Tissue plasminogen activator modulates the cellular and behavioral response to cocaine

Abstract

Cocaine exposure induces long-lasting molecular and structural adaptations in the brain. In this study, we show that tissue plasminogen activator (tPA), an extracellular protease involved in neuronal plasticity, modulates the biochemical and behavioral response to cocaine. When injected in the acute binge paradigm, cocaine enhanced tPA activity in the amygdala, which required activation of corticotropin-releasing factor type-1 (CRF-R1) receptors. Compared with WT mice, tPA؊/؊ mice injected with cocaine displayed attenuated phosphorylation of ERK, cAMP response element binding protein (CREB), and dopamine and cAMP-regulated phosphoprotein 32 kDa (DARPP-32) and blunted induction of immediate early genes (IEGs) c-Fos, Egr-1, and Homer 1a in the amygdala and the nucleus accumbens (NAc). tPA؊/؊ mice also displayed significantly higher basal preprodynorphin (ppDyn) mRNA levels in the NAc in comparison to WT mice, and cocaine decreased ppDyn mRNA levels in tPA؊/؊ mice only. Cocaineinduced locomotor sensitization and conditioned place preference (CPP) were attenuated in tPA؊/؊ mice. Cocaine exposure also had an anxiolytic effect in tPA؊/؊ but not WT mice. These results identify tPA as an important and novel component of the signaling pathway that modulates cocaine-induced changes in neuroadaptation and behavior.behavioral sensitization ͉ conditioned place preference ͉ corticotropin releasing factor ͉ neuronal signaling ͉ plasminogen activator inhibitor C ocaine is one of the most widely abused drugs in the United States, and there are currently no effective pharmacotherapies for cocaine addiction (1). The rewarding and reinforcing properties of cocaine correlate with its ability to inhibit reuptake and consequently increase synaptic concentrations of dopamine (DA). Cocaine induces complex molecular changes in discrete brain regions, leading to altered gene expression and changes in neuronal structure and function. Such drug-induced alterations in neuronal circuitry are associated with the development of addiction (1, 2). The mesolimbic DAergic system is thought to be the primary target for cocaine-induced molecular and behavioral adaptations in the brain (1). In addition, the dynorphin (Dyn)/ kappa opioid receptor (KOP-r) system, which is highly expressed in the nucleus accumbens (NAc), has been implicated in regulating the behavioral effects of cocaine by playing a homeostatic role that opposes alterations in brain function and behavior that result from cocaine exposure (3-5). Further, acute pretreatment with KOP-r agonists is effective in decreasing mesoaccumbal DA neurotransmission and cocaine reward (3, 4).The serine protease tissue plasminogen activator (tPA), which is released from neurons upon excitation and facilitates synaptic plasticity (6), is an attractive candidate for mediating some of cocaine's effects on neuronal plasticity. tPA is expressed in brain regions implicated in drug reward, including the NAc and amygdala, and is thought to regulate proteolytic events involved in neurite outgrowth and long-term...

Alcohol: A stimulant activating brain stress responsive systems with persistent neuroadaptation

“…On the basis of this evidence, we hypothesize that increased basal levels of dynorphin in the nucleus accumbens core may lead to altered dopaminergic signaling after drug exposure. Indeed, in our studies, cocaine-induced conditioned place preference and locomotor sensitization, as well as cocaine withdrawal-induced stress responses, are attenuated in tPA knockout mice (Maiya et al, 2009;Zhou et al, 2010b). Our work also indicates a potential involvement of glial systems in cocaine rewarding and stress responsivity.…”

“…It has been demonstrated that nucleus accumbens dialysate dopamine levels are decreased after stimulation of kappa opioid receptors (Spanagel et al, 1992;Zhang et al, 2004Zhang et al, , 2005b. In tissue plasminogen activator (tPA, endogenous microglia inhibitor) knockout mice, basal levels of dynorphin (but not kappa opioid receptor or enkephalin) mRNA are increased in the nucleus accumbens core (Maiya et al, 2009). On the basis of this evidence, we hypothesize that increased basal levels of dynorphin in the nucleus accumbens core may lead to altered dopaminergic signaling after drug exposure.…”

Neural ECM in addiction, schizophrenia, and mood disorder

“…This is consistent with observations that plasticity-restricting PNN components are reduced after heroin self-administration (Van Den Oever et al, 2010) and protein expression of reelin is increased after cocaine self-administration (Host et al, 2010). Interestingly, an increasing number of studies show that experimental manipulations that reduce ECM breakdown or elevate ECM levels interfere with addictive behavior in different animal models of addiction, including behavioral sensitization (morphine, cocaine, and methamphetamine; Maiya et al, 2009;Mizoguchi et al, 2007;Nagai et al, 2004Nagai et al, , 2005b, CPP (morphine, cocaine, amphetamine, methamphetamine, and nicotine; Brown et al, 2007;Maiya et al, 2009;Mizoguchi et al, 2007;Nagai et al, 2004Nagai et al, , 2005bNagai et al, , 2006, cocaine self-administration (Chen et al, 2013), and reinstatement of heroine seeking (Van Den Oever et al, 2010). In contrast, enhancement of synaptic plasticity by ECM breakdown facilitates extinction of the drug memory (Xue et al, 2014), providing a substrate to suppress drug-seeking urges.…”

Involvement of tissue plasminogen activator in stress responsivity during acute cocaine withdrawal in mice

“…Cocaine induces tPA mRNA expression in the prefrontal cortex and NAc (Hashimoto et al 1998; Bahi and Dreyer 2008). Acute “binge” cocaine enhances tPA activity in the central and medial nucleus of the Amy by a mechanism that requires activation of CRF 1 receptors (Maiya et al 2009). Further, cocaine-induced neuronal signaling and immediate early gene expression in the Amy and NAc, as well as its rewarding effects (as measured by conditioned place preference) are attenuated in tPA-deficient (tPA −/−) mice (Maiya et al 2009).…”