to their respective controls. Behavioural deficits could be efficiently measured using the cylinder test in the PD and stroke animals, and in the case of the PD model, the deficits in gait essentially confirmed results obtained by the cylinder test. However, in the HD model and the stroke model the Catwalk analysis proved more sensitive than the rotarod test and also added new and more detailed information on specific gait parameters.
The automated quantitative gait analysis test may be a useful tool to study both motor impairment and recovery associated with various neurological motor disorders.
BMC Neuroscience 01/2010; 11:92. · 3.04 Impact Factor
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ABSTRACT: Type 1 cannabinoid (CB1) receptors are expressed in high concentrations in the central nervous system, including the basal ganglia, and could have direct or indirect effects on motor behavior through modulation of dopaminergic, glutamatergic and GABA-ergic neurotransmission. Using the CB1 receptor radioligand [(18)F]MK-9470 and small-animal PET, we investigated for the first time in vivo cerebral changes in [(18)F]MK-9470 binding in the 6-hydroxydopamine (6-OHDA) rat model of Parkinson's disease (PD), parallel to dopamine transporter (DAT) imaging, tyrosine hydroxylase (TH) staining, and behavioral measurements. In the 6-OHDA model, relative [(18)F]MK-9470 PET binding decreased in the contralateral cerebellum (-9%, p<0.0004) and caudate-putamen bilaterally (ipsilateral -8%, contralateral -7%; p=0.001 and p<0.0003, respectively). The number of TH(+) neurons in the substantia nigra was inversely correlated to CB1 receptor binding in the ipsilateral cerebellum (p=1.10(-6)). The behavioral outcome was positively related to regional CB1 receptor binding in the contralateral somatosensory cortex (p=4.10(-6)). In vivo [(18)F]MK-9470 PET imaging points to changes in endocannabinoid transmission, specifically for CB1 receptors in the 6-OHDA model of PD, with mainly involvement of the caudate-putamen, but also distant regions of the motor circuitry, including the cerebellum and somatosensory cortex.
Brain research 12/2009; 1316:153-62. · 2.46 Impact Factor
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ABSTRACT: Functional neuroimaging is widely used to unravel changes in brain functioning in psychiatric disorders. In the current study, we review single-photon emission tomography (SPECT), positron emission tomography (PET) and functional magnetic resonance imaging (fMRI) studies in anorexia nervosa (AN), a difficult-to-treat eating disorder with the highest mortality rate among psychiatric disorders. We discuss the role of the parietal cortex, anterior and subgenual cingulate cortex, frontal cortex and temporal lobe in light of the cardinal symptoms of AN. The insights of the current review may ultimately lead to the development of new treatments.
Journal of psychiatric research 06/2009; 43(14):1133-45. · 3.72 Impact Factor
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ABSTRACT: Parkinson's disease (PD) is characterised by degeneration of the nigrostrial connection causing dramatic changes in the dopaminergic pathway underlying clinical pathology. Till now, no MRI tools were available to follow up any specific PD-related neurodegeneration. However, recently, diffusion tensor imaging (DTI) has received considerable attention as a new and potential in vivo diagnostic tool for various neurodegenerative diseases. To assess this in PD, we performed DTI in the acute 6-hydroxydopamine (6-OHDA) rat model of PD to evaluate diffusion properties in the degenerating nigrostriatal pathway and its connecting structures. Injection of a neurotoxin in the striatum causes retrograde neurodegeneration of the nigrostriatal tract, and selective degeneration of nigral neurons. The advantage of this model is that the lesion size is well controllable by the injected dose of the toxin. The degree of functional impairment was evaluated in vivo using the amphetamine rotation test and microPET imaging of the dopamine transporter (DAT). Despite a nearly complete lesion of the nigrostriatal tract, DTI changes were limited to the ipsilateral substantia nigra (SN). In this study we demonstrate, using voxel-based statistics (VBS), an increase in fractional anisotropy (FA), whereas all eigenvalues were significantly decreased. VBS enabled us to visualise neurodegeneration of a cluster of neurons but failed to detect degeneration of more diffuse microstructures such as the nigrostriatal fibres or the dopaminergic endings in the striatum. VBS without a priori information proved to be better than manual segmentation of brain structures as it does not suffer from volume averaging and is not susceptible to erroneous segmentations of brain regions that show very little contrast on MRI images such as SN.
NMR in Biomedicine 04/2009; 22(7):697-706. · 3.21 Impact Factor
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ABSTRACT: Brain neurochemistry can partially account for personality traits as a variance of normal human behavior, as has been demonstrated for monoamine neurotransmission. Positron emission tomography using fluorine 18-labeled MK-9470 now enables quantification of type 1 cannabinoid receptors (CB1R) in the brain.
To investigate whether there is a relationship between human temperament traits and regional cerebral CB1R availability.
Forty-seven [(18)F]MK-9470 baseline scanning sessions were performed and correlated with the temperament dimensions and subdimensions of the 240-item Cloninger Temperament and Character Inventory.
Academic brain imaging center.
Forty-seven nonsmoking, healthy volunteers (paid). Main Outcome Measure Voxel-based correlation of temperament variables of the inventory with regional CB1R availability.
