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In the central nervous system, tissue plasminogen activator (tPA) plays a role in synaptic plasticity and remodeling. Our recent study has suggested that tPA participates in the rewarding effects of morphine by regulating dopamine release. In this study, we investigated the role of tPA in methamphetamine (METH)-related reward and sensitization. Repeated METH treatment dose-dependently induced tPA mRNA expression in the frontal cortex, nucleus accumbens, striatum and hippocampus, whereas single METH treatment did not affect tPA mRNA expression in these brain areas. The METH-induced increase in tPA mRNA expression in the nucleus accumbens was completely inhibited by pre-treatment with R(+)-SCH23390 and raclopride, dopamine D1 and D2 receptor antagonists, respectively. In addition, repeated METH treatment increased tPA activity in the nucleus accumbens. There was no difference in METH-induced hyperlocomotion between wild-type and tPA-deficient (tPA-/-) mice. On the other hand, METH-induced conditioned place preference and behavioral sensitization after repeated METH treatment were significantly reduced in tPA-/-mice compared with wild-type mice. The defect of behavioral sensitization in tPA-/-mice was reversed by microinjections of exogenous tPA into the nucleus accumbens. Our findings suggest that tPA is involved in the rewarding effects as well as the sensitization of the locomotor-stimulating effect of METH.

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The role of the phosphorylation of hippocampal extracellular signal-regulated kinase 1/2 in spatial working memory in rats was assessed with a delayed spatial win-shift task in a radial arm maze. The task consisted of two phases, a training phase and a test phase, separated by a delay. Phosphorylated extracellular signal-regulated kinase 1/2 levels were significantly and transiently increased in the hippocampus by 60 min, and then returned to the control levels 120 min after the training phase. Bilateral microinjections of the PD98059, an inhibitor of the extracellular signal-regulated kinase 1/2 kinase MEK, into the hippocampus impaired performance in the test phase of the delayed spatial win-shift task at 5-min delay. These results suggest that extracellular signal-regulated kinase 1/2 activation in the hippocampus plays a crucial role in spatial working memory.

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