Effects of urokinase-type plasminogen activator in the acquisition, expression and reinstatement of cocaine-induced conditioned-place preference

Abstract

a b s t r a c tCocaine and many other psychostimulants strongly induce urokinase-type plasminogen activator (uPA) expression in the mesolimbic dopaminergic pathway, which plays a major role in drug-mediated behavioral plasticity [Bahi A, Boyer F, Gumy C, Kafri T, Dreyer JL. In vivo gene delivery of urokinase-type plasminogen activator with regulatable lentivirus induces behavioral changes in chronic cocaine administration. Eur J Neurosci 2004;20:3473-88; Bahi A, Boyer F, Kafri T, Dreyer JL. Silencing urokinase in the ventral tegmental area in vivo induces changes in cocaine-induced hyperlocomotion. J Neurochem 2006;98:1619-31; Bahi A, Dreyer JL. Overexpression of plasminogen activators in the nucleus accumbens enhances cocaine-, amphetamine-and morphine-induced reward and behavioral sensitization. Genes Brain Behav 2007]. In this study, the role of mesolimbic dopamine (DA) pathways in the development of cocaine reward was examined by conditioned-place preference in rats with bilateral intra-accumbens injections of uPA-expressing lentiviral vectors. We show that overexpression of uPA in the Nac significantly augments cocaine-induced place preference. Furthermore, while this did not affect the ability of preference to be extinguished, reinstatement with a low dose of cocaine produced significantly greater preference to the cocaine-associated context. Once CPP had been established, and the preference extinguished, reinstatement induced by a priming dose of cocaine was facilitated by uPA. Inhibition of this serine protease expression using doxycycline abolished the augmented acquisition produced by overexpression of uPA but not the expression of the cocaine-induced CPP. When uPA is inhibited during the acquisition phase, animals no longer demonstrate place preference for the environment previously paired with cocaine. B428, a specific uPA inhibitor does not affect drug reinstatement after extinction if uPA has been activated during acquisition, a clear indication that uPA is involved in the acquisition phase of conditioned-place preference. Our results suggest that that increased uPA expression with repeated drug exposure produces conditions for enhanced acquisition of cocaine-induced CPP, indicating that cocaine-induced CPP and reinstatement may be dependent on active extracellular uPA.

Inhibition of urokinase plasminogen activator “uPA” activity alters ethanol consumption and conditioned place preference in mice

“…In addition, continuous unlimited access procedures are also more appropriate to study the pharmacological effects of compounds with long elimination half-lives, such as B428, in rodents and other small animals 25,39. Along these lines, a previous study from our laboratory has shown that in Wistar rats, B428 blocked cocaine-induced psychomotor stimulation 21. In agreement with the current findings, we have also shown in a previous study that ethanol treatment dose-dependently induced the expression and the enzymatic activity of another serine protease, namely, tissue plasminogen activator (tPA), in the NAc 32.…”

“…B428 is a uPA inhibitor, which, when administered at lower doses, has been proven to selectively reduce the activity of uPA in rodents 21–25. Given the reports that suggest that alcohol intake and alcoholism could be mediated by their interaction with serine proteases activity,26 and considering that some of the behavioral effects of psychostimulants depend on the levels of uPA activity,18,19,21 we hypothesized that by reducing the uPA activity, B428 will decrease alcohol consumption, and ethanol-induced CPP will be prevented.…”

Selective lentiviral-mediated suppression of microRNA124a in the hippocampus evokes antidepressants-like effects in rats

“…Viral vector generation was obtained by cotransfection of HEK293T cells by the calcium phosphate method on 10-cm plates with 20 mg of pTK431, 15 mg of pDNRF, and 5 mg of pMDG-VSV-G. The supernatant was harvested 24 and 72 h after infection and viral particles were purified by ultracentrifugation (Bahi et al, 2005(Bahi et al, , 2008b.…”

Lentiviral Vector-Mediated Gene Transfer and RNA Silencing Technology in Neuronal Dysfunctions

“…Thus once place preference had been established, and the preference extinguished, reinstatement induced by a priming dose of cocaine is facilitated by uPA. Furthermore, lentivirus-mediated overexpression of uPA induces cocaine-, but not amphetamine-mediated behavioral changes, whereas, in contrast, tPA-overexpressing animals displayed greater place preference when administered amphetamine or morphine compared to uPA-overexpressing animals [149][150][151]. The behavioral effects are suppressed when tPA has been silenced using specific siRNAsexpressing lentiviruses.…”

“…Lentiviral-mediated overexpression of uPA in the VTA induces doxycycline-dependent expression of its receptor, uPAR, but not its inhibitor, plasminogen activator inhibitor-1 (PAI-1) [149]. Local injection of uPA-specific siRNAs expressing lentiviruses into the ventral tegmental area suppressed cocaine-induced behavioral changes associated with uPA expression [149,150] Lentivirus-mediated overexpression of uPA in the Accumbens shell significantly augments cocaine-induced place preference, whereas its inhibition abolished the acquisition but not the expression of cocaine-induced place preference [149,150]. Furthermore, while this overexpression did not affect the ability of preference to be extinguished, reinstatement with a low dose of cocaine produced significantly greater preference to the cocaine-associated context.…”