Pharmacokinetic Characterization of Xylazine in Goats with Simultaneous Anesthesia Studies

The aim was to study the pharmacokinetics of xylazine as a stable anesthetic in goats.In this study,goats were injected with xylazine at the rate of 0.3 mL·kg-1 intramusculally,and blood samples were collected at 1,3,5,10,20,30,45,60,90,120,180,and 240 min after administration,respectively.Xylazine was extracted by liquid-liquid extraction and separation method,and blood concentration was determined by high performance liquid chromatography(HPLC).The pharmacokinetic characteristics of xylazine in healthy goats were analyzed by pharmacokinetic software.The results showed that the chromatographic peak time of xylazine chromatography was 9-11 min.The specificity of the method was good.The linear correlation coefficient R2 of the standard curve was 0.9982 when the concentration of xylazine was in the range of 10-1×1000 ng.The pharmacokinetic model of xylazine in goats was a one-chamber model with first-order rate absorption,distribution half-life t1/2Ka was(0.49±0.041)min,elimination half-life t1/2Ke was(23.3±2.5)min,and the peak time(Tp)of the highest concentration was(2.8±0.2)min.The total drug clearance CL/F was(0.00016±0.000016)mg·kg-1·min-1(ng·mL-1),and the minimum effective blood concentration was 56.6 ng·mL-1,which was consistent with the clinical anesthetic effect.The results showed that xylazine had the characteristics of rapid absorption,wide distribution,short peak time,slow clearance rate,and long anesthetic time in goats,which could be used as the basic drug for the development of goat complex anesthetic preparation.

Treatment Resistant Depression, Ketamine versus ECT

Recent studies have highlighted the increase in treatment resistant depression. Of particular concern is the rising trend of depression and suicide rates among Young Adults. Ketamine was approved for treatment resistant depression in 2019 by the US Food and Drug Administration. It received an additional indication for treatment of suicidality. While intranasal Ketamine is approved for depression, recent data about intravenous infusion of Ketamine in controlled inpatient settings has been promising. ECT has a long-standing trend for being used for resistant depression and recent comparison trials have revealed positive results when head-to-head comparisons are made with Ketamine. Future studies need to focus on patient selection and wherein treatment algorithm should Ketamine be selected as treatment modality.

Fentanyl and xylazine crisis:Crafting coherent strategies for opioid overdose prevention

The United States is in the throes of a severe opioid overdose epidemic,primarily fueled by the pervasive use of fentanyl and the emerging threat of xylazine,a veterinary sedative often mixed with fentanyl.The high potency and long duration of fentanyl is compounded by the added risks from xylazine,heightening the lethal danger faced by opioid users.Measures such as enhanced surveillance,public awareness campaigns,and the distribution of fentanylxylazine test kits,and naloxone have been undertaken to mitigate this crisis.Fentanyl-related overdose deaths persist despite these efforts,partly due to inconsistent policies across states and resistance towards adopting harm reduction strategies.A multifaceted approach is imperative in effectively combating the opioid overdose epidemic.This approach should include expansion of treatment access,broadening the availability of medications for opioid use disorder,implementation of harm reduction strategies,and enaction of legislative reforms and diminishing stigma associated with opioid use disorder.

Effect of different anesthetic mixtures——ketamine-xylazine, ketamine-acepromazine and tiletamine-zolazepam——on the physiological and blood biochemistry parameters of male rhesus monkeys(Macaca mulatta) at different ages

Background: Anesthetic agents are commonly utilized in the handling of non‐human primates for prevent the stress caused in physical exploration or physical restrain. For this reason, the objective of this work was to describe the effect of age and dissociative anesthetics (ketamine and tiletamine), and their combinations with acepromazine, xylazine and zolazepam, on the physiological and blood biochemical parameters in Macaca mulatta. Methods: Eighty male Macaca mulatta were divided into four experimental groups depending on the anesthetic mixture applied. Each group of 20 males was divided into five sub‐groups according to age. Physiological parameters were recorded every five minutes during a 30‐minute period. A blood sample was drawn to analyze blood biochemistry. Results: Statistical analyses revealed significant differences in the physiological parameters between the ketamine‐acepromazine and ketamine‐xylazine groups compared to the control group. The analysis of blood biochemistry found significant differences by age and by anesthetic mixture among all groups. Conclusion: These findings contribute to standardizing this animal model in biological research.

