Search

• The K+-dependent Na+/Ca2+ exchanger 2 (NCKX2) may not be involved in METH-induced conditioned place preference. • NCKX2 in the PFc might regulate METH-induced behavioral sensitization. • Overexpression of NCKX2 in the PFc attenuated the expression phase of METH-induced behavioral sensitization. • Knockdown of NCKX2 in the PFc enhanced METH-induced behavioral sensitization in mice. Drug addiction, including methamphetamine (METH) addiction, is a significant public health and social issue. Perturbations in intracellular Ca2+ homeostasis are associated with drug addiction. K+-dependent Na+/Ca2+ exchanger 2 (NCKX2) is located on neuronal cell membranes and constitutes a Ca2+ clearance mechanism, with key roles in synaptic plasticity. NCKX2 is associated with motor learning, memory, and cognitive functions. However, the role of NCKX2 in METH addiction remains unclear. In this study, we investigated the expression levels of NCKX2 in four addiction-related brain regions: the prefrontal cortex (PFc), nucleus accumbens (NAc), dorsal striatum (DS), and hippocampus (Hip) in a C57/BL6 mouse model of METH-induced conditioned place preference (CPP) and behavioral sensitization. Levels of NCKX2 were unchanged in these brain regions in mice with METH-induced CPP but were decreased in the PFc and NAc of mice with METH-induced behavioral sensitization. Adeno-associated virus (AAV)-mediated overexpression of NCKX2 in the PFc attenuated the expression phase of METH-induced behavioral sensitization in mice, whereas AAV-mediated knockdown of NCKX2 enhanced the effects of METH. Collectively, our results suggest that NCKX2 is involved in METH-induced behavioral sensitization but does not affect conditioned reward-related memory, highlighting the potential of NCKX2 as a molecular target for studying the mechanisms underscoring METH addiction. [ABSTRACT FROM AUTHOR]

• 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]

• 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]