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

  • Bahi, Amine Institute of Biochemistry, University of Fribourg, Switzerland
  • Boyer, Frederic Institute of Biochemistry, University of Fribourg, Switzerland
  • Kafri, Tal Gene Therapy Center, University of North Carolina at Chapel Hill, North Carolina, USA
  • Dreyer, Jean-Luc Institute of Biochemistry, University of Fribourg, Switzerland
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    20.07.2006
Published in:
  • Journal of Neurochemistry. - 2006, vol. 98, no. 5, p. 1619–1631
addiction
in vivo gene transfer
lentivirus
plasticity
small interfering RNA
urokinase-type plasminogen activator
English 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.
Faculty
Faculté des sciences et de médecine
Department
Département de Médecine
Language
  • English
Classification
Biological sciences
License
License undefined
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Persistent URL
https://folia.unifr.ch/unifr/documents/300249
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