Lack of persistent effects of ketamine in rodent models of depression

RATIONALE: We investigated the immediate and enduring effects of ketamine in behavioral and neurochemical assays predictive of antidepressant activity. MATERIALS AND METHODS: One week after a single administration of ketamine (50-160 mg/kg), otherwise experimentally naive rats and mice were tested either in the forced swim test (FST) or the tail suspension test (TST). Other mice were also tested twice in the FST: immediately and 2 weeks after a single dose (1.25-50 mg/kg) of ketamine. In the next series of experiments, rats treated for 2 weeks twice daily with ketamine (50 or 160 mg/kg) or desipramine (10 mg/kg) were challenged with apomorphine and scored for locomotor activity and assayed for the density of cortical beta-adrenoceptors. The latter test was also carried out in rats that had received a single dose of ketamine (50 mg/kg) 1 week before the assay. The antidepressant-like (FST) and locomotor effects of ketamine (50 mg/kg) and desipramine (10 mg/kg) were assessed after their chronic (2 weeks, twice daily) administration as well. RESULTS: We report the lack of enduring antidepressant-like effect of ketamine in both rats and mice. A 2-week treatment with ketamine neither changed apomorphine-evoked locomotor hyperactivity nor did it decrease the density of cortical beta-adrenoceptors. However, some tolerance to the antidepressant-like effect of ketamine was noted in the FST, but it was accompanied by sensitization to its locomotor stimulatory effects. CONCLUSIONS: These data indicate that ketamine neither produces enduring antidepressant-like effects in rodents nor does it display antidepressant-like behavioral or neurochemical effects after chronic treatment.     

Effects of chronic ketamine use on frontal and medial temporal cognition

Background

Recreational ketamine use has been on the rise worldwide. Previous studies have demonstrated that it disrupts various memory systems, but few studies have examined how it affects learning and frontal functioning. The present study investigates the effects of repeated ketamine self-administration on frontal fluency, attention, learning, and memory along the verbal/nonverbal axis.

Methods

Twenty-five ketamine users and 30 healthy controls took a battery of neuropsychological tests. Frontal fluency was measured by the Verbal Fluency Test for semantic organization ability and the Figural Fluency Test for nonverbal executive functioning. Learning and memory were measured with the Chinese Auditory-Verbal Learning Test for acquisition and retention abilities of verbal information, as well as with the Continuous Visual Memory Test for nonverbal information. Participants also took several tests tapping subdomains of attention. To test for the potential effects of other drug use, 10 polydrug controls were included for comparison with the ketamine users and healthy controls.

Results

Ketamine users had impaired verbal fluency, cognitive processing speed, and verbal learning. Verbal learning impairment was strongly correlated with estimated lifetime ketamine use. Ketamine users showed no impairments in figural fluency, sustained attention, selective attention, visual learning, or verbal/nonverbal memory. However, heavier lifetime ketamine use was significantly correlated with deficits in verbal memory (both immediate recall and delayed recall) and visual recognition memory. Deficits in cognitive processing speed and verbal learning persisted even after polydrug controls were included in the control group, but their inclusion did make the impairment in verbal fluency barely reach statistical significance.

Conclusions

This study suggests that repeated ketamine use causes differential impairment to multiple domains of frontal and medial temporal functioning, possibly specific to verbal information processing.     

Emerging concepts on the use of ketamine for chronic pain

ABSTRACT

Introduction: The use of ketamine infusions for chronic pain has surged, with utilization exceeding the proliferation of knowledge. A proposed mechanism for the long-term benefit in chronic pain is that ketamine may alter the affective-motivational component of pain.

Areas covered: In this review, we discuss the classification and various dimensions of pain, and explore the effects of ketamine on different pain categories and components. The relationship between ketamine’s action at the NMDA receptor, the development of chronic pain, and the its possible role in preventing the persistence of pain are examined. We also summarize animal models evaluating the antinociceptive effects of ketamine and risk mitigation strategies of ketamine-associated side effects.

