Thalamic taste nuclei lesions and taste aversion

Rats with thalamic taste nuclei lesions were adapted to a 23 hr 50 min deprivation schedule and then presented with 0.125 percent saccharin followed by an injection of LiCl or saline. When retested with saccharin, animals with lesions showed a marked attenuation in taste aversion as compared to controls.     

氯化锂增加获得性耐药人肺癌细胞系H460R对TRAIL的敏感性

目的:通过人工诱导建立肿瘤坏死因子相关凋亡诱导配体(TRAIL)获得性耐药的肺癌细胞系,氯化锂联合rhTRAIL作用细胞,以期了解氯化锂增敏TRAIL的现象及机制。方法:通过低剂量rhTRAIL诱导人肺大细胞癌细胞系H460,建立TRAIL耐药细胞株H460R并鉴定,应用MTT和流式细胞术分析氯化锂和rhTRAIL联合给药后亲本株与耐药株细胞增殖和凋亡差异,应用RT-PCR和Western blot检测死亡受体表达。结果:rhTRAIL处理亲本株H460和耐药株H460R后细胞存活率存在显著差异(P<0.01),IC50分别为59.2ng/ml和294.8ng/ml。60ng/ml rhTRAIL处理耐药株及亲本株后平均细胞凋亡比例存在显著差异(10.5%vs 19.4%,P<0.01),耐药株表现出显著的TRAIL耐受现象。但联合20mmol/L氯化锂后,MTT及流式细胞术检测耐药株细胞增殖及凋亡发现H460R对rhTRAIL的敏感性显著增加。进一步研究发现死亡受体DR4和DR5的mRNA及蛋白水平升高,这可能是药物增敏的机制之一。结论:氯化锂能够增加获得性耐药细胞系H460R对TRAIL的敏感性,死亡受体表达增加是可能的增敏机制之一。     

GSK-3β抑制剂LiCl干预大鼠重症急性胰腺炎的量效关系

目的 探讨糖原合成酶激酶-3β(GSK-3β)抑制剂氯化锂(LiCl)干预大鼠重症急性胰腺炎(SAP)的量效关系.方法 50只SPF级雄性Wistar大鼠,按数字表法随机分为五组(n=10):假手术组(SO组)、重症急性胰腺炎组(SAP组)、LiCl 40 mg/kg组、60 mg/kg组和80 mg/kg预处理组(LiCl组).胆胰管逆行注射5%牛磺胆酸钠溶液(0.1 mL/100 g)制备SAP大鼠模型;SO组在胆胰管内注射等量生理盐水替代牛磺胆酸钠.LiCl组造模前30 min经股静脉注射相应浓度LiCl.术后12 h分批处死大鼠,检测血清淀粉酶(AMY)、谷丙转氨酶(ALT)、肌酐(Cr)、腹水量和肺湿干比.光镜下观察胰腺组织病理学变化并进行病理学评分.结果 SAP组大鼠AMY、ALT、Cr、腹水量、肺湿干比、胰腺病理评分均较SO组升高[(7224.14±1872.41)U/L vs(1780.21±231.12)U/L、(250.56±51.56)U/L vs(98.45±10.36)U/L、(85±19)U/L vs(36±4)U/L、(11.05±2.76)g vs(0.33±0.04)g、(3.21±0.61)vs(1.60±0.20)、(11.52±1.23)分vs(0.54±0.02)分],差异均具有统计学意义(P<0.05);LiCl 60 mg/kg组上述指标与SAP组相比较均有下降[(4215.36±940.24)U/L vs(7224.14±1872.41)U/L、(160.25±35.39)U/L vs(250.56±51.56)U/L、(50±11)U/L vs(85±19)U/L、(6.04±1.03)g vs(11.05±2.76)g、(2.70±0.54)vs(3.21±0.61)、(9.03±1.09)分vs(11.52±1.23)分],差异均有统计学意义(P<0.05);而LiCl 40 mg/kg组AMY、腹水量、肺湿干比以及胰腺病理评分与SAP组比较差异均无统计学意义(P>0.05);LiCl-80 mg/kg组大鼠的ALT升高大于SAP组[(312.47±69.41)U/L vs(250.56±51.56)U/L],差异有统计学意义(P<0.05),Cr水平与SAP组比较[(79±17)U/L vs(85±19)U/L]差异无统计学意义(P>0.05).结论 LiCl-60 mg/kg是干预重症急性胰腺炎大鼠模型最佳有效剂量.     

NaCl and LiCl efficacy in the induction of aversion for quinine and saccharin solutions immediately following injection

Rats 24-hr water deprived were injected IP with a fixed amount (10 ml/kg) of solutions of various concentrations of LiCl and NaCl in dosage ranges which in previous experiments either increased or had no effect on water intake. Intake of 0.01% QHCl decreased with increasing concentrations of both NaCl and LiCl. On a molar basis, LiCl was more effective. LiCl also produced an aversion to a palatable solution, 0.1% sodium saccharin; however, NaCl produced no aversion over the dosage range which can be tolerated by the animals.     