Efficacy of repeated intravenous esketamine in adolescents with anxious versus non-anxious depression

Background Patients with anxious major depressive disorder(MDD)are more likely to have poorer outcomes than those with non-anxious MDD.However,the effect of esketamine on adolescents with anxious versus non-anxious MDD has remained unknown.Aims We compared the efficacy of esketamine in adolescents with MDD and suicidal ideation,both anxious and non-anxious.Methods Fifty-four adolescents with anxious(n=33)and non-anxious(n=21)MDD received three infusions of esketamine 0.25mg/kg or active-placebo(midazolam 0.045 mg/kg)over 5 days,with routine inpatient care and treatment.Suicidal ideation and depressive symptoms were assessed using the Columbia Suicide Severity Rating Scale and the Montgomery-Asberg Depression Rating Scale.Multiple-sample proportional tests were used to compare the differences between groups on treatment outcomes 24 hours after the final infusion(day 6,primacy efficacy endpoint)and throughout the 4-week post-treatment(days 12,19 and 33).Results In subjects who received esketamine,a greater number of patients in the non-anxious group than the anxious group achieved antisuicidal remission on day 6(72.7%vs 18.8%,p=0.015)and day 12(90.9%vs 43.8%,p=0.013),and the non-anxious group had a higher antidepressant remission rate compared with the anxious group on day 33(72.7%vs 26.7%,p=0.045).No significant differences in treatment outcomes were observed between the anxious and non-anxious groups at other time points.Conclusions Three infusions of esketamine as an adjunct to routine inpatient care and treatment had a greater immediate post-treatment antisuicidal effect in adolescents with non-anxious MDD than in those with anxious MDD;however,this benefit was temporary and was not maintained over time.

A novel model of drug cue-induced behaviours in rhesus macaque subjected to chronic ketamine exposure

To the Editor,Non-human primate(NHP)models are advantageous for mimicking human addiction with high behavioural validity.1 However,current NHP drug addiction models(eg,self-administration)often require a comprehensive behavioural training paradigm,relatively expensive apparatus and invasive surgical procedures.

Virtual Reality as an Adjunct to Ketamine Infusion Therapy Increases Patient Satisfaction in the Management of Chronic Pain and Depression: A Retrospective Pilot Study

The management of patients with concomitant chronic pain (CP) and Major Depressive Disorder (MDD) remains challenging for clinicians. Current chronic pharmacologic management is often unsuccessful, or has intolerable side effects to the patients. While not restricted to patients with chronic pain, these patients are often diagnosed with depression, presenting with symptoms such as poor mood, anhedonia, and altered cognitive processes. It is estimated that a substantial proportion of treated patients do not derive a substantive benefit from traditional pharmacological treatments for depression. The present study involved a retrospective review of cases, exploring the patient-reported satisfaction with and tolerability of a novel use of virtual reality (VR), coined KVR, as an adjunct to intravenous ketamine infusion therapies. Specifically, the ketamine-virtual reality protocol was employed as a potential adjunctive intervention for patients suffering from chronic pain and depression. Visual Analog Scores (VAS) associated with pain were significantly lower on the third than on the first assessment day. Montgomery-?sberg Depression Rating Scale (MADRS) scores improved following infusion and across days (i.e., sessions). Lastly, 2/3 of patients preferred the use of VR with their ketamine infusion. The results are considered in terms of implementing prospective studies to examine whether the combination therapies have a synergistic benefit and the nature and magnitude of clinically meaningful treatment effects, if any.

Administration of Nebulised Ketamine for Managing Pain in the Intensive Care Unit of Obstetrics and Gynaecology

