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Oligodendrocyte apoptosis mediated demyelination is a pathological change characteristic of compressed spinal cord injury (CSCI). However, the mechanism of demyelination due to oligodendrocyte apoptosis is not known. In this study, after successfully establishing a rat CSCI model using a custom-made compressor, we investigated the pathological changes, MBP expression, as well as apoptosis-related protein (p53, active caspase-3) expression to determine whether or not apoptosis and demyelination occurred after injury. To understand the possible mechanism of oligodendrocyte apoptosis, caspase-12 and cytochrome C were analyzed to explore the relationship between oligodendrocyte apoptosis and endoplasmic reticulum(ER)-mitochondria interaction. The transcription factor, E2F1, was also detected by immunofluorescence and Western blot assays. The results showed that CSCI increased the expression levels of p53, E2F1 and active caspase-3 followed by the swelling and breakdown of myelin sheaths. The number of myelinated nerve fibers also decreased with down-regulated expression of MBP. Expression levels of caspase-12 and cytochrome C were enhanced along with a reduction in the number of oligodendrocytes. After treatment of CSCI in rats with Pifithrin-μ(PFT-μ), a specific inhibitor of p53, pathomorphological changes of myelin sheath improved significantly. Expression levels of E2F1, active caspase-3, caspase-12 and cytochrome C were down-regulated, consistent with reduced the number of apoptotic oligodendrocytes. These results demonstrated that over-expression of p53 could mediate oligodendrocyte apoptosis thus resulting in demyelination in two ways; by enhancing ER-mitochondria interaction and by triggering the E2F1 mediated apoptosis pathway. [ABSTRACT FROM AUTHOR]

Abstract: Cocaine and heroin are psychoactive substances frequently used by woman abusers of childbearing age. In this study, we used in utero electroporation labeling technique and novelty recognition models to evaluate the effects of prenatal exposure of mice to cocaine or heroin on the morphological development of cortical neurons and postnatal cognitive functions. Our results showed that prenatal cocaine exposure increased dendrite outgrowth, and prenatal heroin exposure decreased dendrite length and branch number in pyramidal neurons in the somatosensory cortex. Furthermore, although no effects of prenatal cocaine or heroin exposure on novel object recognition were observed, offspring prenatally exposed to cocaine exhibited no exploration preference for objects placed in novel locations, and mice prenatally exposed to heroin showed a reduced tendency of exploration for objects in novel locations. These data demonstrate that maternal cocaine or heroin administration during pregnancy causes morphological alterations in pyramidal neurons in the somatosensory cortex and suggest that prenatal administration of addictive substances may impair short-term spatial memory in adult offspring. [Copyright &y& Elsevier]

Abstract: In order to substantiate the concept that cocaine behavioral effects may be influenced by histone modification, rats were trained to self-administer cocaine intravenously (0.75mg/(kginjection)), and were systemically pretreated with sodium butyrate (NaBu), a potent histone deacetylase inhibitor, before the test session during the maintenance phase. The effect of NaBu on a control reinforcer (sucrose)-induced self-administration was also assessed. NaBu (100–200mg/kg) was inactive in altering the cocaine (0.75mg/(kginjection))-maintained responding and at the highest dose (400mg/kg) it did increase cocaine-induced lever presses during the maintenance phase. On the other hand, sucrose-reinforcing potential was not altered when NaBu was given at the highest dose (400mg/kg). These findings extend previous observations that changes in histone acetylation are relevant to cocaine-induced behavioral effects. Given that histone acetylase inhibitor enhances cocaine-induced behavioral plasticity, the therapeutic benefits of histone acetyltransferase inhibitors warrant further investigation in the experimental models of cocaine abuse. [Copyright &y& Elsevier]

Abstract: The present study investigated the involvement of dopamine mechanism in the effect of intermittent footshock stress on the morphine-induced place preference. A single intermittent footshock session significantly enhanced the place preference induced by 3.0mg/kg morphine. This enhancing effect was inhibited by selective D1 receptor antagonist SCH23390 and selective D2 receptor antagonist sulpiride pretreatment 20min before footshock session, suggesting dopamine D1 and D2 receptors are required for the development of intermittent footshock stress-induced enhancement of morphine-associated place preference. However, different from D1 and D2 receptors this enhancing effect was blocked by stimulation of dopamine D3 receptor with selective D3 receptor agonist 7-OH-DPAT pretreatment 20min before footshock session which suggest dopamine D3 receptor play a negative mediation effect on the intermittent footshock stress-induced this enhancement. These results indicate that dopamine D1, D2, and D3 receptor subtypes play different roles in footshock stress-induced enhancement of morphine conditioned place preference. [Copyright &y& Elsevier]

Abstract: β-arrestin 2 plays important physiological roles in regulating the function of the μ opioid receptor (μOR) in vivo. Periaqueductal gray (PAG) is a potential structure where morphine produces its antinociception, but it is unclear whether β-arrestin 2 plays its regulatory effect on morphine at PAG. In the present study β-arrestin 2 overexpression was induced by adenovirus at PAG of rats. Morphine was administrated in these rats through PAG microinjection and systemic administration. The antinociceptive effects of morphine were abolished in rats received microinjection of morphine at PAG and partially attenuated in rats received systemic administration of morphine. These findings support the notion that PAG is an important site where β-arrestin 2 plays its regulatory effects on morphine analgesia. [Copyright &y& Elsevier]

Repeated administration of addictive drugs induces neuronal apoptosis and the underlying mechanisms are not clear. Our present study investigated the effects of treatments with different addictive drugs on gene expression of murine double minute clone 2 (MDM2), a key negative regulator of p53 and an important mediator in cell apoptosis. The level of MDM2 gene expression in rat brain was assessed using in situ hybridization histochemistry. In normal adult rat brain, MDM2 expression was at a very low level but MDM2 mRNA-positive cells were detected in various regions including cortex, hippocampus, thalamus, amygdala, periaqueductal gray and locus ceruleus. After a single morphine injection, MDM2 gene expression increased significantly in hippocampus, amygdala and cortex; however, such up-regulation of MDM2 gene expression was significantly reduced after repeated morphine administration. Moreover, 24 h after cessation of chronic morphine exposure, MDM2 mRNA increased again to a level comparable to that of the acute morphine group. Acute heroin or cocaine administration also significantly increased MDM2 gene expression in hippocampus, but not in cortex. In thalamus, no change was detected after acute or chronic treatment with morphine, heroin, or cocaine. Thus we demonstrated for the first time that the administration of addictive drugs regulate MDM2 gene expression in distinct rat brain regions and these data suggest that MDM2 may play an important role in the development of drug addiction. [Copyright &y& Elsevier]