Expert opinion: Although ketamine exerts most of its analgesic effects via the NMDA receptor, recent evidence suggests that other receptors such as AMPA, and active metabolites such as nor-ketamine, may also play a role in pain relief and alleviation of depression. Data from clinical studies performed in patients with chronic pain and depression, and the observation that ketamine’s analgesic benefits outlast its effects on quantitative sensory testing, suggest that the enduring effects on chronic pain may be predominantly due ketamine’s ability to modulate the affective-motivational dimension of pain.     

Developmental neurotoxicity of ketamine in pediatric clinical use

Ketamine is widely used as an anesthetic, analgesic, and sedative in pediatric clinical practice and it is also listed as an illicit drug by most countries. Recent in vivo and in vitro animal studies have confirmed that ketamine can induce neuronal cell death in the immature brain, resulting from widespread neuronal apoptosis. These effects can disturb normal development further altering the structure and functions of the brain. Our recent studies further indicate that ketamine can alter neurogenesis from neural stem progenitor cells in the developing brain. Taken together, these findings identify a novel complication associated with ketamine use in premature infants, term newborns, and pregnant women. Recent data on the developmental neurotoxicity of ketamine are reviewed with proposed future directions for evaluating the safety of ketamine in these patient populations.     

手印中残留氯胺酮成分的检测分析

目的:建立一种手印中残留氯胺酮成分的分析方法。方法:对非渗透性和渗透性两种检材分别提取,采用GC/MS定性和GC/FID定量的方法对粘附有氯胺酮的手印样本进行定性定量分析。结果:氯胺酮浓度在10～4000ng·μL-1之间具有良好的线性关系(r=0.9991),最低检出限为1.635ng·μL-1。结论:通过实验发现,对于不同检材上捺印的手印均能检测到的被测物,通过手印显现方法处理后仍能检出。但随着陈旧时间的递增,有部分未检出。此方法为测定手印残留氯胺酮成分的定量分析提供了分析方法和检测依据。     

Consumer use and understanding of labelling information on edible marijuana products sold for recreational use in the states of Colorado and Washington

BackgroundIn 2014, the states of Colorado and Washington began allowing retail sales of marijuana for recreational use. The regulatory agencies in these states have implemented specific labelling requirements for edible marijuana products sold for recreational use to help address concerns such as delayed activation time, accidental ingestion, and proper dosing.MethodsWe conducted 12 focus groups with 94 adult consumers and nonconsumers of edibles in Denver and Seattle to collect information on their use and understanding of labelling information on edible marijuana products sold for recreational use. Specifically, we asked participants about the usefulness, attractiveness, ease of comprehension, relevancy, and acceptability of the label information.ResultsSome focus group participants look for and read specific information, such as the potency profile and serving size statement, but do not read or were unfamiliar with other labelling features. The focus groups revealed that participants have some concerns about the current labelling of edibles. In particular, participants were concerned that there is too much information on the labels so consumers may not read the label, there is no obvious indication that the product contains marijuana (e.g., a Universal Symbol), and the information on consumption advice is not clear. Participants in both locations suggested that education in a variety of formats, such as web- and video-based education, would be useful in informing consumers about the possible risks of edibles.ConclusionThe focus group findings suggest that improvements are needed in the labelling of edibles to prevent unintentional ingestion among adult nonusers and help ensure proper dosing and safe consumption among adult users. These findings, along with lessons learned from Colorado and Washington, can help inform the labelling of edibles as additional states allow the sale of edibles for recreational use.     

Dextromethorphan, an NMDA-receptor antagonist, enhances the analgesic properties of morphine

