Pharmaco‐electroencephalographic responses in the rat differ between active and inactive locomotor states

Quantitative electroencephalography from freely moving rats is commonly used as a translational tool for predicting drug‐effects in humans. We hypothesized that drug‐effects may be expressed differently depending on whether the rat is in active locomotion or sitting still during recording sessions, and proposed automatic state‐detection as a viable tool for estimating drug‐effects free of hypo‐/hyperlocomotion‐induced effects. We aimed at developing a fully automatic and validated method for detecting two behavioural states: active and inactive, in one‐second intervals and to use the method for evaluating ketamine, DOI, d‐cycloserine, d‐amphetamine, and diazepam effects specifically within each state. The developed state‐detector attained high precision with more than 90% of the detected time correctly classified, and multiple differences between the two detected states were discovered. Ketamine‐induced delta activity was found specifically related to locomotion. Ketamine and DOI suppressed theta and beta oscillations exclusively during inactivity. Characteristic gamma and high‐frequency oscillations (HFO) enhancements of the NMDAR and 5HT_2A modulators, speculated associated with locomotion, were profound and often largest during the inactive state. State‐specific analyses, theoretically eliminating biases from altered occurrence of locomotion, revealed only few effects of d‐amphetamine and diazepam. Overall, drug‐effects were most abundant in the inactive state. In conclusion, this new validated and automatic locomotion state‐detection method enables fast and reliable state‐specific analysis facilitating discovery of state‐dependent drug‐effects and control for altered occurrence of locomotion. This may ultimately lead to better cross‐species translation of electrophysiological effects of pharmacological modulations.     

Differential impacts on multiple forms of spatial and contextual memory in diazepam binding inhibitor knockout mice

Learning and memory are fundamental processes that are disrupted in many neurological disorders including Alzheimer’s disease and epilepsy. The hippocampus plays an integral role in these functions, and modulation of synaptic transmission mediated by γ-aminobutyric acid (GABA) type-A receptors (GABA_ARs) impacts hippocampus-dependent learning and memory. The protein diazepam binding inhibitor (DBI) differentially modulates GABA_ARs in various brain regions, including hippocampus, and changes in DBI levels may be linked to altered learning and memory. The effects of genetic loss of DBI signaling on these processes, however, have not been determined. In these studies, we examined male and female constitutive DBI knockout mice and wild-type littermates to investigate the role of DBI signaling in modulating multiple forms of hippocampus-dependent spatial learning and memory. DBI knockout mice did not show impaired discrimination of objects in familiar and novel locations in an object location memory test, but did exhibit reduced time spent exploring the objects. Multiple parameters of Barnes maze performance, testing the capability to utilize spatial reference cues, were disrupted in DBI knockout mice. Furthermore, whereas most wild-type mice adopted a direct search strategy upon learning the location of the target hole, knockout mice showed higher rates of using an inefficient random strategy. In addition, DBI knockout mice displayed typical levels of contextual fear conditioning, but lacked a sex difference observed in wild-type mice. Together, these data suggest that DBI selectively influences certain forms of spatial learning and memory, indicating novel roles for DBI signaling in modulating hippocampus-dependent behavior in a task-specific manner.     

Cognitive interference as a possible therapeutic strategy to prevent expression of benzodiazepine withdrawal

Benzodiazepines are usually prescribed for anxiety and sleep disorders in long‐term schedules that may cause drug dependence. Discontinuation after prolonged administration may lead to withdrawal expression, being anxiety the most predominant sign. The context‐dependent associative learning process that underlies diazepam dependence can be interfered by pre‐exposure to the drug administration context, an effect known as latent inhibition. Considering this background, the primary aim of the present investigation is to develop a therapeutic strategy to prevent diazepam withdrawal in male Wistar rats by interfering with this learning process. Nitric oxide is a crucial player in learning and memory, hippocampal synaptic transmission and in diazepam withdrawal. Then, a secondary goal is to determine how latent inhibition could alter functional plasticity and neuronal nitric oxide synthase enzyme (NOS‐1) expression within the hippocampus, by using multi‐unitary cell recordings and Western blot, respectively. Our results indicate that chronic diazepam treated animals under latent inhibition did not show anxiety, or changes in hippocampal synaptic transmission, but a significant reduction in NOS‐1 expression was observed. Accordingly, pharmacological NOS‐1 inhibition resembles behavioral and electrophysiological changes induced by latent inhibition. Contrary, diazepam treated animals under Control protocol expressed anxiety and evidenced an increased hippocampal‐plasticity, without alterations in NOS‐1 expression. In conclusion, manipulation of the contextual cues presented during diazepam administration may be considered as an effective non‐pharmacological tool to prevent the withdrawal syndrome. This behavioral strategy may influence hippocampal synaptic transmission, probably by alterations in nitric oxide signaling pathways in this structure.     