Introduction: The use of inhaled ketamine to manage a variety of painful conditions has been endorsed by the American College of Emergency Physicians and the American Academy of Emergency Medicine. Nebulized analgesia has multiple benefits, including rapid, effective and titratable analgesic delivery. The aim of our study is to assess the efficacy and safety of intranasal analgesic-dose ketamine compared to multimodal analgesia in patients presenting with acute postoperative pain or headache after a spinal anaesthetic in the intensive care unit of obstetrics and gynaecology. Materials and Methods: This was a prospective descriptive study, with hospital Ethics Committee approval and written informed consent from study participants. We compared the effect of nebulized ketamine and multimodal analgesia postoperatively in 120 patients belonging to the physical status I - II of the American Society of Anesthesiologists, in the intensive care unit of obstetrics and gynaecology, at the Ibn Rochd University Hospital Center in Casablanca from June 2021 to June 2022. Results: We included 120 patients in our study divided into two groups of 60 patients: the average age was 35 years, with extremes ranging from 18 to 45 years, All patients were hospitalized for postoperative care: all women underwent locoregional anaesthesia with a standard dose according to the service protocol (10 mg of bupivacaine, 25γ of fentanyl, 100γ of morphine), where pain was the common denominator. Among these patients, 59 were admitted for management of postpartum haemorrhage, 43 for postoperative monitoring, 15 for post-spinal anaesthesia headache and 3 for pelviperitonitis. The results of the pain assessment 30 minutes after the ketamine nebulization were marked by a request for analgesia in 12 patients, which is 20% of group A, including 5 patients, whose visual analogue scale (VAS) on admission was between 5 and 7, and 7 patients whose VAS at admission was ≥8;all these patients received a second dose of ketamine by nebulization;the evaluation 30 min after the second dose was marked by a request for analgesia in 4 patients, which is 7% of Group A;in all these patients the VAS at admission was ≥8. Of the total number of patients of Group A, only 4 received morphine when they were requested for analgesia after the second dose of nebulized ketamine. Conclusion: The primary outcome of nebulized ketamine use is a significant reduction in VAS pain score. We believe that nebulized ketamine has a potential effect of reducing pain in the intensive care unit of obstetrics and gynaecology;this may be an additional analgesic modality for clinicians to provide rapid, effective and non-invasive pain relief.

Use of a rat model to characterize 35 arterial pulse wave parameters in a comparative study of isoflurane and Zoletil/ xylazine anesthesia and the effect of Acanthopanax senticosus extract

Background : Information obtained from arterial pulse waveforms (APW) can be usefulfor characterizing the cardiovascular system. To achieve this, it is necessary to know thedetailed characteristics of APWs in different states of an organism, which would allowAPW parameters (APW- Ps) to be assigned to particular (patho)physiological conditions.Therefore, our work aimed to characterize 35 APW- Ps in rats under the influence ofisoflurane (ISO) and Zoletil/xylazine (ZO/XY) anesthesia and to study the effect of rootextract from Acanthopanax senticosus (ASRE) in these anesthetic conditions.Methods : The right jugular vein of anesthetized rats was cannulated for the administrationof ASRE and the left carotid artery for the detection of APWs from which 35APW- Ps were evaluated.Results : We obtained data on 35 APW- Ps, which significantly depended on the anesthesia,and thus, they characterized the cardiovascular system under these two conditions.ASRE transiently modulated all 35 APW- Ps, including a transient decrease insystolic and diastolic blood pressure (BP) and heart rate or increases in pulse BP, d P /d t max , and systolic and diastolic areas. Whereas the transient effects of ASRE weresimilar, the extract had prolonged disturbing effects on the cardiovascular system inrats under ZO/XY but not under ISO anesthesia. This negative effect can result fromthe disturbance caused by ZO/XY anesthesia on the cardiovascular system.Conclusions : We characterized 35 APW- Ps of rats under ISO and ZO/XY anesthesiaand found that ASRE contains compounds that can modulate the properties of thecardiovascular system, which significantly depended on the status of the cardiovascularsystem. This should be considered when using ASRE as a nutritional supplementby individuals with cardiovascular problems.

xylazine+DHE对大鼠的麻醉作用及其对β-内啡肽含量的影响

采用恒温水浴摆尾法测定二甲苯胺噻嗪 ( xylazine) +双氢埃托啡 ( DHE)对大鼠的镇痛作用 ,放射免疫分析法测定不同时间大鼠血液、垂体和下丘脑中 β-内啡肽 ( β-EP)的含量 ,并初步探讨了行为学改变与 β-EP含量变化间的关系。结果表明 ,xylazine+DHE使大鼠在 1 5min时的翻正反射消失阳性率为 93 .3 %,并增加了大鼠的痛阈值及血液β-EP的含量 ,而对垂体和下丘脑β-EP含量的影响则为双相作用 :前时相表现为降低 ,后时相表现为升高 ;统计学分析表明 ,这些作用均较阳性和阴性对照组差异显著。本研究提示 ,xylazine+DHE是一个良好的复合麻醉剂 ;下丘脑释放的 β-EP可能参与了 xylazine+DHE的中枢镇痛作用 ;血液 β-EP主要来自于垂体 ,可能参与了大鼠对 xylazine+DHE作用的适应性反应 。

