• <tr id="yyy80"></tr>
  • <sup id="yyy80"></sup>
  • <tfoot id="yyy80"><noscript id="yyy80"></noscript></tfoot>
  • 99热精品在线国产_美女午夜性视频免费_国产精品国产高清国产av_av欧美777_自拍偷自拍亚洲精品老妇_亚洲熟女精品中文字幕_www日本黄色视频网_国产精品野战在线观看 ?

    Effects of antipsychotic drugs on pain threshold and motor behavior in a rat model of schizophrenia

    2011-04-12 09:23:22GangLIMengMengJIShuaiYANGDongHongCUIHuanJunCAOJianFengYU
    上海精神醫(yī)學 2011年4期
    關鍵詞:哌啶利培壓痛

    Gang LI,Meng Meng JI,Shuai YANG,Dong Hong CUI,Huan Jun CAO,Jian Feng YU*

    Effects of antipsychotic drugs on pain threshold and motor behavior in a rat model of schizophrenia

    Gang LI1,Meng Meng JI1,Shuai YANG1,Dong Hong CUI2,Huan Jun CAO1,Jian Feng YU1*

    Background:Previous investigations have suggested that patients with schizophrenia have decreased pain sensitivity that is partially reversed with antipsychotic treatment.One way to assess this hypothesis is to test it in animal models of schizophrenia.

    Objective:Determine whether or not rats that manifest the expected behavioral changes of a ketamine-induced rat model of schizophrenia have an increased pain threshold,and test whether or not pretreatment with antipsychotic medication reverses this increase in the pain threshold.

    Methods:30 male Wistar rats were randomly assigned to five groups:three groups received intraperitoneal antipscyhotics[risperidone(0.3mg/kg),risperidone(0.9mg/kg)or haloperidol(1mg/kg)]30 minutes prior to receiving intraperitoneal ketamine(100mg/kg);one group received normal saline followed by intraperitoneal ketamine;and a control group received two injections of normal saline.The threshold values for pressure pain and thermal pain were assessed at baseline and at 5,15,30 and 45 minutes after the second injection.The behaviors of another 30 rats treated in the same manner were assessed using the open field test for 120 minutes after receiving the second injection.

    Results:Compared to the control group,rats in the ketamine group(without pretreatment with antipsychotics)had decreased thresholds for pressure pain and increased thresholds for thermal pain at all time periods after administration of ketamine.Pretreatment with haloperidol significantly diminished the ketamine-induced decreased pressure pain threshold at all time periods but low-or high-dose risperidone had no effect on pressure pain thresholds. Pretreatment with low-dose risperidone reduced the ketamine-induced increase in thermal pain threshold 5 minutes after the ketamine injection but not at 15-45 minutes after the ketamine injection;high-dose risperidone and haloperidol had no significant effect on thermal pain thresholds.In the open field test the groups pretreated with antipsychotics had fewer standing upright behaviors(goal-directed behavior),fewer crossed grids(less hyperactivity),and fewer head shakes and circuling body movements(less stereotyped behavior)than the rats treated with ketamine that did not receive pretreatment with antipsychotics.Falls(i.e.,ataxia)were significantly more common in the haloperidol pretreatment group than in the ketamine group(without pretreatment)and than in the two risperidone pretreatment groups.

    Conclusion:We did not confirm previous findings about the inhibition of ketamine-induced increased pain thresholds by antipsychotics in a rat model of schizophrenia.The surprising decrease in pressure-pain thresholds with ketamine may be related to the increased overall activity following ketamine injection(which made it difficult to reliably conduct the pressure pain threshold test).Risperidone and haloperidol effectively reduce many of the psychomimetic effects of ketamine,but haloperidol increased ketamine-induced ataxia while risperidone decreased ataxia,a finding that could be clinically relevant for elderly patients who are prone to falls.

