Tissue Plasminogen Activator Is Not Involved in Methamphetamine-Induced Neurotoxicity

Abstract

Abstract. To investigate the role of tissue plasminogen activator (tPA) in methamphetamine (METH)-induced dopaminergic neurotoxicity, we compared the changes in tyrosine hydroxylase (TH) and dopamine transporter (DAT) levels in the striatum after repetitive treatment of METH at 4 mg/ kg among wild-type, tPA-deficient (tPA−/ −), and protease activated receptor-1-deficient (PAR-1−/ −) mice. METH treatment caused a marked decrease in TH and DAT levels in the striatum of those mice with a similar magnitude. No difference in METH-induced abnormal behavior and hyperthermia was observed among the three types of mice. These results suggest that neither tPA nor PAR-1 is involved in METH-induced dopaminergic neurotoxicity in vivo.Keywords: methamphetamine, neurotoxicity, tissue plasminogen activator Methamphetamine (METH) is an abused drug. It has a strong rewarding effect that is related to the stimulating effect of dopamine release in the brain (1, 2). Repeated treatment with METH in rodents leads to the development of behavioral sensitization, which may be associated with METH psychosis or a strong craving in METH abusers. METH dependence and craving can be modeled by a self-administration paradigm in mice. A recent study demonstrated that glial-derived neurotrophic factor (GDNF) plays an important role in the craving for METH after long-term abstinence using GDNF-deficient mice (3).We have previously demonstrated that endogenous tumor necrosis factor-α (TNF-α) is induced in the brain after repeated administration of METH, and this cytokine acts to suppress METH dependence and its dopaminergic neurotoxicity (1, 2, 4). Thus, METHinduced conditioned place preference (CPP), behavioral sensitization, and loss of tyrosine hydroxylase (TH) in the striatum are potentiated in TNF-α-deficient (TNF-α−/ −) mice compared with wild-type mice, whereas systemic administration of TNF-α in mice suppresses METH-induced hyperlocomotion, behavioral sensitization, conditioned place preference, and the loss of TH in the striatum (2).On the other hand, our recent studies demonstrated that tissue plasminogen activator (tPA) acts as a proaddictive substance to enhance the reward of and behavioral sensitization to METH (4, 5); thus, METHinduced CPP and behavioral sensitization are reduced in tPA-deficient (tPA−/ −) mice compared to wild-type mice. It remains to be determined, however, whether tPA is also involved in the dopaminergic neurotoxicity of METH.In the present study, to investigate the role of tPA in METH-induced dopaminergic neurotoxicity, we compared TH and dopamine transporter (DAT) levels in

Novel agonists & antagonists for protease-activated receptor 2 and C3a receptor

“…As the NMDA receptor contributes to cell death under ischemic conditions, potentiation of NMDA signaling by PAR1 activation is thought to contribute to harmful neuronal effects. In addition, although PAR1 contributes to neurotoxicity in a murine model of blood-induced intracerebral hemorrhage brain injury (Xue et al, 2009), another PAR1−/− mouse model indicates that this receptor is not involved in methamphetamine-induced neurotoxicity (Fukakusa et al, 2008).…”