Regulation of dopamine system responsivity and its adaptive and pathological response to stress

Although, historically, the norepinephrine system has attracted the majority of attention in the study of the stress response, the dopamine system has also been consistently implicated. It has long been established that stress plays a crucial role in the pathogenesis of psychiatric disorders. However, the neurobiological mechanisms that mediate the stress response and its effect in psychiatric diseases are not well understood. The dopamine system can play distinct roles in stress and psychiatric disorders. It is hypothesized that, even though the dopamine (DA) system forms the basis for a number of psychiatric disorders, the pathology is likely to originate in the afferent structures that are inducing dysregulation of the DA system. This review explores the current knowledge of afferent modulation of the stress/DA circuitry, and presents recent data focusing on the effect of stress on the DA system and its relevance to psychiatric disorders.     

A Novel Peroxisome Proliferator-activated Receptor (PPAR)α Agonist and PPARγ Antagonist,Z-551, Ameliorates High-fat Diet-induced Obesity and Metabolic Disorders in Mice

A novel peroxisome proliferator-activated receptor (PPAR) modulator, Z-551, having both PPARα agonistic and PPARγ antagonistic activities, has been developed for the treatment of obesity and obesity-related metabolic disorders. We examined the effects of Z-551 on obesity and the metabolic disorders in wild-type mice on the high-fat diet (HFD). In mice on the HFD, Z-551 significantly suppressed body weight gain and ameliorated insulin resistance and abnormal glucose and lipid metabolisms. Z-551 inhibited visceral fat mass gain and adipocyte hypertrophy, and reduced molecules involved in fatty acid uptake and synthesis, macrophage infiltration, and inflammation in adipose tissue. Z-551 increased molecules involved in fatty acid combustion, while reduced molecules associated with gluconeogenesis in the liver. Furthermore, Z-551 significantly reduced fasting plasma levels of glucose, triglyceride, free fatty acid, insulin, and leptin. To elucidate the significance of the PPAR combination, we examined the effects of Z-551 in PPARα-deficient mice and those of a synthetic PPARγ antagonist in wild-type mice on the HFD. Both drugs showed similar, but weaker effects on body weight, insulin resistance and specific events provoked in adipose tissue compared with those of Z-551 as described above, except for lack of effects on fasting plasma triglyceride and free fatty acid levels. These findings suggest that Z-551 ameliorates HFD-induced obesity, insulin resistance, and impairment of glucose and lipid metabolisms by PPARα agonistic and PPARγ antagonistic activities, and therefore, might be clinically useful for preventing or treating obesity and obesity-related metabolic disorders such as insulin resistance, type 2 diabetes, and dyslipidemia.     

Modulation of PPAR subtype selectivity. Part 2: Transforming PPARα/γ dual agonist into α selective PPAR agonist through bioisosteric modification

A novel series of oxime containing benzyl-1,3-dioxane-r-2-carboxylic acid derivatives (6a-k) were designed as selective PPARα agonists, through bioisosteric modification in the lipophilic tail region of PPARα/γ dual agonist. Some of the test compounds (6a, 6b, 6c and 6f) showed high selectivity towards PPARα over PPARγ in vitro. Further, highly potent and selective PPARα agonist 6c exhibited significant antihyperglycemic and antihyperlipidemic activity in vivo, along with its improved pharmacokinetic profile. Favorable in-silico interaction of 6c with PPARα binding pocket correlate its in vitro selectivity profile toward PPARα over PPARγ. Together, these results confirm discovery of novel series of oxime based selective PPARα agonists for the safe and effective treatment of various metabolic disorders.     

Synthesis and biological activity of a novel class nicotinic acetylcholine receptors (nAChRs) ligands structurally related to anatoxin-a

The introduction of the isoxazole ring as bioisosteric replacement of the acetyl group of anatoxin-a led to a new series of derivatives binding to nicotinic acetylcholine receptors. Bulkier substitutions than methyl at the 3 position of isoxazole were shown to be detrimental for the activity. The binding potency of the most interesting compounds with α1, α7 and α3β4 receptor subtypes, was, anyway, only at micromolar level. Moreover, differently from known derivatives with pyridine, isoxazole condensed to azabicyclo ring led to no activity.     

