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Psychostimulant-induced Plasticity in the mesolimbic dopaminergicPathway

Applicant Dreyer Jean-Luc
Number 100686
Funding scheme Project funding (Div. I-III)
Research institution Division de Biochimie Département de Biologie Université de Fribourg
Institution of higher education University of Fribourg - FR
Main discipline Biochemistry
Start/End 01.08.2003 - 31.03.2007
Approved amount 240'956.00
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All Disciplines (2)

Discipline
Biochemistry
Neurophysiology and Brain Research

Keywords (6)

Neurosciences; Drug addiction; Dopamine; Brain Reward; lentivirus; gene transfer

Lay Summary (English)

Lead
Lay summary
Drug addiction is a major public health issue worldwide and it is typically a brain disorder, that implies the combined expression changes of several hundred genes. Drugs of abuse produces persistent changes in major brain function. Activity-dependent synaptic plasticity of the mesolimbic dopaminergic system plays a crucial role in the development of drug dependence. Current research in the field focuses on the characterization of the many target genes responsible for mediating drug-related behavioral states and how numerous drug-induced molecular changes in several brain regions interact to produce the complex behavioral phenotype that defines addiction.

We have been involved initially in the screening of plasticity genes involved in addiction, We have shown that drug administration induces strong changes of expression of many axon guidance molecules, recapitulating a complex program involved in plasticity during development. This important observation is the focus of further characterization, since neuroadaptation and plasticity-related changes in response to drugs are major issues related to addiction. The role of some candidates are currently under characterization, with emphasis on extracellular proteases involved in plasmin activation (the tissue-type and the urokinase-type plasminogen activator), or membrane proteins (the scaffold tetraspanin CD81, the dopamine receptor D3R, the dopamine transporter and and neurotrophin BDNF receptors) and related proteins (the α - and γ-synucleins, and the neurotrophin BDNF). Our approach consists at preparing lentiviruses overexpressing the gene of interest or lentiviruses expressing siRNA, i.e. enabling to locally knock-down the expression of the same gene candidate. Lentiviruses are particularly well suited for our aim: they incorporate the gene into the targeted area permanently and do not diffuse, being self-inactivating; infection remains then very local and does not induce immune response. In addition our viruses are regulatable, enabling to turn on/off gene expression in vivo locally. We have demonstrated the very high efficacy of this approach. With these lentiviruses overexpressing or silencing specific genes, we are currently investigating the functions of tetraspanins (CD81, a scaffold protein that integrates receptor signaling), of BDNF and of the plasmin system (by activation of urokinase or tissue-type plasminogen activator) in drug-induced synaptic adaptation in the mesolimbic dopaminergic pathway.

In addition we aim at characterizing the role of synucleins in the intracellular regulation of the dopamine transporter, a major target of cocaine. The project should improve the understanding of molecular processes responsible for perturbed behaviors associated with addiction, withdrawal, and relapse and lead to more efficient therapeutical treatments for drug addiction.
Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Associated projects

Number Title Start Funding scheme
59350 Psychostimulant-induced Plasticity in the mesolimbic dopaminergicPathway 01.08.2000 Project funding (Div. I-III)

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