Ketamine和Bicucullin对帕金森模型的影响

目的 为帕金森氏病的发病机理及兴奋性氨基酸受体拮抗剂对帕金森氏病的防治提供理论根据。方法 本实验采用MPTP腹腔注射建立C57BL小黑鼠帕金森氏病模型的过程中 ,同时用兴奋性氨基酸NMDA受体拮抗剂Ketamine和GABA受体拮抗剂Bicucullin ,观察其帕金森行为症状、病理变化及生化改变。结果 Ketamine加MPTP组和Bicucullin加MPTP组及MPTP组和生理盐水组比较 ,上述指标都有明显改变。结论 NMDA受体拮抗剂对小鼠帕金森氏病模型具有防治作用 ,GABA神经元的功能降低可加重帕金森氏病的症状。

Xylazine+DHE合剂对大鼠的ED_(50)值测定及剂量确定

以翻正反射消失和痛阈增加３０％为指标，应用序贯法测定ｘｙｌａｚｉｎｅ＋ＤＨＥ合剂腹腔给药对大鼠的麻醉半数有效量（ａｎｅｓｔｈｅｔｉｃＥＤ５０）和镇痛半数有效量（ａｎａｌｇｅｓｉｃＥＤ５０）；在此基础上，确定给药剂量并检验给药剂量是否合理。结果表明，ｘｙｌａｚｉｎｅ＋ＤＨＥ合剂对大鼠的麻醉ＥＤ５０为８．３６４ｍｇ／ｋｇ，镇痛ＥＤ５０为７．８０２ｍｇ／ｋｇ；确定麻醉剂量为１５．００ｍｇ／ｋｇ，镇痛剂量为１０．０００ｍｇ／ｋｇ。进一步的麻醉和镇痛实验显示，麻醉剂量使９３．３％大鼠的翻正反射消失，镇痛剂量使大鼠的摆尾阈值增加幅度在４０％～６０％，且维持时间在６０ｍｉｎ左右，表明这两个剂量完全符合实验要求。

Effect of propofol and ketamine anesthesia on cognitive function and immune function in young rats

Objective:To investigate the effects of propofol and ketamine on the cognitive function and immune function in young rats.Method:A total of 80 young rats were randomly divided into four groups:Control group,ketamine group(experimental group A),propofol group(experimental group B),ketamine and propofol group(experimental group Q.All rats had continuous injection for three times,serum IL-2,IL-4 and II.-10 and whole brain IL-I P level,hippocampal neuronal apoptosis level were measured.The cognitive ability in rats was tested by water maze.Results:Water maze test showed on the 1st d,the maze test latency of the control group,the experimental group B and the experimental group C water were decreased gradually;Compared with the control group after 3 days,the latency of the experimental group A,experimental group B and experimental group C were all decreased,the crossing circle times were also reduced.Hippocampal neuron apoptosis were(2.3±1.7)%,(14.7±6.9)%,(4.2±3.3)%,(10.2±4.8r%in control group,experimental group A,experimental group B and experimental group C,respectively.The neurons apoptosis of experimental group A was significantly increased.The serum IL-4 and 1L-10 of the experimental group A,experimental group B and experimental group C after anesthesia were significantly higher than the control group.The whole brain IL-1β of the experimental group A,experimental group B and experimental group C were significantly lower than the control group.Conclusions:Propofol can reduce anesthesia effect of ketamine on the cognitive function and immune function in the young rats.