Preclinical studies demonstrated that dextromethorphan hydrobromide (DM) blocks tolerance to the analgesic effects of morphine sulfate (MS) and enhances its analgesic effect. The analgesic enhancing properties of DM in combination with MS have been confirmed in a clinical development program in over 2200 patients. MorphiDex® (MS:DM) is a 1:1 (mg to mg) ratio of morphine sulfate and dextromethorphan hydrobromide. Double-blind, single-dose analgesic efficacy studies in over 800 patients with post-surgical pain demonstrate significantly superior analgesic activity for MS:DM (60:60 mg) over both individual components MS 60 mg and DM 60 mg. MS:DM had a rapid onset of pain relief and at least an 8-hour duration of analgesic effect. ___TAGSTART___BR___TAGEND___Double-blind, multiple-dose studies in 321 patients with cancer and other chronic pain demonstrate MS:DM provides satisfactory pain control, but at a significantly lower mean MS daily dose. In a crossover study (2 weeks per treatment, 89 patients), 80.3 mg/day of MS in MorphiDex® capsules provided equal pain control to 161.5 mg/day of MS alone (P < 0.001). Also, the combination had a significantly longer interval between doses (P = 0.05) and a significantly longer interval between last dose of day and first dose next day (P = 0.01). In a 4-week parallel group study in 232 patients, MS:DM demonstrated pain control at least equivalent to MS alone at a significantly lower MS daily dose (P = 0.04). The data show significant dose escalation for MS alone, but not for MS:DM, to maintain satisfactory pain relief over 4 weeks (P = 0.025). Also, significantly more patients preferred double-blind MS:DM to run-in MS than preferred double-blind MS to run-in MS (P = 0.026). In these double-blind studies, the adverse event profile for MS:DM was similar to that for MS. ___TAGSTART___BR___TAGEND___A 2-week open-label study in 457 patients with chronic pain was conducted to provide guidelines in converting patients from other opioid medication to MS:DM. Patients took only 79% of their prestudy MS equivalent dose as MS from MS:DM (P < 0.0001) and a significantly higher percentage of patients rated MS:DM very good or excellent compared to their prestudy opioid (P < 0.0001). Most patients took 3 to 4 doses per day and used no other opioid for breakthrough pain. MorphiDex® provides a new potent analgesic with a novel mechanism of action and a favorable side effect profile for the treatment of moderate to severe cancer pain.     

东莨菪碱对氯胺酮依赖者焦虑障碍治疗的临床疗效观察

目的：观察东莨菪碱对氯胺酮依赖者焦虑障碍的治疗效果。方法：对30例氯胺酮依赖者焦虑障碍给予东莨菪碱治疗,采用 HAMA 量表评价出院时,出院1、3月后的治疗效果。结果：治疗后患者焦虑症状消失,情绪明显改善,对氯胺酮的渴求明显减弱或消失。结论：东莨菪碱治疗氯胺酮依赖者焦虑障碍具有一定的疗效。     

小剂量氯胺酮用于瑞芬太尼麻醉后痛觉过敏的临床研究

目的观察小剂量氯胺酮是否能抑制瑞芬太尼复合吸入麻醉所致的痛觉过敏。方法腹腔镜下胆囊切除术患者60例,20～60岁,ASA分级Ⅰ～Ⅱ级,随机分为3组：对照组（C组）术中仅用吸入麻醉;瑞芬太尼组（R组）术中持续靶控输注靶浓度4μg/L的瑞芬太尼;氯胺酮组（K组）术中持续靶控输注靶浓度4μg/L的瑞芬太尼,缝皮时给予氯胺酮0.5mg/kg。记录3组患者拔管时间、拔除气管导管后的口述疼痛评分,拔管后2、4、12、24h的视觉疼痛模拟评分（VAS）,4h内再次要求镇痛的人数和拔管后24h内的不良反应。结果R组和K组患者苏醒和拔管时间显著短于C组（P〈0.05）。拔管15min时,R组患者疼痛评分显著高K组和C组（P〈0.01）,拔管后2、4h的VAS评分R组患者疼痛评分显著高K组和C组（P〈0.05）,12hR组和K组VAS评分显著高于C组（P〈0.05）。术后4h内R组患者再次要求镇痛时间较K组和C组多。术后3组患者不良反应无显著差异。结论手术中大剂量应用瑞芬太尼会诱发术后痛觉过敏,氯胺酮对瑞芬太尼麻醉术后疼痛具有明显的抑制作用,且不增加不良反应。     

