Effects of repeated drug administration on behaviors in normal mice and fluoxetine efficacy in chronic unpredictable mild stress mice.

Mental disorders are characterized by high incidence and high recurrence rates, and only part of patients responded to drug medication. In this case, substantial preclinical investigations are needed. Most antipsychotics taken daily orally in clinics are administered through injection, oral gavage, or minipum implant in rodents, which may induce stress and affect the results of behavioral tests. How drug administrations on behaviors and drug efficacy remains an unsolved problem. In this study, we compared the intraperitoneal injection (IP), intragastric administration (IG), and tail vein injection (TVI) on behaviors, as well as the difference between administration-induced stress and chronic unpredictable mild stress (CUMS). Next, we studied the effects of IG on CUMS model and drug efficacy. We found that IP, IG, and TVI, especially IG, induced a behavior-like phenotype of depression and anxiety, which we call the "CUMS-like behaviors". However, such behaviors were not equal to depression. When treated CUMS mice with saline by gavage, they didn't show any aggravated phenotype compared with CUMS alone. We observed that fluoxetine by intraperitoneal injection was more effective than intragastric administration. Our study confirmed that repeated administrations lead to CUMS-like behaviors. Although these behaviors are not depression, they have adverse effects on drug efficacy.

Neonicotinoid insecticides triggers mitochondrial bioenergetic dysfunction via manipulating ROS-calcium influx pathway in the liver.

Extensive use of neonicotinoids insecticides (NNIs) rapidly garnered widespread attention in the toxicology, since they have been found in human samples, including urine, blood, breast milk and hair. However, the precise mechanism is not completely clear regarding the NNIs-induced hepatotoxicity. In this study, we exposed male mice to three neonicotinoids (dinotefuran (DIN), nitenpyram (NIT) and acetamiprid (ACET) for 30 days. Our results showed that NNIs remarkably induced morphological damage in the liver. Simultaneously, we found that three neonicotinoids could activate the store operated Ca2+ entry (SOCE) in the liver. Further results confirmed that reactive oxide species (ROS) scavenger n-acetylcysteine (NAC) attenuated DIN-induced calcium ion (Ca2+) overload and S-phase arrest via restoring protein expression of SOCE and S phase related genes in L02 hepatocytes. Moreover, we found that NAC obviously combated mitochondrial dysfunction caused by DIN via restoring mitochondrial membrane potential. Meanwhile, DIN treatment significantly increased pyruvate content, impaired the activities of tricarboxylic acid (TCA) cycle rate-limiting enzymes and inhibited adenosine triphosphate (ATP) generation, but these effects were reversed by Serca specific activator CDN1163. Collectively, perturbation of redox states can be recognized as the center of S-phase arrest and Ca2+ overload after NNIs exposure. In this regard, Ca2+ homeostasis dysregulation is a causative event of mitochondrial bioenergetic dysfunction in the liver. These data provides a new perspective for understanding NNI-induced hepatotoxicity mechanisms.

Advances in the study of phencyclidine-induced schizophrenia-like animal models and the underlying neural mechanisms.

Schizophrenia (SZ) is a chronic, severe mental disorder with heterogeneous clinical manifestations and unknown etiology. Research on SZ has long been limited by the low reliability of and ambiguous pathogenesis in schizophrenia animal models. Phencyclidine (PCP), a noncompetitive N-methyl-D-aspartate receptor (NMDAR) antagonist, rapidly induces both positive and negative symptoms of SZ as well as stable SZ-related cognitive impairment in rodents. However, the neural mechanism underlying PCP-induced SZ-like symptoms is not fully understood. Nondopaminergic pathophysiology, particularly excessive glutamate release induced by NMDAR hypofunction in the prefrontal cortex (PFC), may play a key role in the development of PCP-induced SZ-like symptoms. In this review, we summarize studies on the behavioral and metabolic effects of PCP and the cellular and circuitary targets of PCP in the PFC and hippocampus (HIP). PCP is thought to target the ventral HIP-PFC pathway more strongly than the PFC-VTA pathway and thalamocortical pathway. Systemic PCP administration might preferentially inhibit gamma-aminobutyric acid (GABA) neurons in the vHIP and in turn lead to hippocampal pyramidal cell disinhibition. Excitatory inputs from the HIP may trigger sustained, excessive and pathological PFC pyramidal neuron activation to mediate various SZ-like symptoms. In addition, astrocyte and microglial activation and oxidative stress in the cerebral cortex or hippocampus have been observed in PCP-induced models of SZ. These findings perfect the hypoglutamatergic hypothesis of schizophrenia. However, whether these effects direct the consequences of PCP administration and how about the relationships between these changes induced by PCP remain further elucidation through rigorous, causal and direct experimental evidence.

Early-life stress contributes to depression-like behaviors in a two-hit mouse model.