    Risperidone;Haloperidol;Ketamine;Schizophrenia;Pain threshold;Motor behavior;Animal models

    1 Introduction

    Ketamine is a glutamate N-Methyl-D-aspartate (NMDA)receptor antagonist and an important intravenous anesthetic.It has satisfactory analgesic effects and mildly inhibits respiratory and circu

    latory functions,but the adverse reactions of this drug have limited its clinical applications[1].Among these adverse reactions are ketamine's psychomimetic properties,which can be used to induce an animal model of schizophrenia[2-4]that is better than the animal model induced by dopamine agonists[5].

    Recent studies report reduced responsiveness to various kinds of pain stimuli in patients with schizophrenia[6]which may be related to a functional disorder of NMDA receptors[7].Though not a core symptom of schizophrenia,changed sensitivity to pain may be clinically important because it has been associated with functional recovery,reintegration into the community and the occurrence of violent behavior[8].

    Antipsychotic drugs can alleviate some symptoms of schizophrenia in both living patients and in animal models[6,9],but findings from studies on the relationship of antipsychotic treatment to the pain threshold in schizophrenia have been contradictory.In some studies haloperidol and risperidone have no effect on pain thresholds[10].But Becker's group[8]—which used an indirect method of assessing pain thresholds and low doses of ketamine (30mg/kg)—reports that pretreatment with antipsychotic drugs can affect pain sensitivity in ketamine-induced rat models for schizophrenia.The present study aims to replicate Becker's findings using an acute dose of ketamine(100mg/kg)to induce a rat model of schizophrenia and direct measures of pain thresholds.

    2 Materials and methods

    2.1 Experimental animals

    Sixty clean-grade male Wistar rats weighing 150-200g purchased from the Shandong Lukang Pharmaceutical Company were housed in a quiet and warm animal room with proper humidity,dimmed lighting and free access to food and water for at least 48 hours before the experiment.The study was carried out from April 1,2010 to May 1,2010.None of the rats died during the experiment.

    2.2 Medications

    Medications used were as follows:ketamine hydrochloride injection(50mg/ml),produced by the Jiangsu Hengrui Medicine Company;risperidone powder,purchased from the Sigma Company in the USA,dissolved in acetic acid and diluted to 0.5mg/ml;and haloperidol injection(5mg/ml) produced by the Shanghai Xudong Haipu Pharmaceutical Company.

    2.3 Medication administration

    Two separate sets of 30 male Wistar rats were used in the study,one for the pain threshold assessment and one for the open field test(Figure 1). Each set of 30 rats was divided into five groups using a random numbers table,with six rats in each group.The first three groups were administered intraperitoneal injections with antipsychotic drugs before receiving ketamine;physiological saline was added to each injection to result in a final volume of 0.4ml.After 30 minutes,these three groups were administered 100mg/kg ketamine diluted to result in a final intraperitoneal injection of 0.4 ml.The antipsychotic doses for the three groups were 1)a low-dose risperidone pretreatment group received 0.3mg/kg risperidone;2)a high-dose risperidone pretreatment group received 0.9 mg/kg risperidone.And 3)a haloperidol pretreatment group received 1mg/kg of haloperidol.(These dosages for assessing pain thresholds were based on the study by Alimohamad and colleagues[11].)The last two groups were administered an intraperitoneal injection of 0.4ml physiological saline as a pretreatment control;the fourth group was subsequently administereda0.4mlintraperitonealinjectionwith 100mg/kg ketamine and the fifth group was subsequently administered a second 0.4ml intraperitoneal injection of physiological saline(the control condition for the ketamine administration).

    2.4 Behavioral experiments

    Pain threshold testing and the open field test were independently conducted by two researchers.

    2.4.1 Determination of pressure pain and thermal pain thresholds

    The pressure pain and thermal pain thresholds were determined using the Electronic Von Frey 2390-5 tenderness meter(IITC Life Science Corporation,USA)and the SW-200 tail light and heat pain test instrument(Chengdu TME Technology Company).Baseline(pretreatment)values of the pressure and thermal pain thresholds for each rat were the average of six measurements assessed with a 15-minute interval between each measurement.

