The 5-HT7 receptors in the VLO contribute to the development of morphine-induced behavioral sensitization in rats.

The 5-hydroxytryptamine 7 receptor (5-HT7R) is one of the most recently cloned serotonin receptors which have been implicated in many physiological and pathological processes including drug addiction. Behavioral sensitization is the progressive process during which re-exposure to drugs intensified the behavioral and neurochemical responses to drugs. Our previous study has demonstrated that the ventrolateral orbital cortex (VLO) is critical for morphine-induced reinforcing effect. The aim of the present study was to investigate the effect of 5-HT7Rs in the VLO on morphine-induced behavioral sensitization and their underlying molecular mechanisms. Our results showed that a single injection of morphine, followed by a low challenge dose could induce behavioral sensitization. Microinjection of the selective 5-HT7R agonist AS-19 into the VLO during the development phase significantly increased morphine-induced hyperactivity. Microinjection of the 5-HT7R antagonist SB-269970 suppressed acute morphine-induced hyperactivity and the induction of behavioral sensitization, but had no effect on the expression of behavioral sensitization. In addition, the phosphorylation of AKT (Ser 473) was increased during the expression phase of morphine-induced behavioral sensitization. Suppression of the induction phase could also block the increase of p-AKT (Ser 473). In conclusion, we demonstrated that 5-HT7Rs and p-AKT in the VLO at least partially contribute to morphine-induced behavioral sensitization.

Phosphorylation of Neurofilament Light Chain in the VLO Is Correlated with Morphine-Induced Behavioral Sensitization in Rats.

Neurofilament light chain (NF-L) plays critical roles in synapses that are relevant to neuropsychiatric diseases. Despite postmortem evidence that NF-L is decreased in opiate abusers, its role and underlying mechanisms remain largely unknown. We found that the microinjection of the histone deacetylase (HDAC) inhibitor Trichostatin A (TSA) into the ventrolateral orbital cortex (VLO) attenuated chronic morphine-induced behavioral sensitization. The microinjection of TSA blocked the chronic morphine-induced decrease of NF-L. However, our chromatin immunoprecipitation (ChIP)-qPCR results indicated that this effect was not due to the acetylation of histone H3-Lysine 9 and 14 binding to the NF-L promotor. In line with the behavioral phenotype, the microinjection of TSA also blocked the chronic morphine-induced increase of p-ERK/p-CREB/p-NF-L. Finally, we compared chronic and acute morphine-induced behavioral sensitization. We found that although both chronic and acute morphine-induced behavioral sensitization were accompanied by an increase of p-CREB/p-NF-L, TSA exhibited opposing effects on behavioral phenotype and molecular changes at different addiction contexts. Thus, our findings revealed a novel role of NF-L in morphine-induced behavioral sensitization, and therefore provided some correlational evidence of the involvement of NF-L in opiate addiction.

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It is of great significance to understand the pattern of soil respiration rate in fragmented forests for further revealing terrestrial ecosystem carbon cycling. With different habitats (island vs. mainland, island edge vs. island interior) of the artificial land-bridge island system in Thousand Island Lake (TIL) region as the objects, we analyzed the seasonal dynamics of soil respiration rate and its relationships with soil physicochemical factors. The results showed that: 1) Soil respiration rates varied significantly across different seasons, with an order of summer (3.74 µmol·m-2·s-1) > autumn (2.30 µmol·m-2·s-1) > spring (1.82 µmol·m-2·s-1) > winter (1.40 µmol·m-2·s-1). 2) Forest fragmentation had significant effects on soil respiration rate, with soil respiration rate of island (2.37 µmol·m-2·s-1) being significantly higher than that of mainland (2.08 µmol·m-2·s-1) and the soil respiration rate of island edge (2.46 µmol·m-2·s-1) being significantly higher than that of island interior (2.03 µmol·m-2·s-1). 3) Soil temperature significantly promoted soil respiration rate, explaining 56.1% of the total variation. 4) There was a significant positive correlation between soil respiration rate and soil total carbon, ammo-nium nitrogen content, and vegetation coverage. The soil total carbon and ammonium nitrogen content of island edge were significantly higher than those of island interior. In all, forest fragmentation promoted soil respiration rate, with soil physicochemical factors as the drivers for its variation.

Association between a TCF4 Polymorphism and Susceptibility to Schizophrenia.

The basic helix-loop-helix (bHLH) transcription factor 4 (TCF4) had been identified as a susceptibility gene associated with schizophrenia (SCZ) by GWAS, but inconsistent results have been found in other studies. To validate these findings and to reveal the effects of different inheritance models, rs2958182, rs1261085, rs8766, and rs12966547 of the TCF4 gene were genotyped in the Northwest Han Chinese population (448 cases and 628 controls) via a multiplex polymerase chain reaction SNPscan assay. Single SNP, genotype, and association analyses with three different models were performed. We observed genotype and allele distributions of four SNPs that showed nonsignificant associations in the Northwest Han Chinese population. However, published datasets (51,892 cases and 68,498 controls) were collected and combined with our experimental results to ascertain the association of the TCF4 gene SNPs and SCZ, which demonstrated that rs2958182 (P=0.003) was a significant signal based on a systematic meta-analysis. To clarify the biological role of rs2958182, it is important to improve the understanding of the pathophysiology of SCZ.

Theoretical study of the mechanism of the manganese catalase KatB.

The mechanism of the H2O2 disproportionation catalyzed by the manganese catalase (MnCat) KatB was studied using the hybrid density functional theory B3LYP and the quantum chemical cluster approach. Compared to the previous mechanistic study at the molecular level for the Thermus thermophilus MnCat (TTC), more modern methodology was used and larger models of increasing sizes were employed with the help of the high-resolution X-ray structure. In the reaction pathway suggested for KatB using the Large chemical model, the O-O homolysis of the first substrate H2O2 occurs through a µ-η1:η1 coordination mode and requires a barrier of 10.9 kcal/mol. In the intermediate state of the bond cleavage, two hydroxides form as terminal ligands of the dimanganese cluster at the Mn2(III,III) oxidation state. One of the two Mn(III)-OH- moieties and a second-sphere tyrosine stabilize the second substrate H2O2 in the second-sphere of the active site via hydrogen bonding interactions. The H2O2, unbound to the metals, is first oxidized into HO2· through a proton-coupled electron transfer (PCET) step with a barrier of 9.5 kcal/mol. After the system switches to the triplet surface, the uncoordinated HO2· replaces the product water terminally bound to the Mn(II) and is then oxidized into O2 spontaneously. Transition states with structural similarities to those obtained for TTC, where µ-η2-OH-/O2- groups play important roles, were found to be higher in energy.