睡眠宝胶囊中非法掺入化学药品的检测方法研究

目的 建立薄层色谱结合超高压液相色谱-质谱联用法快速筛查及鉴定睡眠宝胶囊中非法掺加的氯氮平、地西泮、艾司唑仑。方法 采用硅胶GF254板,乙酸乙酯-无水乙醇-氨水(50∶2∶0.5)为展开剂,在254 nm下检视。色谱条件为：Aglient ZORBAX SB C₁₈柱(100 mm×2.1 mm,1.8 μm),流动相20 mmol·L^-1醋酸铵溶液-甲醇(50∶50),流速0.3 mL·min^-1,检测波长225 nm,柱温35 ℃,正离子扫描检测。结果 睡眠宝胶囊非法掺入氯氮平、地西泮、艾司唑仑在254 nm下显明显的斑点,通过UPLC-PDA-Q TOF MS可进一步快速确证。结论 本方法操作简便,结果可靠,可用于快速筛查及确证睡眠宝胶囊中非法掺入氯氮平、地西泮及艾司唑仑。     

Sleep spindle dynamics during NREM and REM sleep following distinct general anaesthesia in control rats and in a rat model of Parkinson’s disease cholinopathy

On the basis of our previous studies and the important role of the thalamo‐cortical network in states of unconsciousness, such as anaesthesia and sleep, and in sleep spindles generation, we investigated sleep spindles (SS) and high‐voltage sleep spindle (HVS) dynamics during non‐rapid eye movement (NREM) and rapid eye movement (REM) sleep following different types of general anaesthesia in both physiological controls and in a rat model of Parkinson's disease (PD) cholinopathy, to follow the impact of anaesthesia on post‐anaesthesia sleep at the thalamo‐cortical level through an altered sleep spindle dynamics. We recorded 6 hr of spontaneous sleep in all rats, both before and 48 hr after ketamine/diazepam or pentobarbital anaesthesia, and we used 1 hr of NREM or REM sleep from each to validate visually the automatically detected SS or HVS for their extraction and analysis. In the controls, SS occurred mainly during NREM, whereas HVS occurred only during REM sleep. Ketamine/diazepam anaesthesia promoted HVS, prolonged SS during NREM, induced HVS of increased frequency during REM, and increased SS/HVS densities during REM versus NREM sleep. Pentobarbital anaesthesia decreased the frequency of SS during NREM and the HVS density during REM sleep. Although the pedunculopontine tegmental nucleus lesion prolonged SS only during NREM sleep, in these rats, ketamine/diazepam anaesthesia suppressed HVS during both sleep states, whereas pentobarbital anaesthesia promoted HVS during REM sleep. The different impacts of two anaesthetic regimens on the thalamo‐cortical regulatory network are expressed through their distinct sleep spindle generation and dynamics that are dependent on the NREM and REM state regulatory neuronal substrate.     

安定配合硬膜外阻滞镇痛分娩的临床研究

目的:探讨产程活跃期应用安定加低浓度、小剂量、局麻药甲磺酸罗哌卡因及舒芬太尼实施自控镇痛泵镇痛分娩方法及对产程和母婴的影响。方法:实验组采取活跃期安定缓慢静脉推注联合低浓度、小剂量的1.192%甲磺酸罗哌卡因复合舒芬太尼实施硬膜外阻滞,微量自控泵给药的镇痛分娩;对照组自然分娩;两组比较分析。结果:实验组产妇第一产程平均时间(186.46±8.52)min、自然分娩率增91.25%、剖宫产率6.25%。产妇身心状态评估:宫缩时表情自然73例,心率、血压平稳,宫缩无影响。对照组产妇第一产程平均时间(270.68±12.34)min、自然分娩率66.25%、剖宫产率28.75%,产妇身心状态评估表情自然12例(P<0.01);心率、血压增快,具有统计学意义(P<0.05)。结论:安定配合硬膜外阻滞镇痛分娩的效果好,能缩短产程,降低剖宫产率,保持产妇良好的心态,提高产科质量,是比较理想的分娩镇痛方法。     

Midazolam andDiazepam for Pediatric Seizures in the Prehospital Setting

Objective. The objective of this study was to compare the efficacy andadverse events associated with the use of diazepam andmidazolam for the treatment of pediatric seizures in the prehospital setting. Methods. This was a retrospective cohort study of all patients younger than 18 years treated for a seizure with a benzodiazepine by emergency medical services in Multnomah County, Oregon, from 1998 to 2001. The emergency medical services system consists of a single private advanced life support transporting ambulance service with fire department first responders that are all advanced life support capable. The benzodiazepine used changed from diazepam to midazolam at the midpoint of this period. The primary outcomes were termination of the seizure by arrival to the emergency department (ED), recurrence of seizure while in the ED, or the requirement for active airway interventions including intubation. The two cohorts were also compared for demographics, past history of seizures, long-term use of seizure medications, response times, route of administration, use of second doses of benzodiazepines, andfinal disposition. Results. Forty-five patients were treated with diazepam, and48 were treated with midazolam. The two cohorts were comparable except the diazepam cohort had a significantly increased proportion of patients with previous afebrile seizures (53% vs. 25%; p = 0.005). The midazolam cohort had an increased use of nonintravenous route for initial dosing (65% vs. 42%; p = 0.02). The two cohorts were equivalent in rates of termination of seizures before to ED arrival, recurrence of seizures in the ED, requiring airway support or a second dose of benzodiazepine, andadmission to the hospital. Conclusions. Diazepam andmidazolam appear to be equivalent in treating seizures andcausing adverse events. Paramedics appear to be administering midazolam intramuscularly more often than they use diazepam rectally.     

