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• Low (0.33 mg/kg) dose of LY235959 could increase mice locomotor activity. • High (3.0 mg/kg) dose of LY235959 could induce some symptoms caused by NMDAR inhibition. • Medium (1.0 mg/kg) dose of LY235959 could disrupt development phase of METH-induced behavioral sensitization. Drug addiction can be described as a chronic and relapsing brain disease. Behavioral sensitization is common animal model in the study of addiction and N-Methyl-D-aspartate subtype of glutamate receptor (NMDAR) is believed play key role in this process. LY235959 is a competitive NMDAR antagonist, however, its effect on methamphetamine (METH)-induced behavioral sensitization is not been reported yet. In this study, we choose three doses (0.33 mg/kg, 1.0 mg/kg, and 3.0 mg/kg) of LY235959 to investigate its effect on locomotor activity, METH-induced behavioral sensitization and different phases of it in C57/BL6 mice. We also used western blotting to examine the PP2A/B – AKT cascade which had been proved involved in METH-induced behavioral sensitization in the dorsal striatum (DS). The results showed that only 0.33 mg/kg LY235959 increased locomotor activity dramatically, however, 1.0 mg/kg and 3.0 mg/kg of LY235959 could attenuate METH-induced behavioral sensitization markedly. We also found that LY235959 only disrupted the development phase of METH-induced behavioral sensitization and the following western blotting results further indicated that PP2A/B – AKT cascade might involve in this process. Taken together, these results indicated that LY235959 attenuates development phase of METH-induced behavioral sensitization through the PP2A/B - AKT cascade in the DS. [ABSTRACT FROM AUTHOR]

• 2 mg/kg Methamphetamine (METH) induced hyperlocomotion in mice. • 0.5 mg/kg SCH23390 attenuated acute METH-induced hyperlocomotion. • 0.5 mg/kg SCH23390 reversed increased activity of protein phosphatase 2A. • 0.1 mg/kg LB100 attenuated acute METH-induced hyperlocomotion. • 0.1 mg/kg LB100 reversed decreased activity of phosphorylated CaMKIIα. Drug addiction is underscored by the transition from experimental use to dependent use of addictive drugs. Acute use of methamphetamine (METH) causes a range of clinical symptoms, including hyperlocomotion. Dopamine D1 receptor (D1R)-mediated negative regulation of phosphorylated calcium/calmodulin-dependent protein kinase IIα (p-CaMKIIα, threonine [Thr] 286) is involved in the acute effects induced by single METH administration. Protein phosphatase 2A (PP2A) is a potential bridge that links D1R and p-CaMKIIα (Thr 286) after acute METH administration. However, the mechanisms underlying hyperlocomotion induced by single METH administration remain unclear. In this study, SCH23390 (a D1R inhibitor) and LB100 (a PP2A inhibitor) were administered to examine the involvement of D1R and PP2A signaling in acute METH-induced hyperlocomotion in mice. The protein levels of methylated PP2A-C (m-PP2A-C, leucine [Leu] 309), phosphorylated PP2A-C (p-PP2A-C, tyrosine [Tyr] 307), PP2A-C, p-CaMKIIα (Thr 286), and CaMKIIα in the prefrontal cortex (PFc), nucleus accumbens (NAc), and caudate putamen (CPu) were measured. Administration of 0.5 mg/kg SCH23390 reversed the acute METH-induced increase in protein levels of m-PP2A-C (Leu 309) and the decrease in protein levels of p-PP2A-C (Tyr 307) in the CPu, but not in the PFC and NAc. Moreover, prior administration of 0.1 mg/kg LB100 attenuated hyperlocomotion induced by single METH administration and reversed the decrease in protein levels of p-CaMKII (Thr 286) in the PFC, NAc, and CPu. Collectively, these results indicate that the D1R/PP2A/p-CaMKIIα signaling cascade in the CPu may be involved in hyperlocomotion after a single administration of METH. [ABSTRACT FROM AUTHOR]

• 1 mg/kg Methamphetamine (METH) induced conditioned place preference (CPP) in mice. • LB100 did not affect the natural preference of mice. • LB100 inhibited the acquisition of METH-induced CPP in mice. • LB100 accelerated the extinction of METH-induced CPP in mice. • LB100 hindered the reinstatement of METH-induced CPP in mice. Protein phosphatase 2A (PP2A) is an evolutionarily conserved serine/threonine phosphatase abundant in mammalian brains. Although recent research has revealed that PP2A plays important roles in cocaine and morphine addictions, the mechanism of action of PP2A in methamphetamine (METH) addiction is unclear. LB100 is a PP2A inhibitor able to penetrate the blood-brain barrier (BBB); the role of LB100 in METH-induced conditioned place preference (CPP) has not yet been reported. Here, we explored the roles of LB100 in distinct phases of METH-induced CPP. Our findings indicate that LB100 inhibits the acquisition and reinstatement of METH-induced CPP and promotes the extinction of METH-induced CPP. Moreover, LB100 alone did not affect the natural preference of mice. Intriguingly, repeated administration of LB100 in the extinction phase did not inhibit the reinstatement of METH-induced CPP, but LB100 injection prior to METH administration could significantly block it. Taken together, we found that LB100 has significant effects on different phases of METH-induced CPP, and is therefore, a potentially promising therapeutic for METH addiction. [ABSTRACT FROM AUTHOR]