The Rewards of Nicotine: Regulation by Tissue Plasminogen Activator–Plasmin System through Protease Activated Receptor-1

Nagai, Taku; Ito, Makoto; Nakamichi, Noritaka; Mizoguchi, Hideaki; Kamei, Hiroyuki; Fukakusa, Ayumi; Nabeshima, Toshitaka; Takuma, Kazuhiro; Yamada, Kiyofumi

doi:10.1523/jneurosci.3139-06.2006

Cited by 62 publications

(82 citation statements)

References 47 publications

(57 reference statements)

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“…Furthermore, both PAR1 (Striggow et al, 2001), and NMDA receptor subunits (Ishii et al, 1993) are highly expressed in brain regions involved with emotional learning, including hippocampus and amygdala. These results it well with suggestions that serine proteases can impact learning (Baranes et al, 1998;Pawlak et al, 2002;Nagai et al, 2004Nagai et al, ,2006Pang et al, 2004;Pawlak et al, 2005), and may suggest that PAR1 is a substrate at which serine proteases such as plasmin exert their actions.…”

Section: Discussionsupporting

confidence: 86%

Learning and memory deficits in mice lacking protease activated receptor-1

Almonte

Hamill

Chhatwal

et al. 2007

Neurobiology of Learning and Memory

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The roles of serine proteases and protease activated receptors have been extensively studied in coagulation, wound healing, inflammation, and neurodegeneration. More recently, serine proteases have been suggested to influence synaptic plasticity. In this context, we examined the role of protease activated receptor 1 (PAR1), which is activated following proteolytic cleavage by thrombin and plasmin, in emotionally-motivated learning. We were particularly interested in PAR1 because its activation enhances the function of NMDA receptors, which are required for some forms of synaptic plasticity. We examined several baseline behavioral measures, including locomotor activity, expression of anxiety-like behavior, motor task acquisition, nociceptive responses, and startle responses in C57Bl/6 mice in which the PAR1 receptor has been genetically deleted. In addition, we evaluated learning and memory in these mice using two memory tasks, passive avoidance and cued fear-conditioning. Whereas locomotion, pain response, startle, and measures of baseline anxiety were largely unaffected by PAR1 removal, PAR1−/− animals showed significant deficits in a passive avoidance task and in cued fear conditioning. These data suggest that PAR1 may play an important role in emotionally-motivated learning.

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Section: Discussionsupporting

confidence: 86%

Learning and memory deficits in mice lacking protease activated receptor-1

Almonte

Hamill

Chhatwal

et al. 2007

Neurobiology of Learning and Memory

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“…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]. Using the morphine self-administration procedure, the same group described very recently that tPA deficient mice display more morphine intake in a dose-dependent manner as compared to their wild type littermates [71].…”

Section: Discussionmentioning

confidence: 99%

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

Bahí

Kusnecov

Dreyer

2008

Behavioural Brain Research

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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.

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“…tPA has been shown to regulate morphine-and nicotine-induced DA release in the NAc and is required for morphine and nicotine reward and sensitization (12)(13)(14). Deletion or overexpression of tPA alters methamphetamine-induced place preference and sensitization (13,15).…”

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confidence: 99%

Tissue plasminogen activator modulates the cellular and behavioral response to cocaine

Maiya

Zhou

Norris

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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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...

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The Rewards of Nicotine: Regulation by Tissue Plasminogen Activator–Plasmin System through Protease Activated Receptor-1

Cited by 62 publications

References 47 publications

Learning and memory deficits in mice lacking protease activated receptor-1

Learning and memory deficits in mice lacking protease activated receptor-1

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

Tissue plasminogen activator modulates the cellular and behavioral response to cocaine

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