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Silencing urokinase in the ventral tegmental area in vivo induces changes in cocaine-induced hyperlocomotion
, Boyer Frederic, Kafri Tal, Luc Dreyer Jean
Published in Wiley
PMID: 16923171
Volume: 98
Issue: 5
Pages: 1619 - 1631

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.

About the journal
JournalData powered by TypesetJournal of Neurochemistry
PublisherData powered by TypesetWiley
Open AccessNo