In vitro and in vivo evaluation of 6-aminopyrazolyl-pyridine-3-carbonitriles as JAK2 kinase inhibitors

Synthesis and biological evaluation of a series of 6-aminopyrazolyl-pyridine-3-carbonitriles as JAK2 kinase inhibitors was reported. Biochemical screening, followed by profile optimization, resulted in JAK2 inhibitors exhibiting good kinase selectivity, pharmacokinetic properties, physical properties and pharmacodynamic effects.     

注意缺陷多动障碍低觉醒模型的新证据

注意缺陷多动障碍（Attention Deficit Hyperactivity Disorder,ADHD）是儿童期常见的一种发展性的异常,其病因及发生机理至今未明。低觉醒模型是ADHD成因的一种假设。本文从睡眠障碍导致的低觉醒探讨ADHD发生机理。通过对ADHD儿童的睡眠障碍进行分析以及将ADHD外在表现与睡眠剥夺后的表现进行对比分析,得出ADHD儿童存在的低觉醒是由于外显的或内隐的睡眠障碍引起的,一方面间接证明了低觉醒模型,另一方面为ADHD的成因研究开拓了新的思路。     

Targeted Training of Ultrasonic Vocalizations in Aged and Parkinsonian Rats

Voice deficits are a common complication of both Parkinson disease (PD) and aging; they can significantly diminish quality of life by impacting communication abilities. ^{1, 2} Targeted training (speech/voice therapy) can improve specific voice deficits,^{3, 4} although the underlying mechanisms of behavioral interventions are not well understood. Systematic investigation of voice deficits and therapy should consider many factors that are difficult to control in humans, such as age, home environment, age post-onset of disease, severity of disease, and medications. The method presented here uses an animal model of vocalization that allows for systematic study of how underlying sensorimotor mechanisms change with targeted voice training. The ultrasonic recording and analysis procedures outlined in this protocol are applicable to any investigation of rodent ultrasonic vocalizations.The ultrasonic vocalizations of rodents are emerging as a valuable model to investigate the neural substrates of behavior.^5-8 Both rodent and human vocalizations carry semiotic value and are produced by modifying an egressive airflow with a laryngeal constriction.^{9, 10} Thus, rodent vocalizations may be a useful model to study voice deficits in a sensorimotor context. Further, rat models allow us to study the neurobiological underpinnings of recovery from deficits with targeted training.To model PD we use Long-Evans rats (Charles River Laboratories International, Inc.) and induce parkinsonism by a unilateral infusion of 7 μg of 6-hydroxydopamine (6-OHDA) into the medial forebrain bundle which causes moderate to severe degeneration of presynaptic striatal neurons (for details see Ciucci, 2010).^{11, 12} For our aging model we use the Fischer 344/Brown Norway F1 (National Institute on Aging).Our primary method for eliciting vocalizations is to expose sexually-experienced male rats to sexually receptive female rats. When the male becomes interested in the female, the female is removed and the male continues to vocalize. By rewarding complex vocalizations with food or water, both the number of complex vocalizations and the rate of vocalizations can be increased (Figure 1).An ultrasonic microphone mounted above the male''s home cage records the vocalizations. Recording begins after the female rat is removed to isolate the male calls. Vocalizations can be viewed in real time for training or recorded and analyzed offline. By recording and acoustically analyzing vocalizations before and after vocal training, the effects of disease and restoration of normal function with training can be assessed. This model also allows us to relate the observed behavioral (vocal) improvements to changes in the brain and neuromuscular system.     

咬合运动与注射醋酸泼尼松龙治疗滑膜炎的疗效比较

目的:比较咬合运动和关节下腔注射醋酸泼尼松龙治疗颞下颌关节滑膜炎的临床效果。方法:选择牙列完整、无第三磨牙阻生、符合颞下颌关节滑膜炎诊断标准的120例患者,随机分为实验组和对照组,每组60例。实验组行咬合运动,每次3-4个循环,每日3-4次,治疗周期为12个月;对照组给予醋酸泼尼松龙0.0125g+0.5ml2%利多卡因关节下腔注射一次,比较两种方法的治疗效果。结果:实验组的60例患者均在治疗后1-2w疼痛消失,追踪3-12个月无复发。对照组的60例患者,2个周后有18例无效,无效率为30%,两组比较其结果有显著性差异(P<0.001);3个月后有22例无效,无效率为36.67%,两组比较其结果有显著性差异(P<0.001)。结论:咬合运动组的治疗效果显著高于醋酸泼尼松龙注射组,咬合运动能有效的治疗滑膜炎并减少患者的治疗痛苦。