Browsing by Author "Verdurand, M"

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    Comparison of cannabinoid CB1 receptor binding in adolescent and adult rats: a positron emission tomography study using [18F]MK-947
    (Hindawi Publishing Corporation, 2011-01-01) Verdurand, M; Nguyen, VH; Stark, D; Zahra, D; Grégoire, MC; Greguric, I; Zavitsanou, K
    Despite the important role of cannabinoid CB1 receptors (CB1R) in brain development, little is known about their status during adolescence, a critical period for both the development of psychosis and for initiation to substance abuse. In the present study, we assessed the ontogeny of CB1R in adolescent and adult rats in vivo using positron emission tomography with [18F]MK-9470. Analysis of covariance (ANCOVA) to control for body weight that would potentially influence [18F]MK-9470 values between the two groups revealed a main effect of age ( 𝐹 ( 1 , 1 0 9 ) = 5 . 0 , 𝑃 = 0 . 0 2 ) on [18F]MK-9470 absolute binding (calculated as percentage of injected dose) with adult estimated marginal means being higher compared to adolescents amongst 11 brain regions. This finding was confirmed using in vitro autoradiography with [3H]CP55,940 ( 𝐹 ( 1 0 , 9 9 ) = 1 4 0 . 1 , 𝑃 < 0 . 0 0 0 1 ). This ontogenetic pattern, suggesting increase of CB1R during the transition from adolescence to adulthood, is the opposite of most other neuroreceptor systems undergoing pruning during this period. Copyright © 2011 Mathieu Verdurand et al.
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    Differential Treatment Regimen-Related Effects of HU210 on CB(1) and D(2)-Like Receptor Functionality in the Rat Basal Ganglia
    (Karger, 2012-02-01) Nguyen, VH; Wang, H; Verdurand, M; Zavitsanou, K
    Background/Aims: Functional linkages between the cannabinoid CB(1) and the dopaminergic systems have been reported although the observations and the mechanisms hypothesizing their interactions at the G protein-coupled receptor (GPCR) functionality level are conflicting. Methods: Administration of a potent cannabinoid agonist, HU210, at various doses (25-100 μg/kg) and treatment regimens (1- to 14-day treatment) in rats was carried out to investigate the effect of HU210 treatment on the CB(1) and D(2)-like agonist-mediated GPCR activation. Results: The desensitizations (reduced coupling) of both D(2) agonist- and CB(1) agonist-mediated GPCR activation was found to be treatment duration dependent and region specific, suggesting implication of receptor tolerance and adaptation due to the cannabinoid treatment. The effect of HU210 on the CB(1) agonist-mediated GPCR desensitization in all treatment groups was not dose dependent. Conclusions: The desensitization of D(2)-like receptors found after a cannabinoid treatment in this study strengthens the evidence that the two neurotransmitter systems interact at the intercellular level; this interaction might occur via multiple mechanisms, which also vary according to region. Copyright © 2012 S. Karger AG, Basel.
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    Feasibility of imaging the ontogeny of CB1 receptors in adolescent and adult rats in vivo with [18F]MK 9470 and PET: a pilot study
    (Royal Australian and New Zealand College of Psychiatrists (RANZCP), 2010-09-23) Verdurand, M; Nguyen, VH; Stark, D; Zahra, D; Grégoire, MC; Greguric, I; Zavitsanou, K
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    GABAA receptor density is altered by cannabinoid treatment in the hippocampus of adult but not adolescent rats.
    (Elsevier, 2010-09-10) Verdurand, M; Dalton, VS; Zavitsanou, K
    Cannabinoids are known to induce transient psychotic symptoms and cognitive dysfunction in healthy individuals and contribute to trigger schizophrenia in vulnerable individuals, particularly during adolescence. Converging preclinical evidence suggests important interactions between cannabinoid and GABAergic systems. In the present study, we compared the effects of cannabinoid treatment on GABAA receptor binding in the brain of adolescent and adult rats. Adolescent (5weeks old) and adult (10weeks old) rats were treated with the synthetic cannabinoid HU210 (25, 50 or 100I14g/kg/day) or vehicle for 1, 4 or 14days. Rats were sacrificed 24h after the last injection and GABAA receptor density was measured in several brain regions using [35S]TBPS and in vitro autoradiography. Adolescent rats had higher numbers of GABAA receptors compared to adults. A 24% increase of binding in adult rats treated with 100I14g/kg HU210 for 14days compared to controls was observed in the CA1 region of the hippocampus (16.1 versus 12.9fmol/mg tissue equivalent, t =2.720, p <0.05). HU210 did not affect GABAA receptors in adolescent rats in any treatment regimen and in adult rats treated with HU210 for 1 or 4days. These data suggest that long-term, high-dose treatment with HU210 increases GABAA receptors in the hippocampus of adult rats, changes that may interfere with associated hippocampal cognitive functions such as learning and memory. In addition, our results suggest that the adolescent brain does not display the same compensatory mechanisms that are activated in the adult brain following cannabinoid treatment. © 2010, Elsevier Ltd.