Respiratory effects of buprenorphine/naloxone alone and in combination with diazepam in naive and tolerant rats

Respiratory depression has been attributed to buprenorphine (BUP) misuse or combination with benzodiazepines. BUP/naloxone (NLX) has been marketed as maintenance treatment, aiming at preventing opiate addicts from self-injecting crushed pills. However, to date, BUP/NLX benefits in comparison to BUP alone remain debated. We investigated the plethysmography effects of BUP/NLX in comparison to BUP/solvent administered by intravenous route in naive and BUP-tolerant Sprague-Dawley rats, and in combination with diazepam (DZP) or its solvent. In naive rats, BUP/NLX in comparison to BUP significantly increased respiratory frequency (f, P < 0.05) without altering minute volume (V_E). In combination to DZP, BUP/NLX significantly increased expiratory time (P < 0.01) and decreased f (P < 0.01), tidal volume (V_T, P < 0.001), and V_E (P < 0.001) while BUP only decreased V_T (P < 0.5). In BUP-tolerant rats, no significant differences in respiratory effects were observed between BUP/NLX and BUP. In contrast, in combination to DZP, BUP/NLX did not significantly alter the plethysmography parameters, while BUP increased inspiratory time (P < 0.001) and decreased f (P < 0.01) and V_E (P < 0.001). In conclusion, differences in respiratory effects between BUP/NLX and BUP are only significant in combination with DZP, with increased depression in naive rats but reduced depression in BUP-tolerant rats. However, BUP/NLX benefits in humans remain to be determined.     

复方樟柳碱联合地西泮治疗眼睑痉挛的临床疗效与安全性

目的 观察复方樟柳碱联合地西泮注射治疗眼睑痉挛的临床疗效与安全性。方法 分析眼睑痉挛患者48例 52只眼,随机分为研究组与对照组,每组 24例 26只眼;记录眼睑痉挛分级。研究组给予患眼复方樟柳碱 2 mL 颞浅动脉旁注射联合地西泮0.5 mL眼轮匝肌注射。复方樟柳碱每日1次,连续14 d。地西泮每周1次,连续3次。对照组口服甲钴胺片 0.5 mg,每日 3次,连续 14 d。配合充足休息与心情放松。评估 2组的治疗后眼睑痉挛分级、总有效率、复发率与安全性。结果 研究组治疗后完全缓解率、明显缓解率、部分缓解率分别为42.31%、30.77%、19.23%, 对照组分别为15.38%、23.08%、26.92%,差异有统计学意义（Z=-2.829,P＜0.01）。研究组总有效率为92.31%,对照组总有效率为65.38%,差异有统计学意义（χ2=5.650,P＜0.05）。研究组复发率为7.69%,对照组复发率为38.46%,差异有统计学意义（χ2＝6.933,P＜0.01）。研究组眼睑皮下淤血发生率为19.23%,对照组眼睑皮下淤血发生率为11.54%,差异无统计学意义（χ2＝0.148,P＞0.05）。2组均未见严重不良反应或并发症。结论 复方樟柳碱联合地西泮注射可以安全有效地治疗眼睑痉挛,是眼睑痉挛的简单经济有效的治疗方法。     

低剂量奥氮平合并地西冸治疗酒精使用障碍的疗效和不良反应分析

目的：探讨低剂量奥氮平合并地西冸治疗酒精使用障碍的疗效和安全性。方法：将 2013 年 1 月～2018 年 12 月 60 例酒精使用障碍患者按照随机数字表法分为对照组(n=30)与观察组(n=30)。对照组采用营养支持治疗以及地西泮治疗,观察组则采用低剂量奥氮平合并地西冸治疗。对比两组患者的临床疗效及患者的低血压、便秘、 头痛、体质量增加、锥体外系反应及嗜睡等不良发应的发生率。结果：对照组治疗有效率为 73.33%,观察组治疗有效率为 93.3%,观察组治疗效果显著好于对照组(P＜0.05);观察组患者的身体质量、低血压及锥体外系反应均高于对照组;但患者出现嗜睡、便秘及头痛的不良发应发生率相当,差异无统计学意义(P>0.05)。结论：低剂量奥氮平合并地西冸治疗酒精使用障碍疗效相比于单独使用地西冸疗效更好,可以在临床上推广。