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Thèse Aurélie Boucher

"Un modèle animal de vulnérabilité génétique à la schizophrénie précipitée par les cannabinoides chez la souris neuréguline 1.

Le 14 novembre 2008

Abstract


An animal model of neuregulin 1 genetic susceptibility to cannabinoid-induced schizophrenia

Cannabis use may increases the risk of developing schizophrenia by precipitating the disorder in genetically vulnerable individuals. Human studies have shown neuregulin 1 (NRG1) as a susceptibility gene for schizophrenia, thus the aim of this thesis is to evaluate the effects of cannabinoids in mice heterozygous for Nrg1 (Nrg1 HET mice). When acutely administered with Δ9-tetrahydrocannabinol (THC), the main psychoactive constituent of cannabis, Nrg1 HET mice exhibited an increased prepulse inhibition, a model of attentional deficit impaired in schizophrenia patients. In addition, THC increased neuronal activity as measured by Fos immunohistochemistry in the ventral part of the lateral septum (LSV) specifically in Nrg1 HET mice. With repeated administration of the synthetic analogue of THC, CP 55,940, Nrg1 HET mice developed tolerance to the locomotor suppressant and hypothermic effects of the drug faster than wild-type (WT) control mice. In contrary, Nrg1 HET mice did not develop tolerance to the anxiogenic effects of CP 55,940, unlike WT mice. Chronic treatment with CP 55,940 also increased Fos expression in the LSV of Nrg1 HET mice, with no such effect seen in WT mice. Finally, long term THC exposure induced deficits in spatial memory in WT mice, an effect that could be particularly interesting to evaluate in Nrg1 HET mice for future studies. Taken together, the results from this thesis provide the first evidence of an interaction between cannabinoids and neuregulin deficiency in an animal model and may enhance our understanding on how drugs of abuse increase the development of psychosis.


Centre de Neurosciences Intégratives et Cognitives,
CNRS, UMR 5228, Univ. Bx 1,
Talence, France

Focus




Aurelie Boucher
a préparé sa thèse sous la direction de Jacques MICHEAU et de Jonathon ARNOLD, une cotutelle entre l'Université de Bordeaux 1 et de Sydney 

Jury

M. ARNOLD Jonathon , E-C, University of Sydney
M. GUILLOU Jean-Louis , MC (HDR), Université de Bordeaux 1
M. MCGREGOR Iain , E-C, University of Sydney
M. MICHEAU Jacques , Prof, Université de Bordeaux 1
M. RIEDEL Gernot , Prof, University of Aberdeen
MME THIEBOT Marie-Hélène , DR INSERM, Université Paris 6

Publications récentes

A. A. Boucher, L. Vivier, M. Metna-Laurent, C. Darnet, L. Brayda-Bruno, N. Mons, J. C. Arnold, J. Micheau. Acute and chronic treatment of D9-tetrahydrocannabinol on learning and memory –correlates with Zif 268 expression in mouse forebrain./ //Behavioural Pharmacology.

A. A. Boucher, G. E. Hunt, T. Karl, J. Micheau, I. S. McGregor, J. C. Arnold. Heterozygous neuregulin 1 mice display greater baseline and Delta(9)-tetrahydrocannabinol-induced c-Fos expression. /Neuroscience/.
2007 Nov 23;149(4):861-870.
     
A. A. Boucher, J. C. Arnold, L. Duffy, P. R. Schofield, J. Micheau, T. Karl. Heterozygous neuregulin 1 mice are more sensitive to the behavioural effects of Delta9-tetrahydrocannabinol.
/Psychopharmacology/. 2007 Jun;192(3):325-36.