BackgroundThe aim of this study was to explore how changes in the expression of BDNF in MLDS change the effect of BDNF on dopamine (DA) neurons, which may have therapeutic implications for heroin addiction.Material/MethodsWe established a rat model of heroin addiction and observed changes in the expression of BDNF, DA, dopamine receptor (DRD), dopamine transporter (DAT), and other relevant pathways in NAc. We also assessed the effect of BDNF overexpression in the NAc, behavioral changes of heroin-conditioned place preference (CPP), and naloxone withdrawal in rats with high levels of BDNF. We established 5 adult male rat groups: heroin addiction, lentivirus transfection, blank virus, sham operation, and control. The PCR gene chip was used to study gene expression changes. BDNF lentivirus transfection was used for BDNF overexpression. A heroin CPP model and a naloxone withdrawal model of rats were established.ResultsExpression changes were found in 20 of the 84 DA-associated genes in the NAc of heroin-addicted rats. Weight loss and withdrawal symptoms in the lentivirus group for naloxone withdrawal was less than in the blank virus and the sham operation group. These 2 latter groups also showed significant behavioral changes, but such changes were not observed in the BDNF lentivirus group before or after training. DRD3 and DAT increased in the NAc of the lentivirus group.ConclusionsBDNF and DA in the NAc are involved in heroin addiction. BDNF overexpression in NAc reduces withdrawal symptoms and craving behavior for medicine induced by environmental cues for heroin-addicted rats. BDNF participates in the regulation of the dopamine system by acting on DRD3 and DAT.
BackgroundSynaptic plasticity plays an important role in the process of addiction. This study investigated the relationship between synaptic plasticity and changes in addictive behavior and examined the expression of synaptic plasticity-associated proteins and genes in the nucleus accumbens (NAc) region in different rat models.Material/MethodsHeroin addiction, SIRT1-overexpression, and SIRT1-silenced rat models were established. Polymerase chain reaction gene chip technology, immunohistochemistry, Western blotting, and transmission electron microscopy were used to detect changes in synaptic plasticity-related gene and protein expression, and changes in the ultrastructure of synapses, in the NAc.ResultsNaloxone withdrawal symptoms appeared in the SIRT1-overexpression group. In the SIRT1-silenced group the symptoms were reduced. Immunohistochemistry and Western blotting results showed that FOXO1 expression decreased in the heroin addiction (HA) group but increased in the SIRT1-silenced group (p<0.05). The expression of Cdk5, Nf-κB, PSD95, and Syn was enhanced in the HA group (p<0.05) and further increased in the SIRT1-overexpression group but were reduced in the SIRT1-silenced group (p<0.05). The number of synapses increased in the HA group (p<0.05) along with mitochondrial swelling in the presynaptic membrane and obscuring of the synaptic cleft.ConclusionsSIRT1 and other synaptic plasticity-related genes in NAc are involved in the regulation of heroin addiction. SIRT1 overexpression can increase behavioral sensitization in the NAc of rats, and SIRT1 silencing might ease withdrawal symptoms and reduce conditioned place preferences.
Background: Acute kidney injury (AKI), a prevalent complication of sepsis, causes substantial burden on patients’ families as well as the society. More reliable markers are urgently required for the prevention and treatment of AKI. Pleckstrin homology-like domain, family A, member 1 (PHLDA1) was implicated in various diseases, but its involvement in sepsis-induced AKI remains to be explored. The JNK/ERK pathway has been revealed as being involved in progression of sepsis. One previous study demonstrated that PHLDA1 could activate the JNK/ERK pathway in hepatic ischemia/reperfusion injury. Nevertheless, involvement of PHLDA1 in sepsis-triggered AKI through the JNK/ERK pathway has not been probed. Methods: A cecal ligation and punctured (CLP) mice model of sepsis-induced AKI was estab-lished. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and immunofluorescence staining were applied to evaluate the expression of PHLDA1. Concentration of blood urea nitrogen (BUN) and serum creatinine (Scr), inflammation markers, including interleukin-6 (IL-6), IL-1β, and tumor necrosis factor-α, as well as oxidative stress-associated proteins (catalase, malondialdehyde, superoxide dismutase, and glutathione), in the kidney tissues of mice were evaluated by enzyme-linked-immunosorbent serologic assay. Western blot analysis was applied for measuring protein expression levels. Results: The BUN and SCr levels in mice were obviously elevated in the CLP group compared to the sham group. Moreover, the expression of PHLDA1 was also elevated in the CLP group in comparison to the sham group. Down-regulation of PHLDA1 alleviated renal injury, inflam-mation, and oxidative stress in AKI model. Mechanistic study showed that PHLDA1 knockdown suppressed the activation of c-JUN N-terminal kinase/p38 and extracellular signal-regulated kinase (JNK/ERK) pathway. Conclusion: Down-regulation of PHLDA1 suppressed inflammation and oxidative stress through the modulation of JNK/ERK pathway in sepsis-induced AKI. The results could offer a novel insight into the treatment of patients with sepsis-induced AKI.
Neurotrophins, brain-derived neurotrophic factors (BDNF), neurotrophin-3 (NT-3), and neurotrophin-4 (NT-4), have been implicated in the modulation of heroin dependency. This study was designed to explore the expression alterations of BDNF, NT-3, and NT-4 in the context of heroin dependence and withdrawal in the rat nucleus accumbens (NAc). Heroin dependence was induced by a progressive intraperitoneal treatment of heroin. The results showed that the expression levels of BDNF and NT-4 were significantly decreased in the NAc of rats with heroin addiction in comparison with the control group, whereas there was a significant increase in BDNF and NT-4 expressions in the groups of rats with both naloxone-induced and spontaneous withdrawal. Moreover, NT-3 expression was markedly increased in the NAc of rats with heroin addiction and spontaneous withdrawal in comparison with the control group, but decreased in the NAc of rats with naloxone-induced withdrawal. These results indicated that chronic administration of heroin results in the alterations of BDNF, NT-3, and NT-4 expressions in the rat NAc. BDNF, NT-3, and NT-4 may play a critical role in the development of heroin dependency and withdrawal.
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