In vivo gene delivery of urokinase-type plasminogen activator with regulatable lentivirus induces behavioural changes in chronic cocaine administration

Amine Bahi, Frederic Boyer, Christèle Gumy, Tal Kafri, Jean Luc Dreyer

Research output: Contribution to journalArticlepeer-review

40 Citations (Scopus)

Abstract

Serine proteases play a key function in extracellular processes affecting central nervous system plasticity. Recently, the role of extracellular proteolytic processes in regulating synaptic structure and function has been described. However, to date direct evidence linking extracellular serine protease activity with drug-related behavioural changes has not been documented. Importantly, in a screening for genes induced after drug treatment we found that urokinase plasminogen-type activator (uPA) was strongly regulated by cocaine in several protocols of drug administration. Cocaine-induced up-regulation could be verified on microarray analysis under several protocols of drug administration, then further fully confirmed by means of qRT-PCR. As a result, we chose to investigate further uPA function in the mesolimbic dopaminergic pathway, a major target area of cocaine and drugs of misuse. Our approach was based on the characterization of cocaine-induced behavioural changes following lentiviral vector delivery of a doxycycline-regulated uPA expression cassette (or of its mutated form), into specific rat brain areas (the hippocampus, the nucleus accumbens and the ventral tegmental area). We show that doxycycline-dependent over-expression of uPA in these regions yields a 10- to 12.3-fold increase in locomotor activity after cocaine administration. These behavioural effects were completely abolished when the active site of the protease was point-mutated and used as a dominant negative. The physiological relevance of these drastic behavioural changes is discussed.

Original languageEnglish
Pages (from-to)3473-3488
Number of pages16
JournalEuropean Journal of Neuroscience
Volume20
Issue number12
DOIs
Publication statusPublished - Dec 2004
Externally publishedYes

Keywords

  • Addiction
  • Drugs of abuse
  • Lentivirus plasticity
  • Rat
  • Serine proteases

ASJC Scopus subject areas

  • General Neuroscience

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