    The specific method of determining the pain thresholds was based on the protocol developed by Johnson and colleagues[12].When assessing the pressure pain threshold a researcher gently holds the rat and after the rat was in a quiet state presses their posterior instep until the rat lifts its leg in avoidance.The pressure pain meter records the force on the rat's instep in grams.When assessing the thermal pain threshold the tail of a quiet rat is exposed to a light source(thus generating heat);the time until the rat flicks its tail(the flick reflex)is recorded as the thermal pain threshold.To prevent burning of the tail,exposure is terminated if the rat fails to flick its tail for 20 seconds,and 20 seconds is recorded as the threshold.The tenderness and thermal pain thresholds were assessed 5,15,30 and 45 minutes after the second intraperitoneal injection(which was ketamine in 5 groups and normal saline in one group).

    2.4.2 Open field test

    An open field test was conducted to verify that the ketamine dosages employed were inducing pschyomimetic(i.e.,schizophreniform)activity in the rats.Based on the standard method[13],the open field test was conducted with a 100cm×100cm× 40cm box with black walls and a bottom divided into a 5×5 grid with 25 squares of equal size.A digital camera attached to the top of the box recorded the test,which was conducted in a soundproof room.The rats had 30 minutes of environmental acclimation at 10:00 to 12:00 every morning for seven continuous days before the actual test.On the day of the test,the rats were kept in the open box for acclimation for 10 minutes,and then they were administered medications following the same procedure as that described for the pain threshold tests(above).After the second injection the rats were placed in the central square of the grid and their behavior was recorded for 120 minutes.Each of the 30 rats was tested once.The feces and urine in the box were removed after each test.

    The following variables were recorded:the number of grids crossed(assessing motor status),the frequency of falling(assessing ataxia),the frequency of upright standing behavior(assessing conscious activities),the frequency of circling body movements(assessing stereotyped behavior),and the frequency of head shaking(assessing stereotyped behavior).This is the standard method of assessing results for the open field test and has been employed in previous research on rat behavior after administration of ketamine[14,15].

    2.5 Statistical Methods

    To show percent change in pain thresholds from baseline in the different groups,we used the standard method employed by Becker and colleagues[8]:percent change=[(Experimental pain threshold-baseline pain threshold)/baseline pain threshold]×100%.

    The SPSS 11.5 software package was used for statistical analysis.All results were expressed as means and standard deviations.One-way ANOVA was used to compare the five groups,if significantly different,post-hoc tests were used to make subsequent pairwise comparisons between groups(LSD if the groups had equal variances and Dunnett's T3if the groups had unequal variances).Statistical significance was defined at the 0.05 level.

    3 Results

    3.1 Effects of ketamine on pain threshold and open field motor behavior

    In comparison to the control group,the pressure pain thresholds of rats that received ketamine without antipsychotic pretreatment were significantly lower at all four time points(Table 1),while their thermal pain thresholds were significantly higher at all four time points(Table 2).

    In the open field trial compared to the control group,rats that received ketamine without antipsychotic pretreatment had significant increases in grid crossings,falls,head shaking behaviors and circling body movements;but the number of upright standing behaviors(which are considered goal-oriented behaviors)were significantly decreased(Table 3).

    3.2 Effects of antipsychotics on pain threshold

    3.2.1 Pressure pain threshold

    At all four time points the pressure pain thresholds for rats treated with ketamine were significantly higher in rats pretreated with high-dose risperidone than in those with no antipsychotic pretreatment and than in those pretreated with haloperidol or low-dose risperidone.The differences between the pain threshold in the latter three groups were not statistically significant(Table 1).Thus pretreatment with high-dose risperidone reduced,but did not eliminate,the decrease in the pressure pain threshold induced by ketamine.