高效液相色谱法测定兔血浆中盐酸氯胺酮含量

目的建立高效液相色谱法测定兔血浆中盐酸氯胺酮含量。方法采用岛律LC-6A液相色谱仪,色谱柱:Diamonsil C18柱(200mm×4.6mm,5μm),流动相:甲醇:水(50∶50),流速:1.0mL/min,柱温:25℃,检测波长:275nm。用高氯酸沉淀血浆蛋白,以非那西丁为内标,测定血浆中盐酸氯胺酮的浓度。结果血浆中杂质不干扰样品峰和内标峰,1.0、10.0、100.0μg/mL的回收率分别为93.9%,88.1%,85.6%;批内精密度均小于8.0%,批间精密度均小于9.0%,最低检测限为0.1μg/mL,线性范围为1.0～100.0μg/mL。结论该方法稳定且精密度好,准确可靠,适用于盐酸氯胺酮血浆浓度测定。     

维拉帕米增强氯胺酮对小鼠的镇痛作用

目的:观察钙通道拮抗剂维拉帕米对静脉麻醉药氯胺酮镇痛效应的影响。方法:取40只小鼠,雌雄各半,随机分为4组:生理盐水对照组(NS)、氯胺酮处理组(K)、维拉帕米处理组(V)、维拉帕米和氯胺酮联合用药组(V+K),通过醋酸致小鼠扭体法观察小鼠给药后扭体潜伏期和次数的变化。另取40只小鼠,雌雄各半,随机分为上述4组,利用甩尾实验分别观察给药后小鼠对热水和冰水痛阈值的改变。结果:维拉帕米单独用药对小鼠扭体潜伏期和次数、热水和冰水痛阈值均无显著影响;氯胺酮能够延长醋酸致小鼠扭体的潜伏期,并且减少醋酸致小鼠扭体的次数,升高小鼠对热水和冰水甩尾痛阈值;而维拉帕米能够进一步增强氯胺酮延长小鼠扭体潜伏期,减少扭体次数和升高小鼠甩尾痛阈值的效应。结论:维拉帕米能够显著增强氯胺酮对小鼠的镇痛效应。     

Parametric determinants in pre-stimulus modification of acoustic startle: interaction with ketamine

Prepulse inhibition of the acoustic startle response is a form of reflex modification known to be sensitive to drugs and to subtle procedural manipulations. The present study examined the importance of prepulse length and prepulse-pulse interval in the expression of prepulse inhibition and its modification by the noncompetitive N-methyl-d-aspartate antagonist, ketamine. In contrast to a previous report, ketamine disrupted prepulse inhibition at doses of 5.6 and 10 mg/kg when its short time course was taken into consideration. In a second experiment, the amount of prepulse inhibition was found to be directly related to prepulse length, with prepulse inhibition produced by shorter prepulse durations slightly more sensitive to disruption by ketamine. A third experiment examined prepulse-pulse time intervals (30–2000 ms). While prepulse inhibition produced by prepulses occurring 60–500 ms before the startle stimulus was disrupted by 10 mg/kg of ketamine, prepulses preceding the startle stimulus by only 30 ms produced either no effect or slight prepulse facilitation under control conditions, and significant prepulse facilitation when ketamine was administered. A fourth experiment examined the time course of prestimulus modification by continuous lead stimuli, ranging in onset from 15 to 75 ms before the startle stimulus. Prepulse facilitation, when observed, tended to occur in earlier portions of the session and was enhanced by ketamine. These results suggest that prestimulus modification of the startle reflex has important parametric and experiential determinants that may influence the effects of drugs. Some of these temporal determinants may have relevance to sensorimotor function in schizophrenia.     

Tri-city study of Ecstasy use problems: a latent class analysis

This study used latent class analysis to examine distinctive subtypes of Ecstasy users based on 24 abuse and dependence symptoms underlying standard DSM-IV criteria. Data came from a three site, population-based, epidemiological study to examine diagnostic nosology for Ecstasy use. Subject inclusion criteria included lifetime Ecstasy use exceeding five times and once in the past year, with participants ranging in age between 16 and 47 years of age from St. Louis, Miami, U.S. and Sydney, Australia. A satisfactory model typified four latent classes representing clearly differentiated diagnostic clusters including: (1) a group of sub-threshold users endorsing few abuse and dependence symptoms (negatives), (2) a group of 'diagnostic orphans' who had characteristic features of dependence for a select group of symptoms (mild dependent), (3) a 'transitional group' mimicking the orphans with regard to their profile of dependence also but reporting some abuse symptoms (moderate dependent), and (4) a 'severe dependent' group with a distinct profile of abuse and dependence symptoms. A multinomial logistic regression model indicated that certain latent classes showed unique associations with external non-diagnostic markers. Controlling for demographic characteristics and lifetime quantity of Ecstasy pill use, criminal behavior and motivational cues for Ecstasy use were the most efficient predictors of cluster membership. This study reinforces the heuristic utility of DSM-IV criteria applied to Ecstasy but with a different collage of symptoms that produced four distinct classes of Ecstasy users.     