Neonatal ketamine exposure-induced hippocampal neuroapoptosis in the developing brain impairs adult spatial learning ability

Ketamine exposure can lead to selective neuroapoptosis in the developing brain.p66ShcA,the cellular adapter protein expressed selectively in immature neurons,is a known pro-apoptotic molecule that triggers neuroapoptosis when activated.Sprague-Dawley rats at postnatal day 7 were subcutaneously injected in the neck with ketamine 20 mg/kg,six times at 2-hour intervals.At 0,1,3,and 6 hours after final injection,western blot assay was used to detect the expression of cleaved caspase-3,p66ShcA,and phosphorylated p66ShcA.We found that the expression of activated p66ShcA and caspase-3 increased after ketamine exposure and peaked at 3 hours.The same procedure was performed on a different group of rats.At the age of 4 weeks,spatial learning and memory abilities were tested with the Morris water maze.Latency to find the hidden platform for these rats was longer than it was for control rats,although the residence time in the target quadrant was similar.These findings indicate that ketamine exposure resulted in p66ShcA being activated in the course of an apoptotic cascade during the neonatal period.This may have contributed to the deficit in spatial learning and memory that persisted into adulthood.The experimental protocol was approved by the Institutional Animal Care and Use Committee at the University of Texas at Arlington,USA (approval No.A13.008) on January 22,2013.

Effect of Preemptive Ketamine Administration on Postoperative Visceral Pain after Gynecological Laparoscopic Surgery

The pain following gynecological laparoscopic surgery is less intense than that following open surgery; however, patients often experience visceral pain after the former surgery. The aim of this study was to determine the effects of preemptive ketamine on visceral pain in patients undergoing gynecological laparoscopic surgery. Ninety patients undergoing gynecological laparoscopic surgery were randomly assigned to one of three groups. Group 1 received placebo. Group 2 was intravenously injected with preincisional saline and local infiltration with 20 m L ropivacaine（4 mg/m L） at the end of surgery. Group 3 was intravenously injected with preincisional ketamine（0.3 mg/kg） and local infiltration with 20 m L ropivacaine（4 mg/m L） at the end of surgery. A standard anesthetic was used for all patients, and meperidine was used for postoperative analgesia. The visual analogue scale（VAS） scores for incisional and visceral pain at 2, 6, 12, and 24 h, cumulative analgesic consumption and time until first analgesic medication request, and adverse effects were recorded postoperatively. The VAS scores of visceral pain in group 3 were significantly lower than those in group 2 and group 1 at 2 h and 6 h postoperatively（P〈0.05 and P〈0.01, respectively）. At 2 h and 6 h, the VAS scores of incisional pain did not differ significantly between groups 2 and 3, but they were significantly lower than those in group 1（P〈0.01）. Groups 1 and 2 did not show any differences in visceral pain scores at 2 h and 6 h postoperatively. Moreover, the three groups showed no statistically significant differences in visceral and incisional pain scores at 12 h and 24 h postoperatively. The consumption of analgesics was significantly greater in group 1 than in groups 2 and 3, and the time to first request for analgesics was significantly longer in groups 2 and 3 than in group 1, with no statistically significant difference between groups 2 and 3. However, the three groups showed no significant difference in the incidence of shoulder pain or adverse effects. Preemptive ketamine may reduce visceral pain in patients undergoing gynecological laparoscopic surgery.

Ketamine induces tau hyperphosphorylation at serine 404 in the hippocampus of neonatal rats

Male Wistar 7-day-old rats were injected with 40 mg/kg ketamine intraperitoneally, followed by three additional injections of 20 mg/kg ketamine each upon restoration of the righting reflex. Neonatal rats injected with equivalent volumes of saline served as controls. Hippocampal samples were collected at 1,7 or 14 days following administration. Electron microscopy showed that neuronal structure changed noticeably following ketamine treatment. Specifically, microtubular structure became irregular and disorganized. Quantitative real time-PCR revealed that phosphorylated tau mRNA was upregulated after ketamine. Western blot analysis demonstrated that phosphorylated tau levels at serine 396 initially decreased at 1 day after ketamine injection, and then gradually returned to control values. At 14 days after injection, levels of phosphorylated tau were higher in the ketamine group than in the control group. Tau protein phosphorylated at serine 404 significantly increased after ketamine injection and then gradually decreased with time. However, the levels of tau protein at serine 404 were significantly greater in the ketamine group than in the control group until 14 days. The present results indicate that ketamine induces an increase of phosphorylated tau mRNA and excessive phosphorylation of tau protein at serine 404, causing disruption of microtubules in the neonatal rat hippocampus and potentially resulting in damage to hippocampal neurons.

