Silencing urokinase in the ventral tegmental area in vivo induces changes in cocaine-induced hyperlocomotion

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

Research output: Contribution to journalArticlepeer-review

15 Citations (Scopus)

Abstract

Serine proteases in the nervous system have functional roles in neural plasticity. Among them, urokinase-type plasminogen activator (uPA) exerts a variety of functions during development, and is involved in learning and memory. Furthermore, psychostimulants strongly induce uPA expression in the mesolimbic dopaminergic pathway. In this study, doxycycline-regulatable lentiviruses expressing either uPA, a dominant-negative form of uPA, or non-regulatable lentiviruses expressing small interfering RNAs (siRNAs) targeted against uPA have been prepared and injected into the ventral tegmental area (VTA) of rat brains. Over-expression of uPA in the VTA induces doxycycline-dependent expression of its receptor, uPAR, but not its inhibitor, plasminogen activator inhibitor-1 (PAI-1). uPAR expression in the VTA is repressed upon silencing of uPA with lentiviruses expressing siRNAs. In addition, over-expression of uPA in the VTA promotes a 15-fold increase in locomotion activity upon cocaine delivery. Animals expressing the dominant-negative form of uPA did not display such hyperlocomotor activity. These cocaine-induced behavioural changes, associated with uPA expression, could be suppressed in the presence of doxycycline or uPA-specific siRNAs expressing lentiviruses. These data strongly support the major role of urokinase in cocaine-mediated plasticity changes.

Original languageEnglish
Pages (from-to)1619-1631
Number of pages13
JournalJournal of Neurochemistry
Volume98
Issue number5
DOIs
Publication statusPublished - Sep 2006
Externally publishedYes

Keywords

  • Addiction
  • In vivo gene transfer
  • Lentivirus
  • Plasticity
  • Small interfering RNA
  • Urokinase-type plasminogen activator

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

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