Positive AMPA receptor modulation in the treatment of neuropsychiatric disorders: A long and winding road

Glutamatergic transmission is widely implicated in neuropsychiatric disorders, and the discovery that ketamine elicits rapid-acting antidepressant effects by modulating α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPAR) signaling has spurred a resurgence of interest in the field. This review explores agents in various stages of development for neuropsychiatric disorders that positively modulate AMPARs, both directly and indirectly. Despite promising preclinical research, few direct and indirect AMPAR positive modulators have progressed past early clinical development. Challenges such as low potency have created barriers to effective implementation. Nevertheless, the functional complexity of AMPARs sets them apart from other drug targets and allows for specificity in drug discovery. Additional effective treatments for neuropsychiatric disorders that work through positive AMPAR modulation may eventually be developed.     

Procedures for Assessing Change After Alcoholism Treatment

No abstract available for this article.     

丙泊酚合用氯胺酮在小儿腹部以下手术麻醉中的疗效观察

目的探讨丙泊酚单独使用及与氯胺酮合用在小儿椎管内麻醉中的疗效。方法选取我科40名腹部以下手术的患儿,随机分为两组(Ⅰ组和Ⅱ组),分别以单独使用丙泊酚及联合氯胺酮给药的方式,记录术中生命体征及不良事件情况。术后记录恶心、呕吐等不适及疼痛评分。结果两组术中均无呼吸暂停等严重事件发生,手术开始及手术开始后各时段Ⅰ组的生命体征均有显著差异(P<0.05),Ⅱ组手术开始时的收缩压与手术前有显著差异(P<0.05)。两组术后恢复时间与不适发生无显著差异(P>0.05),Ⅱ组术后镇痛效果优于Ⅰ组(P<0.05)。结论丙泊酚合用氯胺酮能够提供更平稳的镇静效果,减轻不良反应的发生,同时不影响苏醒时间,术后不良反应及疼痛发生率较低,是一种理想的小儿椎管内麻醉方法。     

氯胺酮麻醉前不同时间肌内注射阿托品对小儿呼吸道的影响

目的探讨氯胺酮麻醉前不同时间肌内注射阿托品对小儿呼吸道的影响。方法将2012年1月至2013年6月在廊坊市第四人民医院住院的100例患儿按随机数字表法分为两组:A组(50例)于氯胺酮麻醉前30~60 min肌内注射阿托品(0.02 mg/kg),B组(50例)阿托品(0.02 mg/kg)与氯胺酮同时间肌内注射。两组患儿均于氯胺酮肌内注射2~4 min后入室准备手术,术中观察记录两组患儿呼吸道和肺部的听诊变化及脉搏血氧饱和度(Sp O2)变化。结果 A组Ⅰ级(即呼吸道未受影响)44例,Ⅱ级以上(即呼吸道受到不同程度影响)6例,阳性率为12%(6/50);B组Ⅰ级33例,Ⅱ级以上17例,阳性率为34%(17∕50)。两组患儿呼吸道受影响程度的比较,差异有统计学意义(P<0.01)。结论小儿氯胺酮麻醉前30 min肌内注射阿托品,能有效降低氯胺酮对患儿呼吸道的影响,提高术中患儿的安全系数。     

不同麻醉药物在人工流产术麻醉时的效果及对呼吸循环的影响

目的探讨不同麻醉药物在人工流产术麻醉时的效果及其对呼吸循环的影响。方法选择2012年3月至2013年3月南宁市第六人民医院收治的拟行人工流产术的患者248例,采用随机数字表法分为四组,分别采用单纯丙泊酚、丙泊酚复合芬太尼、丙泊酚复合瑞芬太尼、丙泊酚复合氯胺酮麻醉,然后对四组患者的镇痛效果、各组麻醉药物的总用量及对呼吸、循环系统的影响进行评价。结果四组人流患者术中及术后镇痛效果比较,差异具有统计学意义(H=16.944,24.072,P<0.05)。丙泊酚复合瑞芬太尼麻醉组麻醉药物用量显著地少于其他三组(P<0.05),四组患者术前、术中、术后的心率和血氧饱和度组间及组间·不同时点间比较无统计学意义(P>0.05),不同时点间比较具有统计学意义(P<0.05);四组患者术中心率明显地低于术前及术后,术前、术后比较差异不显著;患者术前血氧饱和度明显地高于术中及术后,术中、术后比较变化不显著。结论丙泊酚复合麻醉是较理想的麻醉方法,建议根据患者的情况选择不同的复合麻醉药物。     

Effects of ketamine administration on mTOR and reticulum stress signaling pathways in the brain after the infusion of rapamycin into prefrontal cortex

Recent studies show that activation of the mTOR signaling pathway is required for the rapid antidepressant actions of glutamate N-methyl-D-aspartate (NMDA) receptor antagonists. A relationship between mTOR kinase and the endoplasmic reticulum (ER) stress pathway, also known as the unfolded protein response (UPR) has been shown. We evaluate the effects of ketamine administration on the mTOR signaling pathway and proteins of UPR in the prefrontal cortex (PFC), hippocampus, amygdala and nucleus accumbens, after the inhibiton of mTOR signaling in the PFC. Male adult Wistar rats received pharmacological mTOR inhibitor, rapamycin (0.2 nmol), or vehicle into the PFC and then a single dose of ketamine (15 mg/kg, i.p.). The immunocontent of mTOR, eukaryotic initiation factor 4E-binding protein 1 (4E-BP1), eukaryotic elongation factor 2 kinase (eEF2K) homologous protein (CHOP), PKR-like ER kinase (PERK) and inositol-requiring enzyme 1 (IRE1) – alpha were determined in the brain. The mTOR levels were reduced in the rapamycin group treated with saline and ketamine in the PFC; p4EBP1 levels were reduced in the rapamycin group treated with ketamine in the PFC and nucleus accumbens; the levels of peEF2K were increased in the PFC in the vehicle group treated with ketamine and reduced in the rapamycin group treated with ketamine. The PERK and IRE1-alpha levels were decreased in the PFC in the rapamycin group treated with ketamine. Our results suggest that mTOR signaling inhibition by rapamycin could be involved, at least in part, with the mechanism of action of ketamine; and the ketamine antidepressant on ER stress pathway could be also mediated by mTOR signaling pathway in certain brain structures.