Effect of Xylazine Anesthesia on Glu and GABA Amino Acid Neurotransmitters in Rat

Neurotransmitters of the central nervous system were the important way to study the mechanism of anesthesia. The effect of different doses of xylazine anesthetic on the glutamate(Glu) and γ-aminobutyric-acid(GABA) were investigated and the mechanism of xylazine anesthetic on the central nervous system were explored in this study. A total of 88 rats were randomly divided into three groups, including normal saline control group, group with low dose of xylazine and group with high dose of xylazine.Cerebrum, cerebellum, hippocampus, thalamus and brainstem were collected. The results showed that the concentration of Glu in the hippocampus, thalamus and brainstem decreased first and then increased, but it increased first and then decreased in the cerebrum and cerebellum during the period of anesthesia. The concentration of GABA in the cerebrum, thalamus, brainstem and hippocampus increased first and then decreased. The results showed that xylazine inhibited Glu and promoted GABA with different dose dependence. The results and methods could provide guides for the clinical use of xylazine.

Effects of ketamine on mouse hippocampal inflammatory cytokines IL-6,IL-1β and TNF-α levels in acute and chronic administration models

OBJECTIVE Ketamine is an injectable anesthetic and recreational drug of abuse commonly used worldwide. Many experimental studies have shown that ketamine can impair cognitive function and induce psychotic states. Neuroinflammation has been suggested to play an important role in neurodegeneration. Meanwhile,ketamine has been showed to modulate the levels of inflammatory cytokines.Therefore,we sought to investigate whether the effects of ketamine on the central nervous system is associated with the inflammatory cytokines. METHODS We established acute(single or multiple intraperitoneal injection) and chronic(six months daily intraperitoneal injection) ketamine administration models in C57BL/6 mice,evaluated the spatial recognition memory and emotional response by applying the Y maze test and open field test. We analyzed the changes of inflammatory cytokines interleukin-6(IL-6),interleukin-1β(IL-1β) and tumor necrosis factor-α(TNF-α) levels in mouse hippocampus,employing Western blot,quantitative reverse transcriptase-polymerase chain reaction(qR T-PCR) and immunohistochemistry. RESULTS Ketamine induced spatial recognition memory deficit,reduced anxiety-like behaviors in mice after chronic administration,and it was dose-dependent. Moreover,we found that ketamine could increase the levels of mouse hippocampal inflammatory cytokines IL-6 and IL-1β after single,multiple and long-term administration in a dose-dependent manner. However,the level of TNF-α expressed differently in mouse hippocampus under different conditions. Single administration of ketamine increased the level of TNF-α,whereas multiple and long-term administration decreased it significantly. We considered that TNF-α might exist bi-directional regulatory pathway,which was associated with the dose and duration of ketamine administration. CONCLUSION Our results suggest that the alterations of inflammatory cytokines IL-6,IL-1β and TNF-α levels may be involved in the neurotoxicity of ketamine.

Neuron-protective effect of subanesthestic-dosage ketamine on mice of Parkinson's disease

Objective: To discuss the neuron-protective effect and possible mechanism of subanesthestic-dosage ketamine on Parkinson's disease mice induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine.Methods: A total of 30 mice were divided equally into three groups, model control group(MC group), ketamine treatment group(KT group), and blank control group(BC group), respectively.The Parkinson's disease mice of MC group and KT groups were established by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine(20 mg/kg/d), while mice in KT group were treated by intraperitoneal injection of subanesthestic-dosage ketamine(8 mg/kg).Differences on behaviors and the number of nigra dopaminergic neurons of mice in each group were compared through the behavioral test and tyrosine hydroxylase immunohistochemistry experiments after the treatments.Furthermore, Western blot was used to test the expression of autophagy-related gene LC3-Ⅱ, Beclin1, Parkin, PINK1,and mTOR.Results: Compared with the BC group, the neuroethology scores were lower and the amount of TH positive cells were less both in MC and MT groups; In KT group, the neuroethology scores were higher and the amount of tyrosine hydroxylase positive cells were significantly more than that in MC group(P < 0.05).Moreover, expression levels of autophagy-related proteins LC3-II, Beclin1, Parkin, and PINK1 were higher, while the mTOR expression level was lower than that in MC group.Conclusions: The subanesthestic-dosage ketamine has some protective effects on the coordinating ability of movement and cognitive ability of Parkinson's disease mice induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine.This is probably due to that the autophagy activity of cells is activated by subanesthestic-dosage ketamine and that the neurons are protected.