BACKGROUND: Depression is a common psychological disorder with pathogenesis involving genetic and environmental interactions. Early life stress can adversely affect physical and emotional development and dramatically increase the risk for the development of depression and anxiety disorders. METHODS: To examine potential early life stress driving risk for anxiety and depression, we used a two-hit developmental stress model，injecting poly(I: C) into neonatal mice on P2-P6 followed by peripubertal unpredictable stress in adolescence. RESULTS: Our study shows that early-life and adolescent stress leads to anxiety and depression-related behavioral phenotypes in male mice. Early-life stress exacerbated depression-like behavior in mice following peripubertal unpredictable stress. We confirmed that early life stress might be involved in the decreased neuronal activity in the medial prefrontal cortex (mPFC) and might be involved in shaping behavioral phenotypes of animals. We found that increased microglia and neuroinflammation in the mPFC of two-hit mice and early life stress further boost microglia activation and inflammatory factors in the mPFC region of mice following adolescent stress. LIMITATIONS: The specific neural circuits and mechanisms by which microglia regulate depression-like behaviors require further investigation. CONCLUSIONS: Our findings provide a novel insight into developmental risk factors and biological mechanisms in depression and anxiety disorders.

Strontium Alleviates Endoplasmic Reticulum Stress in a Nonalcoholic Fatty Liver Disease Model.

The purpose of this study was to explore the effects of strontium on fatty liver, and to clarify the possible mechanisms by which strontium improves nonalcoholic fatty liver disease (NAFLD). We also evaluated how strontium affected the endoplasmic reticulum stress (ERS) pathways. We established an in vitro model of NAFLD using a human hepatocyte cell line (L02) treated with 0.2 mM palmitic acid. The Sprague-Dawley rats were fed with a high-fat diet (HFD) to establish NAFLD model in vivo. After strontium treatment, the total cholesterol (TC), triglyceride (TG), and lipid deposition in L02 cells and liver tissues were determined. Strontium treatment suppressed intracellular TC and TG levels and lipid accumulation in L02 cells, and the effect of high concentrations of strontium were more obvious. Strontium significantly reduced the mRNA and protein expression of glucose-regulated protein 78 (GRP78), activating transcription factor 6 (ATF6), inositol requiring enzyme 1 (IRE1), SREBP cleavage activator protein (SCAP), sterol regulatory element binding protein 1c (SREBP-1c), and SREBP-2 in L02 cells. In HFD-fed rats, strontium treatment reduced serum TC, TG, and low density lipoprotein cholesterol (LDL-C) levels, concurrent with a decrease in hepatic lipid accumulation. Furthermore, strontium treatment reduced the expression of GRP78 and SREBP-2 protein in liver tissues. Overall, strontium alleviated hepatic steatosis by decreasing ERS-related protein expression in vivo and in vitro models. The results indicated that strontium has the potential to become a new therapy for the prevention and treatment of NAFLD.

[Effects of Rb1 and Rg1 on the expression of Bcl-2, Bax in apoptosis of HK-2 cells induced by the serum of kidney ischemia/reperfusion].

AIM: To explore effects of Ginsenosides (Rb1, Rg1) on the expression of Bcl-2, Bax in the serum of kidney ischemia/reperfusion inducing apoptosis of HK-2 cells. METHODS: The serum of rabbits with renal ischemia/reperfusion (SIR) and the control serum of rabbits (SC) were acquired and cultured with HK-2 cells. Detected apoptosis with TUNEL assay. The experiment was designed as: control group,ischemia/ reperfusion group, Rb1 blocking group and Rg1 blocking group. To detect the expression of Bcl-2, Bax with immunocytochemistry after 24 hours' cultured. RESULTS: The expression of Bax in Rb1 blocking group and Rg1 blocking group were significantly decreased (P < 0.01), the ratios of Bcl-2/Bax were increased as compared with ischemia/reperfusion group. CONCLUSION: Rb1 and Rg1 have protective effects on apoptosis of HK-2 cells induced by serum of kidney ischemia/reperfusion.

[Study on the effect of volume expansion by 0.9% and 1.8% sodium solution on cardiac-renal reflex in rabbits].

AIM: To study the effect of volume expansion by 0.9% and 1.8% sodium solution on cardiac-renal reflex activity and the role of cardiac-renal reflex in the regulation of integrated function. METHODS: 18 health pentobarbital-anaesthetized rabbits were divided evenly into 2 groups at random, bilateral sino-aortic denervation, intubated via right jugular vein to monitor CVP, left renal nerve separated and ending sectioned to record ERSNA, bilateral ureter intubated to collect urine, right femoral intubated to get blood sample. 15% of whole body blood volume of 0.9% and 1.8% sodium solution were injected via jugular vein 10 ml per minute respectively. The CVP, ERSNA, bilateral urine volume and coefficient of sodium excretion were measured before treated, during treated, one minute, five minutes and ten minutes after treated. RESULTS: Volume expansion by 0.9% and 1.8% sodium solution respectively resulted in the increase of CVP by 64.00% +/- 15.56% and 77.00% +/- 23.74%; the decrease of the frequency of ERSNA by 44.00% +/- 13.64% and 63.00% +/- 12.49%, the average burst time of ERSNA by 37.00% +/- 16.49% and 31.00% +/- 10.69%, the increase of average interval of ERSNA bursts by 60.00% +/- 18.38% and 68.00% +/- 27.04%; the increase of urine volume by 158.00% +/- 28.10% and 640.00% +/- 155.39% in left kidney, 192.00% +/- 32.26% and 1343.00% +/- 429.95% in the right; the increase of coefficient of sodium excretion by 132.00% +/- 35.23% and 376.00% +/- 121.72% in the left, 300.00% +/- 76.99% and 856.00% +/- 261.48% in the right. CONCLUSION: Volume expansion by different solution stimulate the receptors of cardiopulmonary and regulate the water and sodium excretion of the kidney by the cardiac-renal reflex to modulate the stabilization of blood volume.