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    Increased brain metabolism after acute administration of the synthetic cannabinoid HU210: A small animal PET imaging study with (18)F-FDG
    (Elsevier, 2012-02-10) Nguyen, VH; Verdurand, M; Dedeurwaerdere, S; Wang, HQ; Zahra, D; Grégoire, MC; Zavitsanou, K
    Cannabis use has been shown to alter brain metabolism in both rat models and humans although the observations between both species are conflicting. In the present study, we examined the short term effects of a single-dose injection of the synthetic cannabinoid agonist HU210 on glucose metabolism in the rat brain using small animal (18)F-2-fluoro-deoxyglucose (FDG) Positron Emission Tomography (PET) 15min (Day 1) and 24h (Day 2) post-injection of the agonist in the same animal. Young adult male Wistar rats received an intra-peritoneal injection of HU210 (100μg/kg, n=7) or vehicle (n=5) on Day 1. Approximately 1mCi of (18)F-FDG was injected intravenously into each animal at 15min (Day 1) and 24h (Day 2) post-injection of HU210. A 5-min Computer Tomography (CT) scan followed by a 20-min PET scan was performed 40min after each (18)F-FDG injection. Standardised Uptake Values (SUVs) were calculated for 10 brain regions of interest (ROIs). Global increased SUVs in the whole brain, hence global brain metabolism, were observed following HU210 treatment on Day 1 compared to the controls (21%, P<0.0001), but not in individual brain regions. On Day 2, however, no statistically significant differences were observed between the treated and control groups. At the 24h time point (Day 2), SUVs in the HU210 treated group returned to control levels (21-30% decrease compared to Day 1), in all ROIs investigated (P<0.0001). In the control group, SUVs did not differ between the two acquisition days in all brain regions. The present results suggest that high-dose HU210 increases brain glucose metabolism in the rat brain shortly after administration, in line with normalised human in vivo studies, an effect that was no longer apparent 24h later. Copyright © 2011 Elsevier Inc. All rights reserved.
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    Increases in [3H]Muscimol and [3H]Flumazenil binding in the dorsolateral prefrontal cortex in schizophrenia are linked to α4 and γ2S mRNA levels respectively
    (PLOS (Public Library of Science), 2013-01-08) Verdurand, M; Fillman, SG; Weickert, CS; Zavitsanou, K
    Background GABAA receptors (GABAAR) are composed of several subunits that determine sensitivity to drugs, synaptic localisation and function. Recent studies suggest that agonists targeting selective GABAAR subunits may have therapeutic value against the cognitive impairments observed in schizophrenia. In this study, we determined whether GABAAR binding deficits exist in the dorsolateral prefrontal cortex (DLPFC) of people with schizophrenia and tested if changes in GABAAR binding are related to the changes in subunit mRNAs. The GABA orthosteric and the benzodiazepine allosteric binding sites were assessed autoradiographically using [3H]Muscimol and [3H]Flumazenil, respectively, in a large cohort of individuals with schizophrenia (n = 37) and their matched controls (n = 37). We measured, using qPCR, mRNA of β (β1, β2, β3), γ (γ1, γ2, γ2S for short and γ2L for long isoform, γ3) and δ subunits and used our previous measurements of GABAAR α subunit mRNAs in order to relate mRNAs and binding through correlation and regression analysis. Results Significant increases in both [3H]Muscimol (p = 0.016) and [3H]Flumazenil (p = 0.012) binding were found in the DLPFC of schizophrenia patients. Expression levels of mRNA subunits measured did not show any significant difference in schizophrenia compared to controls. Regression analysis revealed that in schizophrenia, the [3H]Muscimol binding variance was most related to α4 mRNA levels and the [3H]Flumazenil binding variance was most related to γ2S subunit mRNA levels. [3H]Muscimol and [3H]Flumazenil binding were not affected by the lifetime anti-psychotics dose (chlorpromazine equivalent). Conclusions We report parallel increases in orthosteric and allosteric GABAAR binding sites in the DLPFC in schizophrenia that may be related to a “shift” in subunit composition towards α4 and γ2S respectively, which may compromise normal GABAergic modulation and function. Our results may have implications for the development of treatment strategies that target specific GABAAR receptor subunits. © 2013 Verdurand et al.