氯胺酮对全身麻醉后阴茎勃起治疗效果的观察

目的 探讨氯胺酮对全身麻醉后阴茎勃起的治疗效果.方法 2011年4月至2013年8月于宁波大学医学院附属医院接受手术治疗的男性患者共741例,其中18例麻醉后发生阴茎勃起为勃起组,余723例为无勃起组.勃起组患者采用静脉注射氯胺酮进行治疗.对勃起组阴茎萎缩变软的时间,注射前后患者的血压、心率、心律及2组麻醉苏醒时间、术后意识障碍、恶心呕吐等情况进行观察.结果 勃起组患者注射氯胺酮后阴茎萎缩变软的时间为（2.9 ±0.4） min;注射前患者的血压为（110±11）/（70 ±9） mmHg（1 mmHg=0.133 kPa）,明显低于注射后的（147±11）/（94±10） mmHg,差异有统计学意义（t=7.51,t=10.26,均P＜0.05）;注射后患者的心率为（89±9）次/min,明显快于注射前（64±8）次/rain,差异有统计学意义（=8.25,P＜0.05）.勃起组患者的麻醉苏醒时间、术后意识障碍率、术后恶心呕吐率与非勃起组患者相比,差异均无统计学意义（t=0.90,x2=0.60,x2=0.52,均P＞0.05）.结论 氯胺酮治疗全身麻醉后阴茎勃起疗效明显,安全迅速.     

From ecstasy to MDMA: Recreational drug use,symbolic boundaries,and drug trends

BackgroundEcstasy pills with MDMA as the main ingredient were introduced in many European countries in the 1980s, and were often linked to the rave and club scenes. However, use gradually levelled off, in part as a response to increased concerns about possible mental health consequences and fatalities. Extensive use of MDMA now seems to be re-emerging in many countries. In this study, we investigated the cultural and social meaning associated with MDMA use in Oslo, Norway, with an emphasis on how users distinguish MDMA crystals and powder from “old ecstasy pills”.MethodsQualitative in-depth interviews (n = 31, 61,3% males) were conducted with young adult party-goers and recreational MDMA/ecstasy users (20–34 years old, mean age 26.2 years).ResultsResearch participants emphasised three important perceived differences between the MDMA crystals and ecstasy pills: (i) The effects of MDMA were described as better than ecstasy; (ii) MDMA was regarded as a safer drug; (iii) Users of MDMA crystals were described as more distinct from and less anchored in out-of-fashion rave culture than those using ecstasy. These differences were an important part of the symbolic boundary work MDMA users engaged in when justifying their drug use.ConclusionMDMA has re-emerged as an important psychoactive substance in Oslo’s club scene. One important reason for this re-emergence seems to be its perceived differentiation from ecstasy pills, even though the active ingredient in both drugs is MDMA. This perceived distinction between MDMA and ecstasy reveals the importance of social and symbolic meanings in relation to psychoactive substance use. Insights from this study can be important in terms of understanding how trends in drug use develop and how certain drugs gain or lose popularity.     

氯胺酮对大鼠学习记忆功能及海马神经元的影响

目的了解多次氯胺酮给药对学习记忆功能的影响及机制。方法SD大鼠30只随机分为高剂量组、低剂量组和1个对照组,高、低剂量组大鼠分别予以氯胺酮50和10 mg/kg腹腔注射给药,1次/d,连续7 d。对照组予以等量生理盐水。用水迷宫测试各组大鼠寻找隐匿台的逃避潜伏期和空间搜索能力,原位检测海马神经元凋亡情况,电子显微镜观察神经元超微结构变化。结果高剂量组逃避潜伏期显著延长(P<0.01),并且空间搜索能力明显降低(P<0.01);高剂量组海马神经元凋亡指数显著高于对照组(P<0.01);电子显微镜显示高剂量组海马神经元有明显变性。结论多次使用氯胺酮对学习记忆有损害,这种损害作用可能与海马神经元病变有关。     