Novelty seeking was inversely correlated with global CB1R availability (r = -0.33, P = .02), with the most significant correlation in the left amygdala (r = -0.41, P = .005). In particular, the subdimension extravagance showed a highly significant inverse correlation to global CB1R availability (r = -0.53, P <.001), most pronounced in the amygdala, anterior cingulate, parietal cortex, and precuneus. Also, disorderliness was inversely correlated with global CB1R availability (r = -0.31, P = .04).
Low baseline cerebral CB1R availability is related to a high novelty-seeking personality, in particular to extravagance, most pronounced in the amygdala. Further investigation of the functional role of the CB1R is warranted in pathological behavior known to be strongly related to novelty seeking, such as addiction and eating disorders.
Archives of general psychiatry 02/2009; 66(2):196-204. · 12.26 Impact Factor
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ABSTRACT: There is substantial evidence that the endocannabinoid system and in particular the type 1 cannabinoid receptor (CB1R) is involved in epilepsy. We evaluated the in vivo effect of chronic administration of the anti-epileptic drugs valproate (VPA) and levetiracetam (LEV) on rat brain CB1 receptors using the positron emission tomography (PET) tracer [(18)F]MK-9470. Six Wistar rats were treated with VPA (200mg/kg) or LEV (50mg/kg) IP daily for 2 weeks. Dynamic imaging after intravenous injection of 18 MBq [(18)F]MK-9470 was performed on a FOCUS 220 microPET at baseline and after chronic treatment. Six animals were used as controls and were injected with saline, using the same protocol. Parametric images based on standardized uptake values (SUV) were generated and were spatially normalized to Paxinos space. These CB1R images were analyzed using a predefined volume of interest (VOI)-based analysis. Differences in SUV values between chronic and baseline scans in each condition (saline, VPA and LEV treatment) were calculated in each VOI. Direct binding affinity of the drugs at CB1R was assessed by competitive binding assay in Chinese hamster ovarian cells expressing human CB1R. Chronic injections of saline did not produce significant changes in global [(18)F]MK-9470 binding (p=0.43), nor in tracer binding in individual VOIs. We found a significant increase in global cerebral [(18)F]MK-9470 binding after chronic VPA administration compared to sham treated animals (+32.5%, p<0.001), as well as in tracer binding in all individual VOIs. After chronic administration of LEV, there was no significant change in global cerebral CB1R binding (+6.9%, p=0.81), nor in tracer binding in individual VOIs. As VPA does not exhibit high affinity for CB1R (displacement of [(3)H]-SR141716A 1.3+/-14.0%), such upregulation is most likely caused by an indirect effect on the endocannabinoid system. This increase in CB1R tracer binding and possibly signaling may represent a supplementary and new mechanism of VPA, but not LEV, since activation of CB1Rs has been shown to decrease excitability and excitotoxicity on-demand.
Neuropharmacology 06/2008; 54(7):1103-6. · 4.81 Impact Factor
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ABSTRACT: The endocannabinoid system (ECS) is implicated as a regulator of homeostasis of several cerebral functions and is a novel target for drug treatment of neuropyschiatric disorders. So far, the cerebral cannabinoid-type 1 receptor (CB1R) has only been studied using in vitro, animal model, electrophysiological and post-mortem data. We have used positron emission tomography (PET) using a high-affinity, subtype-selective radioligand, [(18)F]MK-9470, to assess the in vivo cerebral CB1R distribution and its variation with healthy aging and gender. Fifty healthy volunteers (25 M/25 F, 18-69 years) underwent [(18)F]MK-9470 PET. Parametric [(18)F]MK-9470 binding maps were constructed, corrected for partial volume effects and analyzed using statistical parametric mapping in a combined categorical (gender) and covariate (age) design. We found that [(18)F]MK-9470 binding to CB1R increased with aging but only in women (p(FWE)<0.05, corrected for multiple comparisons); this was most pronounced in the basal ganglia, lateral temporal cortex and limbic system, especially in the hippocampus. Men showed higher [(18)F]MK-9470 binding then women (p<0.001, uncorrected), in clusters of the limbic system and cortico-striato-thalamic-cortical circuit. Region-dependent and gender-related upregulation of [(18)F]MK-9470 binding with aging is in line with ex vivo findings in rodent studies and may be associated with a changing homeostatic capacity or compensation mechanisms in the ECS that is modulated by sex hormones. In vivo PET of the CB1R will likely improve our understanding of the ECS in several neurological and psychiatric disorders.
NeuroImage 03/2008; 39(4):1533-41. · 5.89 Impact Factor
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ABSTRACT: The unilateral 6-hydroxydopamine (6-OHDA) lesion rat model is a well-known acute model for Parkinson's disease (PD). Its validity has been supported by invasive histology, behavioral studies and electrophysiology. Here, we have characterized this model in vivo by multitracer imaging [glucose metabolism and dopamine transporter (DAT)] in relation to behavioral and histological parameters.