    3.2.2 Thermal pain threshold

    At the fifth minute following ketamine injection,the thermal pain threshold in rats pretreated with low-dose risperidone was significantly lower than in the other three groups.At other time points,however,therewerenostatisticallysignificant differences in the thermal pain thresholds between the four groups(Table 2).Thus pre-treatment with low-dose risperidone had a transient effect onreducing the increase in the thermal pain threshold induced by ketamine.

    3.3 Effects of antipsychotic pretreatment on ketamine-induced motor behaviors

    3.3.1 Total numbers of passed grids

    The total number grid crossing of rats in the three antipsychotic pretreatment groups were significantly less than in ketamine-treated rats that did not have pretreatment with antipsychotic medications.The number of grid crossings in the high-dose risperidone group and in the haloperidol group were not significantly different from the control group,but the number of grid crossings in the lowdose risperidone group remained significantly higher than in the control group.Thus high-dose risperidone and haloperidol eliminated the effect of ketamine on grid crossings while low-dose resperidone reduced,but did not eliminate,this effect.

    3.3.2 Total numbers of upright standing behaviors

    None of the rats in the three pretreatment groups exhibited any upright standing behaviors during the 120-minute observation period;this was significantly less than in ketamine-treated rats who did not receive pretreatment with antipsychotics and significantly less than in the control group.

    3.3.3 Total numbers of falls

    3.3.4 Total numbers head shakes circling bodymovements

    The total number of head shakes and circling body movements in the three antipsychotic pretreatment groups were significantly less than in rats that received ketamine without pretreatment with antipsychotics.The high-dose risperidone group had fewer head shaking and circling body movements than rats in the other two antipsychotic pretreatment groups but the differences between the low-dose risperidone group and the haloperidol group were not statistically significant(Table 3).

    4 Discussion

    4.1 Main findings

    Similar to previous studies we found that ketamine induces hyperactivity,stereotyped behavior and ataxia and decreases goal-directed behavior[16].The reduction in goal directed behavior (i.e.,standing on hind legs)induced by ketamine was magnified,not ameliorated,by pretreatment with both risperidone and haloperidol.Risperidone had a significant inhibitory effect on the ketamineinduced hyperactivity,stereotyped behavior and ataxia.Haloperidolalso alleviated hyperactivity and stereotyped behaviors,but appeared to aggravate ataxia.Thus the therapeutic efficacy of risperidone on the psychomimetic effects induced by high-dose ketamine was better than that of haloperidol,a finding which parallels conclusions from two clinical investigations[11,17].Falls are a major cause for morbidity and can be fatal in the elderly,particularly in elderly with mental disorders[18],so the finding of decreased ataxia with risperidone has important clinical implications.

    As expected the thermal pain threshold was increased with ketamine but,against expectations,we found that the pressure pain threshold was significantly decreased after the intraperitoneal injection of ketamine.We hypothesize that this inconsistency between the decrease in the pressure pain threshold and the analgesic effects of ketamine may be related to the side effect of increased movements induced by ketamine.The test method for the pressure pain threshold in the present study was based on the lifting of lower limbs after manually applying pressure.Unfortunately,as we saw in the open box test,ketamine induces hyperactivity(i.e,increased movement).This made any results obtained from this measure of the pressure pain threshold suspect.Our results could be interpreted as increased movements with ketamine(thus appearing to have a decreased pressure pain threshold)that were reduced by high-dose risperidone. The opposite effects of ketamine on the pressure pain and thermal pain thresholds could also be explained by differential effects of ketamine on the different afferent nerves which relay pressure and thermal pain,though we consider this a less plausible hypothesis.