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    Prenatal poly I:C age-dependently alters cannabinoid type 1 receptors in offspring: a longitudinal small animal PET study using [18F]MK-9470
    (Elsevier, 2014-05-10) Verdurand, M; Dalton, VS; Nguyen, VH; Grégoire, MC; Zahra, D; Wyatt, NA; Burgess, L; Greguric, I; Zavitsanou, K
    Evidence suggests that there is a link between the endocannabinoid system (ECS) and neuropsychiatric illnesses, including schizophrenia. Whilst the ECS has been shown to be involved in immune system regulation in various ways, it is known that infections during pregnancy can modulate the immune system of the mother and increase the risk for schizophrenia in offspring. In animal studies, maternal immune activation following administration of viral or bacterial mimics has been shown to reproduce many key structural, behavioural, and pharmacological abnormalities in offspring that resemble schizophrenia. In the present study, we used Positron Emission Tomography (PET) and [18F]MK-9470, a selective high-affinity inverse agonist radioligand for cannabinoid type 1 receptors (CB1R), to longitudinally assess CB1R expression in the progeny of female rats exposed to the viral mimic polyriboinosinic–polyribocytidilic acid (poly I:C) (4 mg/kg i.v.) or vehicle at gestational day 15 (GD 15). PET scans were performed in offspring at postnatal days (PND) 32–42 (adolescence) and in the same animals again at PNDs 75–79 (adulthood). Sixteen regions of interest were assessed, encompassing the whole rat brain. At adolescence, offspring exposed prenatally to poly I:C had significantly lower CB1R relative Standard Uptake Values (rSUV) compared to controls in the globus pallidus (p = 0.046). In adulthood, however, poly I:C exposed offspring had higher levels of CB1R rSUV in sensory cortex (p = 0.034) and hypothalamus (p = 0.032) compared to controls. Our results suggest that prenatal poly I:C leads to long term alterations in the integrity of the ECS that are age and region-specific. The increased CB1R expression in adulthood following poly I:C mirrors the increased CB1R observed in patients with schizophrenia in post-mortem and in vivo PET studies. © Elsevier
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    Synergistic effect between maternal infection and adolescent cannabinoid exposure on serotonin 5HT1A receptor binding in the hippocampus: testing the “two hit” hypothesis for the development of schizophrenia
    (Hindawi, 2012-06-07) Dalton, VS; Verdurand, M; Walker, A; Hodgson, DM; Zavitsanou, K
    Infections during pregnancy and adolescent cannabis use have both been identified as environmental risk factors for schizophrenia. We combined these factors in an animal model and looked at their effects, alone and in combination, on serotonin 5 H T 1 A receptor binding (5 H T 1 A R ) binding longitudinally from late adolescence to adulthood. Pregnant rats were exposed to the viral mimic poly I:C on embryonic day 15. Adolescent offspring received daily injections of the cannabinoid HU210 for 14 days starting on postnatal day (PND) 35. Hippocampal and cortical 5 H T 1 A R binding was quantified autoradiographically using [3H]8-OH-DPAT, in late adolescent (PND 55), young adult (PND 65) and adult (PND 90) rats. Descendants of poly I:C treated rats showed significant increases of 15–18% in 5 H T 1 A R in the hippocampus (CA1) compared to controls at all developmental ages. Offspring of poly I:C treated rats exposed to HU210 during adolescence exhibited even greater elevations in 5 H T 1 A R (with increases of 44, 29, and 39% at PNDs 55, 65, and 90). No effect of HU210 alone was observed. Our results suggest a synergistic effect of prenatal infection and adolescent cannabinoid exposure on the integrity of the serotoninergic system in the hippocampus that may provide the neurochemical substrate for abnormal hippocampal-related functions relevant to schizophrenia. © 2012 Victoria S. Dalton et al.