Eighteen female adult Wistar rats (eight 6-OHDA-lesioned, ten controls) were investigated using multitracer [(18)F]-fluoro-2-deoxy-D: -glucose (FDG) and [(18)F]-FECT {2'-[(18)F]-fluoroethyl-(1R-2-exo-3-exe)-8-methyl-3-(4-chlorophenyl)-8-azabicyclo(3.2.1)-octane-2-carboxylate} small animal positron emission tomography (PET). Relative glucose metabolism and parametric DAT binding images were anatomically standardized to Paxinos space and analyzed on a voxel-basis using SPM2: , supplemented by a template-based predefined volumes-of-interest approach. Behavior was characterized by the limb-use asymmetry test; dopaminergic innervation was validated by in vitro tyrosine hydroxylase staining.
In the 6-OHDA model, significant glucose hypometabolism is present in the ipsilateral sensory-motor cortex (-6.3%; p = 4 x 10(-6)). DAT binding was severely decreased in the ipsilateral caudate-putamen, nucleus accumbens and substantia nigra (all p < 5 x 10(-9)), as confirmed by the behavioral and histological outcomes. Correlation analysis revealed a positive relationship between the degree of DAT impairment and the change in glucose metabolism in the ipsilateral hippocampus (p = 3 x 10(-5)), while cerebellar glucose metabolism was inversely correlated to the level of DAT impairment (p < 3 x 10(-4)).
In vivo cerebral mapping of 6-OHDA-lesioned rats using [(18)F]-FDG and [(18)F]-FECT small animal PET shows molecular-functional correspondence to the cortico-subcortical network impairments observed in PD patients. This provides a further molecular validation supporting the validity of the 6-OHDA lesion model to mimic multiple aspects of human PD.
European Journal of Nuclear Medicine 02/2008; 35(1):124-34. · 4.53 Impact Factor
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ABSTRACT: PurposeThe unilateral 6-hydroxydopamine (6-OHDA) lesion rat model is a well-known acute model for Parkinson’s disease (PD). Its validity
has been supported by invasive histology, behavioral studies and electrophysiology. Here, we have characterized this model
in vivo by multitracer imaging [glucose metabolism and dopamine transporter (DAT)] in relation to behavioral and histological
parameters.
MethodsEighteen female adult Wistar rats (eight 6-OHDA-lesioned, ten controls) were investigated using multitracer [18F]-fluoro-2-deoxy-D-glucose (FDG) and [18F]-FECT {2′-[18F]-fluoroethyl-(1R-2-exo-3-exe)-8-methyl-3-(4-chlorophenyl)-8-azabicyclo(3.2.1)-octane-2-carboxylate} small animal positron
emission tomography (PET). Relative glucose metabolism and parametric DAT binding images were anatomically standardized to
Paxinos space and analyzed on a voxel-basis using SPM2, supplemented by a template-based predefined volumes-of-interest approach. Behavior was characterized by the limb-use asymmetry
test; dopaminergic innervation was validated by in vitro tyrosine hydroxylase staining.
ResultsIn the 6-OHDA model, significant glucose hypometabolism is present in the ipsilateral sensory-motor cortex (−6.3%; p = 4 × 10−6). DAT binding was severely decreased in the ipsilateral caudate-putamen, nucleus accumbens and substantia nigra (all p < 5 × 10−9), as confirmed by the behavioral and histological outcomes. Correlation analysis revealed a positive relationship between
the degree of DAT impairment and the change in glucose metabolism in the ipsilateral hippocampus (p = 3 × 10−5), while cerebellar glucose metabolism was inversely correlated to the level of DAT impairment (p < 3 × 10−4).
ConclusionsIn vivo cerebral mapping of 6-OHDA-lesioned rats using [18F]-FDG and [18F]-FECT small animal PET shows molecular–functional correspondence to the cortico-subcortical network impairments observed
in PD patients. This provides a further molecular validation supporting the validity of the 6-OHDA lesion model to mimic multiple
aspects of human PD.
European journal of nuclear medicine and molecular imaging 12/2007; 35(1):124-134. · 4.99 Impact Factor
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ABSTRACT: Anorexia nervosa (AN) is a disorder that is difficult to treat with psycho- or pharmacotherapy. In order to identify involved neurocircuitry, we investigated the cerebral metabolic alterations in the activity-based anorexia (ABA) rat model, where restriction of the food intake period induces hyperactivity and decreased body weight. Cerebral (18)F-fluorodeoxyglucose uptake was investigated in rats in the activity-based anorexia model (n=9) and compared to controls (n=10), using a CTI Focus microPET 220. Regional metabolic changes were investigated using statistical parametric mapping (SPM2) and correlated to weight and hyperactivity measures on a voxel-by-voxel basis. Higher regional metabolism was found in ABA rats in the mediodorsal thalamus, ventral pontine nuclei and cerebellum, while hypometabolism was seen in the left rhinal and bilateral insular cortex, and bilateral ventral striatum (p<0.001). A positive correlation was observed between body weight loss and brain metabolism in the cingulate cortex and surrounding motor and somatosensory cortex (p<0.001). Thus, in the ABA model metabolic changes are present in brain areas related to disease status and weight loss, which share several characteristics with the human disease.
NeuroImage 04/2007; 35(1):214-21. · 5.89 Impact Factor