    Low-dose risperidone had some effect in reversing the ketamine-induced increase in the thermal pain threshold at 5 minutes after the ketamine injection but not at 15,30 or 45 minutes after the injection.High-dose risperidone and haloperidol had no statistically significant effect on the ketamine-induced increased thermal pain threshold at any of the time points.The transient effect of lowdose risperidone in inhibiting the increased ketamine-induced thermal pain threshold suggests that risperidone's 5-serotonin(5-HTA)and dopamine (DA)antagonistic effects[19,20]play a role in the pain threshold abnormalities seen in schizophrenia,but this hypothesis would need to be tested further. The lack of inhibition of the increased pain threshold over longer periods with low-dose risperidone and with high-dose risperidone and haloperidol—which contradicts the results of Becker and colleagues[8]—remains unexplained,but it may be related to the complex relationship between the analgesic and psychomimetic effects of ketamine or to the higher doses of ketamine(100mg/kg)employed in this study compared to previons studies (30mg/kg)[8].

    4.2 Limitations

    The biggest limitation of the study was that the pressure pain threshold test might have been contaminated by the hyperkinetic side-effects of ketamine.There do not appear to be many remedies to address this problem.One cannot ethically test pain thresholds in humans with schizophrenia.And most measures of pain rely on when a pain stimulus causes movement so other factors that affect movement(such as ketamine administration)can confound the results.Future studies need to find creative ways to control for this issue.The indicators that are frequently used to assess the analgesic effect of ketamine include thermal pain,pressure pain,and visceral pain thresholds[21].This study did not assess the visceral pain threshold,so different results might have been obtained had this measure been included.And the small number of experimental animals in each group(six)may have made it difficult to identify real differences between the groups.

    4.3 Implications

    The present study has supported the notion that that risperidone and haloperidol can effectively reduce some,but not all,of the psychomimetic effects of ketamine.One of the most interesting findings was that risperidone was better at alleviating ketamine-induced ataxia than haloperidol,which could have important implications for the treatment of schizophrenia,particularly elderly individuals with schizophrenia(and,perhaps,dementia).

    No clear conclusions can be drawn about the effect of antipsychotic treatment on the pain thresholds of persons with schizophrenia.Pressure pain thresholds are typically assessed in terms of voluntary movement,so the assessment can be confounded when the subject is treated with a medication that increases movement(such as ketamine). The test of thermal pain was less affected by this problem because it was based on involuntary movement(the rat's flick reflex)but in this case we only found a significant inhibition of the ketamine-induced decreased thermal pain threshold for one of the three medication regimens at one of the four time periods.

    Funding

    This study was funded by the‘Innovation of Technology for College Students'fund of Weifang Medical University(KX2009012).The study did not receive any financial support from pharmaceutical companies.

    1. Hirota K,Lambert DG.Ketamine:its mechanism(s)of action and unusual uses.Br J Anaesth,1996,77(4):441-444.

    2. Hunt MJ,Kessal K,Garcia R.Ketamine induces dopamine-dependent depression of evoked hippocampal activity in the nucleus accumbens in freely moving rats.J Neurosci,2005,25 (2):524-531.

    3. Corlett PR,Honey GD,F(xiàn)letcher PC.From prediction error to psychosis:ketamine as a pharmacological model of delusions. J Psychopharmacol,2007,21(3):238-252.

    4. Morgan CJ,Rossell SL,Pepper F,Smart J,Blackburn J,Brandner B,et al.Semantic priming after ketamine acutely in healthy volunteers and following chronic self-administration in substance users.Biol Psychiatry,2006,59(3):265-272.

    5. Mouri A,Noda Y,Enomoto T,Nabeshima T.Phencyclidine animal models of schizophrenia:approaches from abnormality of glutamatergic neurotransmission and neurodevelopment. Neurochem Int,2007,51(2-4):173-184.

    6. Kilts CD.The changing roles and targets for animal models of schizophrenia.Biol Psychiatry,2001,50(11):845-855.

    7. Olney JW,F(xiàn)arber NB.Glutamate receptor dysfunction and Schizophrenia.Arch Gen Psychiatry,1995,52(12):998-1007.

    8. Becker A,Grecksch G,Zernig G,Ladstaetter E,Hiemke C,et al.Haloperidol and risperidone have specific effects on altered pain sensitivity in the ketamine model of schizophrenia.Psychopharmacology,2009,202(4):579-587.

