Drug Dependence, Synaptic Plasticity, and Tissue Plasminogen Activator

Abstract

Abstract. The mesocorticolimbic dopaminergic system plays an important role in the reinforcing effects of drugs of abuse, and the activity-dependent synaptic plasticity of the system is involved in drug dependence. A DNA microarray screening revealed that the expression levels of tissue plasminogen activator (tPA) mRNA in the nucleus accumbens of morphine-or methamphetamine-dependent rats were significantly increased compared with those in control animals. Since tPA plays a role in synaptic plasticity, we hypothesized that tPA may contribute to the development of drug dependence. Single and repeated morphine treatment as well as repeated methamphetamine treatment induced tPA mRNA expression in the nucleus accumbens, which was associated with an increase in the enzyme activity. Conditioned place preference induced by morphine was markedly reduced in mice with a targeted deletion of the tPA gene (tPA-/ -mice), being accompanied by a loss of morphine-induced dopamine release. Similarly, methamphetamine-induced conditioned place preference and locomotor sensitization were reduced in tPA-/ -mice. The defects of morphine-induced hyperlocomotion as well as methamphetamineinduced locomotor sensitization in tPA-/ -mice were reversed by microinjection of exogenous tPA or plasmin into the nucleus accumbens. These results support our hypothesis that tPA plays a role in long-lasting neuronal changes related to drug dependence.

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

“…These cocaine-induced behavioral changes, associated with uPA expression, could be suppressed in the presence of doxycycline or of siRNA targeted against uPA [18,19]. Collectively, these and other data [13] strongly support a major role for urokinase in psychostimulant-mediated plasticity changes.…”

“…The present study firmly consolidates these data and points to an important role of the plasmin system in chronic cocaine. Other studies have shown that the plasmin system releases dopamine in the NAc upon psychostimulants, which activates long-term synaptic plasticity and remodeling, and acutely participates in the rewarding effects of drugs such as methamphetamine or morphine [13,14,16,17,69]. It has been shown that tPA regulates nicotine-induced reward and dopamine release through protease activated receptor-1 [70].…”

“…For example, metamphetamineinduced dopamine release in the nucleus accumbens recruits the plasminogen activator-plasmin system [13], inducing long-term synaptic plasticity and remodeling, and increasing drug-induced reward [14,15]. The plasmin system also participates in the rewarding effects of morphine by acutely regulating morphine-induced dopamine release in the nucleus accumbens (NAc) [13,16]. A single morphine treatment induced tPA expression in the NAc in a naloxone-sensitive manner, with tPA expression diminishing after repeated morphine administration.…”

The Role of Tissue-Type Plasminogen Activator System in Amphetamine-Induced Conditional Place Preference Extinction and Reinstatement

“…The present findings are consistent with the view that tPA activator plays a key role in neuroplasticity and is a neuromodulator in the CNS (Yamada et al, 2005). Moreover, as previously mentioned, the tPA-plasmin system is involved in the rewarding effects of drugs of abuse (eg, morphine), possibly through regulation of dopamine release in the NAc (Nagai et al, 2004Ito et al, 2006Ito et al, , 2007Yan et al, 2007).…”

GluN2D Subunit-Containing NMDA Receptors Control Tissue Plasminogen Activator-Mediated Spatial Memory

“…In the brain parenchyma, tPA is involved in physiological processes, including synaptic plasticity (Huang et al, 1996;Calabresi et al, 2000;Zhuo et al, 2000;Mataga et al, 2002;Pang et al, 2004) and behaviors (Seeds et al, 1995(Seeds et al, , 2003Madani et al, 1999;Pawlak et al, 2002Pawlak et al, , 2003Matys et al, 2004;Yamada et al, 2005). tPA also displays important roles in models of acute and chronic brain disorders, such as ischemic brain injury, seizure, and multiple sclerosis (Tsirka et al, 1995;Chen and Strickland 1997;Wang et al, 1998;Wu et al, 2000;Gveric et al, 2001;Lu et al, 2002;Liot et al, 2006).…”