Bahi Amine, Kusnecov Alexander W, Dreyer Jean-Luc
Division of Biochemistry, Department of Medicine, University of Fribourg, Chemin du Musée 5, CH-1700 Fribourg, Switzerland.
Behav Brain Res. 2008 Aug 5;191(1):17-25. doi: 10.1016/j.bbr.2008.03.004. Epub 2008 Mar 13.
Cocaine 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.
可卡因和许多其他精神兴奋剂可强烈诱导中脑边缘多巴胺能通路中尿激酶型纤溶酶原激活剂（uPA）的表达，该通路在药物介导的行为可塑性中起主要作用[巴伊A，博耶F，古米C，卡夫里T，德雷尔JL。用可调节慢病毒体内递送尿激酶型纤溶酶原激活剂可诱导慢性可卡因给药后的行为变化。欧洲神经科学杂志2004；20：3473 - 88；巴伊A，博耶F，卡夫里T，德雷尔JL。体内沉默腹侧被盖区的尿激酶可诱导可卡因诱导的运动亢进变化。神经化学杂志2006；98：1619 - 31；巴伊A，德雷尔JL。伏隔核中纤溶酶原激活剂的过表达增强可卡因、苯丙胺和吗啡诱导的奖赏及行为敏感化。基因、大脑与行为2007]。在本研究中，通过对双侧伏隔核内注射表达uPA的慢病毒载体的大鼠进行条件性位置偏爱实验，研究了中脑边缘多巴胺（DA）通路在可卡因奖赏形成中的作用。我们发现，伏隔核中uPA的过表达显著增强了可卡因诱导的位置偏爱。此外，虽然这并不影响偏爱消退的能力，但用低剂量可卡因进行恢复时，对与可卡因相关环境的偏爱显著增强。一旦建立了条件性位置偏爱并使其消退，启动剂量的可卡因诱导恢复时，uPA会起到促进作用。使用强力霉素抑制这种丝氨酸蛋白酶的表达可消除uPA过表达所产生的增强的习得，但不影响可卡因诱导的条件性位置偏爱的表达。当在习得阶段抑制uPA时，动物不再对先前与可卡因配对的环境表现出位置偏爱。如果在习得过程中uPA已被激活，特异性uPA抑制剂B428不会影响消退后的药物恢复，这清楚地表明uPA参与了条件性位置偏爱的习得阶段。我们的结果表明，反复药物暴露导致uPA表达增加，为增强可卡因诱导的条件性位置偏爱的习得创造了条件，表明可卡因诱导的条件性位置偏爱和恢复可能依赖于细胞外活性uPA。