    9. Hou YZ,Guo JH,Zhou F,Tang YY,Luo J,Xie JK,et al.The double-blind study of risperidone and haloperidal in the treatment of schizophrenia.Shanghai Arch Psychiatry,2001,13 (3):149-151.(in Chinese)

    10. Jochum T,Letzsch A,Greiner W,Wagner G,Sauer H,B?r KJ. Influence of antipsychotic medication on pain perception in schizophrenia.Psychiatry Res,2006,142(2-3):151-156.

    11. Alimohamad H,Sutton L,Mouyal J,Rajakumar N,Rushlow WJ.The effects of antipsychotics on beta-catenin,glycogen synthase kinase-3 and dishevelled in the ventral midbrain of rats.J Neurochem,2005,95(2):513-525.

    12. Johnson MI,Ashton CH,Bousfield DR,Thompson JW.Analgesic effects of different frequencies of transcutaneous electrical nerve stimulation on cold-induced pain in normal subjects. Pain,1989,39(2):231-236.

    13. Blokland A,Lieben C,Deutz NE.Anxiogenic and depressivelike effects,but no cognitive deficits,after repeated moderate tryptophan depletion in the rat.J Psychopharmacol,2002,16 (1):39-49.

    14. Watanabe M,Yoshikawa M,Takeyama K,Hashimoto A,Kobayashi H,Suzuki T.Subchronic administration of ketamine decreases the mRNA expression of serine racemase in rat brain. Tokai J Exp Clin Med,2010,35(4):137-143.

    15. Car H,Oksztel R,Nadlewska A,Wis'niewski K.NMDA receptor antagonists change behavioral activity of rats treated with (S)-4CPG.Pol J Pharmacol,2001,53(4):331-339.

    16. Liu WL,Bian ZZ,Gu ZL,Jiang XG,Guo CY,Zhao YB.Behavior study of ketamine-induced symptoms similar to schizophrenia in mice.Journal of Forensic Medicine,2009,25(3):172-175.(in Chinese)

    17. Zhong XB,Liu XM.A comparative study of extrapyramidal symptoms(EPS)of risperidone and haloperidol.Medical Information,2009,1(7):3-4.(in Chinese)

    18. Finkelsein E,Prabhu M,Chen H.Increased prevalence of falls among elderly individuals with mental health and substance abuse conditions.Am J Geriatr Psychiatry,2007 Jul,15(7):611-619.

    19. Zhen FX,F(xiàn)u JM,Dong Z.Advance in search for the receptoral pharmacology of atypical antipsychotic.Chin J Clin Pharmacol,2003,19(5):393-396.(in Chinese)

    20. Davis JM,Chen N,Glick ID.A meta-analysis of the efficacy of second-generation antipsychotics.Arch Gen Psychiatry,2003,60(6):553-564.

    21. Huang C,Li HT,Shi YS,Han JS,Wan Y.Ketamine potentiates the effect of electroacupuncture on mechanical allodynia in a rat model of neuropathic pain.Neuroscience Letters,2004,368(3):327-331.

    (received date:2010-12-22;accepted date:2011-05-04)

    抗精神病藥物對精神分裂癥大鼠模型痛閾和運動行為的影響

    李 剛1紀蒙蒙1楊 帥1崔東紅2曹煥軍1于劍鋒1

    基金項目:濰坊醫(yī)學院大學生科技創(chuàng)新基金(KX2009012)

