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Psychostimulant-induced plasticity in the rat mesolimbic dopaminergic pathway

English title Psychostimulant-induced plasticity in the rat mesolimbic dopaminergic pathway
Applicant Dreyer Jean-Luc
Number 116492
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 01.05.2007 - 31.12.2010
Approved amount 227'000.00
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Keywords (6)

neurochemistry; drug addiction; dopamine; brain reward; lentivirus; gene-transfer

Lay Summary (English)

Lead
Lay summary
Drug addiction is a major public health issue and typically a multi-genetic brain disorder, implying combined changes of expression of several hundred genes. Drugs of abuse produce persistent alterations in brain function. Activity-dependent synaptic plasticity of the mesolimbic dopaminergic system (the “reward pathway”) plays a crucial role in the development of drug dependence. Our past work aimed at characterizing the role of some genes candidates by means of lentivirus-mediated gene transfer with lentiviruseses overexpressing the genes of interest or expressing siRNA (i.e. enabling local knock-down of the same gene candidate). The approach we developed, based on local in vivo gene transfer using doxycycline-regulatable lentiviral-based molecular tools, is ideal for investigating the role of a gene in behavior and whether a particular gene is involved in acquisition, learning or retrieval of behavioral sensitization. The current project proposes the following extension of that research: Part 1): Regulation Mechanisms of Gene Expression: drug administration induces strong changes of expression of several hundred genes, including many axon guidance molecules, recapitulating a complex program involved in plasticity during development. Here we address the question: what are the central regulatory mechanisms that control the expression of this complex gene expression pattern? In silico analysis proved that most genes identified in earlier screening display binding sites for a limited number of common transcription factors in their promoter region, or can be regulated by a few miRNAs. Based on these analyses and preliminary data, we propose several experiments focused to investigate the influence of two transcription factors and three miRNAs, in a view to test a hypothesis for the regulation of genes differentially expressed in response to cocaine. Part 2): the role of Tetraspanin Web in Addiction: Tetraspanins are scaffold proteins that integrate receptor signaling. We showed that the tetraspanin CD81 plays a major role in addiction and propose that this may be due to its interaction with integrin signaling. Modification of integrin signaling would rapidly change synaptic plasticity and receptor clustering in the mesolimbic pathway and affect dopaminergic response. Part 3): the function of the Plasmin System in Addiction: Plasmin is activated by proteases, urokinase-type (uPA) or tissue-type (tPA) plasminogen activators. Both are strongly up-regulated in response to psychostimulants. Silencing these plasminogen activators completely blocks drug-induced locomotor activity and place preference. Also tetraspanins drastically affect plasmin activity and prevent uPA binding to its receptor uPAR by promoting stable association of uPAR with specific integrins (eg. ?5?1), redistributing uPAR to focal adhesion. We propose a hypothesis to explain these effects in relation to cocaine-induced CD81-expression and will test it.
Direct link to Lay Summary Last update: 21.02.2013

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