糖原合成酶激酶-3β磷酸化 促进人腹膜间皮细胞转分化的实验研究

目的：探讨糖原合成酶激酶（GSK）-3β磷酸化在人腹膜间皮细胞(HPMC)转分化中的作用。方法：从人腹膜组织中分离和培养人原代腹膜间皮细胞。观察GSK-3β抑制剂氯化锂（LiCl）对HPMC GSK-3β磷酸化的影响,在不同时间点（0,1,3,6,12 h）和不同浓度（0,5,10,20,40 mmol/L）LiCl下Western 印迹检测p-GSK-3β和总GSK-3β表达水平的变化。Western 印迹检测20 mmol/L LiCl作用HPMC不同时间,α-SMA和E-cadherin蛋白的表达。间接免疫荧光染色方法检测α-SMA的表达和分布。结果：LiCl促进HPMC GSK-3β磷酸化在一定范围内呈浓度依赖性和时间依赖性（P＜0.05）,但总GSK-3β水平不变（P＞0.05）。20 mmol/L LiCl干预HPMC 24 h后,α-SMA表达显著增高（P＜0.05）,E-cadherin表达显著下调（P＜0.05）。间接免疫荧光结果显示20 mmol/L LiCl作用24 h后α-SMA表达显著增高（P＜0.05）。结论：GSK-3β磷酸化能诱导HPMC发生上皮-间质细胞转分化,为治疗腹膜纤维化提供了新的思路。     

Drug Development Targeting the Glycogen Synthase Kinase-3β (GSK-3β)-Mediated Signal Transduction Pathway: The Role of GSK-3β in the Maintenance of Steady-State Levels of Insulin Receptor Signaling Molecules and Nav1.7 Sodium Channel in Adrenal Chromaffin Cells

Glycogen synthase kinase-3 (GSK-3) is constitutively active in nonstimulated cells, where the majority of its substrates undergo inactivation/proteolysis by phosphorylation. Extracellular stimuli (e.g., insulin) catalyze inhibitory Ser⁹-phosphorylation of GSK-3β, turning on signaling and causing other biological consequences otherwise constitutively suppressed by GSK-3β. Regulated and dysregulated activities of GSK-3β are pivotal to health, disease, and therapeutics (e.g., insulin resistance, neurodegeneration, tumorigenesis, inflammation); however, the underlying mechanisms of multifunctional GSK-3β remain elusive. In cultured bovine adrenal chromaffin cells, 1) constitutive and negatively-regulated activities of GSK-3β up- and down-regulated insulin receptor, insulin receptor substrate-1 (IRS-1), IRS-2, and Akt levels via controlling proteasomal degradation and protein synthesis; 2) nicotinic receptor/protein kinase C-α (PKC-α) / extracellular signal-regulated kinase (ERK) pathway up-regulated IRS-1 and IRS-2 levels, enhancing insulin-induced the phosphoiNOSitide 3-kinase (PI3K) / Akt / GSK-3β pathway; 3) inhibition of calcineurin by cyclosporin A or FK506 down-regulated IRS-2 level, attenuating insulin-like growth factor-I (IGF-I)-induced ERK and GSK-3β pathways; and 4) insulin, IGF-I or therapeutics (e.g., lithium) up-regulated the voltage-dependent Na_v1.7 sodium channel.     

Effects of water deprivation and prior LiCl exposure in conditioning taste aversions

The phenomenon of attenuated taste aversion conditioning following preexposure to a lithium chloride UCS was demonstrated in Experiment 1. The amount of fluid consumed during the preconditioning phase was shown to be a factor in the degree of attenuated conditioning. The pharmacological properties of LiCl, and the effects of either ad lib or restricted fluid intake in conjunction with state dependent variables were proposed to account for the results. In Experiment 2 the water scheduling and LiCl habituation procedures of Experiment 1 were replicated, and serum lithium was assessed in the various groups on conditioning day. The groups did not differ, ruling out an incremental illness hypothesis of attenuated conditioning.     

Using profiles of saccharin and water drinking to detect and discriminate actions of drugs and toxicants

Experiments were conducted to investigate the feasibility of using the pattern of saccharin and water drinking to detect acute and chronic administration of drugs and toxicants. Procedural variables were found to be crucial. When rats were naive for the saccharin drinking fluid, a single injection of LiCl or 2-deoxyglucose produced persistant saccharin aversion. Hypertonic saline produced only a transient saccharin aversion. If rats were pre-exposed to saccharin, the 2-deoxyglucose injection and hypertonic NaCl produced an increase in saccharin drinking but LiCl was without effect. Several types of chronic treatment were given to saccharin-experienced rats. Chronic 2-deoxyglucose, LiCl, and Pb administration produced gradually developing saccharin aversion and qualitatively different patterns of saccharin and water drinking. Chronic administration of hypertonic NaCl or insulin or chronic food deprivation had no impact on saccharin preference. It was concluded that patterns of saccharin and water drinking can be used to detect the administration of a drug or toxicant and perhaps even the time course of action, but may not detect a substance given previous to saccharin, perhaps because the animal cannot associate these now familiar perturbations with the novel saccharin solution. This means that existing toxic states may not be detected by using saccharin preference as a probe.     

The effects of LiCl preexposure on amphetamine-induced taste aversions: an assessment of blocking

Preexposure to lithium chloride attenuated the subsequent acquisition of amphetamine-induced taste aversions. This attenuation was independent of the similarity of the preexposure and conditioning environments, an effect inconsistent with an associative interpretation of the effects of LiCl preexposure. These results were discussed in terms of the mechanism underlying the effects of drug preexposure on taste aversion learning.     

Control of polydipsic drinking by a taste aversion procedure

Rats were given daily sessions with free access to food and saccharin flavored water. After fluid consumption had stabilized food was delivered once every minute. Water was always available in the home cage. All rats showed the marked increase in fluid consumption known as schedule-induced polydipsia. The rats were then poisoned with lithium chloride after each of three sessions in an attempt to condition a taste aversion to the saccharin. On recovery from the toxicosis all rats showed first a reduction and then a recovery in saccharin intake. To establish the nature of this effect, the rats were poisoned after saccharin consumption in the home cage. Again there was a marked reduction in polydipsic drinking in the experimental chamber. These results indicate that common incentive mechanisms govern normal and polydipsic drinking and stand in contrast to published results pointing to different drive systems in the brain mediating normal and polydipsic drinking.