Comparative pharmacology of the optical isomers of ketamine in mice

Relative pharmacology potencies of the optical isomers of ketamine have been estimated in ICR mice. The (+)-isomer was 3× more potent than (?)-ketamine as an analgesic using the phenylquinone writhing test, only 1.5 × more potent in terms of hypnotic activity 1.8 more potent in causing locomotor stimulation. At equianalgesic doses (+)-ketamine caused less stimulation of locomotor activity than the (?)-isomer. These potency differences did not appear to be due to differences in biodisposition although stereoselective metabolism was demonstrated in vivo. Analgesia induced by ketamine was reversed by 10 mg.kg of naloxone.     

Cannabinoid CB(1) receptor antagonist rimonabant attenuates reinstatement of ketamine conditioned place preference in rats

Recent evidence suggests that cannabinoid CB(1) receptors may represent effective targets for therapeutic agents used to treat cocaine and heroin relapse. However, the role of cannabinoid CB(1) receptors in the potential treatment for other drugs of abuse is still largely unknown. The present study was conducted to determine whether cannabinoid CB(1) receptors play a similar role in relapse to ketamine abuse. To establish a ketamine reinstatement model in the conditioned place preference paradigm, rats were trained to develop place preference conditioned by ketamine, which was subsequently extinguished through daily exposure to the test chambers in the absence of ketamine. On the day following the last extinction session, four groups of rats were injected with ketamine (1, 5, 10 and 15 mg/kg, i.p.) to reinstate previously extinguished conditioned place preference. To investigate the effects of rimonabant, a cannabinoid CB(1) receptor antagonist, on reinstatement of ketamine-induced place preference, different doses of rimonabant (0.1, 0.5 and 3 mg/kg, i.p) were injected 30 min prior to the ketamine (5 and 15 mg/kg, i.p.) priming injection in a separate group of rats. To determine whether rimonabant itself produces conditioned place preference or conditioned place aversion, rats were trained for conditioned place preference or place aversion with rimonabant (0, 0.1, 0.5, 3.0 mg/kg, i.p.). While ketamine priming injections reinstated extinguished place preference, rimonabant administration significantly attenuated the reinstatement of ketamine-induced place preference in a dose-dependent manner. Importantly, rimonabant itself did not produce conditioned place preference or place aversion. Since the reinstatement effects of ketamine administration were inhibited by rimonabant, these findings suggest that a cannabinoid CB(1) receptor antagonist may be useful in preventing relapse to ketamine abuse.     

Phencyclidine and ketamine: Comparison with the effect of cocaine on the noradrenergic neurones of the rat brain cortex

Summary In slices of the rat occipital cortex, the influence of phencyclidine and ketamine on the accumulation of ³H-noradrenaline and the subsequent outflow of tritium was investigated, and was compared with the effect of cocaine.-All three drugs inhibited the accumulation of tritium during incubation of the slices with ³H-noradrenaline. Phencyclidine was slightly, whereas ketamine was much less effective than cocaine.-All three drugs accelerated the spontaneous outflow of tritium from slices preincubated with ³H-noradrenaline. The acceleration caused by low concentrations probably reflects an inhibition of the re-uptake of spontaneously released ³H-noradrenaline; in addition, high concentrations (10^–4M phencyclidine, 3×10^–4–10^–3M cocaine and 10^–3–3×10^–3M ketamine) appear to release tritiated compounds from the neurones. The distance between uptakeinhibiting and releasing concentrations was much greater for cocaine than for phencyclidine and ketamine.-All three drugs enhanced the overflow of tritium evoked by electrical field stimulation. The increase probably reflects an inhibition of the re-uptake of released ³H-noradrenaline; in addition, phencyclidine appears to enhance the release of noradrenaline per pulse.-The actions of phencyclidine and ketamine on central noradrenergic neurones may contribute to the characteristic psychotropic side-effects of these general anaesthetics.