    作者單位:1濰坊醫(yī)學院261053;2上海交通大學醫(yī)學院附屬精神衛(wèi)生中心200030。

    通信作者:于劍鋒,電子信箱yujf@wfmc.edu.cn

    背景既往研究提示精神分裂癥患者的疼痛敏感性降低并且可以被抗精神病藥物部分逆轉。對這一假說的評價方法之一是檢測精神分裂癥模型。

    目的在顯示出預期的行為學改變的氯胺酮誘導的精神分裂癥大鼠模型中,檢測是否出現(xiàn)痛閾升高,并且檢測抗精神病藥物預處理是否逆轉這種痛閾升高。

    方法將30只雄性Wistar大鼠隨機分為5組,其中3組先腹腔注射抗精神病藥物預處理[利培酮(0.3 mg/kg)、利培酮(0.9 mg/kg)或氟哌啶醇(1 mg/kg)],30 min后再腹腔注射氯胺酮(100 mg/kg);1組先腹腔注射生理鹽水,再腹腔注射氯胺酮;1個對照組接受2次生理鹽水注射。測定大鼠在基線以及第二次注射后第5、15、30和45 min的壓痛和熱痛閾值。另外的30只大鼠做同樣處理,用曠場實驗觀測大鼠在第二次注射后120 min內的行為改變。

    結果 與對照組相比,在所有時間段內,氯胺酮組大鼠(未用抗精神病藥物)出現(xiàn)壓痛閾降低、熱痛閾升高。在所有時間段內,氟哌啶醇預處理明顯減輕了氯胺酮誘導的壓痛降低,但高或低劑量的利培酮對壓痛閾無明顯影響。用低劑量利培酮預處理減輕了氯胺酮誘導的第5 min時段的熱痛閾升高,但不包括第15~45 min時段。高劑量利培酮和氟哌啶醇對熱痛閾無明顯影響。在曠場實驗中,抗精神病藥物預處理的各組比僅用氯胺酮處理的一組有較少的直立行為(目標指向的行為),較少的穿越格子行為(較低的高運動性),較少的搖頭和轉圈運動。氟哌啶醇預處理組比氯胺酮組(無預處理)和2個利培酮預處理組相比,摔倒(即共濟失調)更為常見。

    結論我們不能肯定先前所見的在精神分裂癥大鼠模型中抗精神病藥物對氯胺酮誘導的痛閾升高有抑制作用。氯胺酮引起的壓痛閾明顯降低可能與氯胺酮注射后增強的全身活動性有關(這使壓痛閾檢測難以可靠進行)。利培酮和氟哌啶醇有效減輕多方面的氯胺酮引起的擬精神病癥狀,而氟哌啶醇增強了氯胺酮引起的共濟失調,利培酮降低了共濟失調。這一資料與易于摔倒的老年患者有臨床相關性。

    利培酮 氟哌啶醇 氯胺酮 精神分裂癥 痛閾 運動行為 動物模型

    number of falls in rats that

    pretreatmentwithhaloperidolwassignificantly higher than in the other four groups.Rats that received ketamine without pretreatment with antipsychotics had significantly more falls than rats pretreated with risperidone,and rats pretreated with low-dose risperidone had significantly more falls than rats pretreated with high-dose risperidone.

    10.3969/j.issn.1002-0829.2011.04.005

    1Weifang Medical University,Weifang 261053;

    2Shanghai Mental Health Center,Shanghai Jiao Tong University School of Medicine,Shanghai 200030

    *Correspondence:yujf@wfmc.edu.cn

    猜你喜歡
    哌啶利培壓痛
    N-甲基哌啶的合成方法研究
    浙江化工(2024年2期)2024-03-15 02:27:40
    帕利哌酮與氟哌啶醇治療兒童抽動障礙對照研究
    壓痛點密集型銀質針溫針灸治療肱骨外上髁炎的臨床觀察
    內熱針治療第三腰椎橫突綜合癥近期及遠期臨床療效觀察
    壓痛點推拿法治療椎動脈型頸椎病35例療效觀察
    新型CCR5拮抗劑:N-[1-{5-溴-2-[(4-氯芐基)氧基]芐基}-4-哌啶基]-N-乙基吡啶甲酰胺的合成
    合成化學(2015年1期)2016-01-17 08:53:55
    認知行為與利培酮聯(lián)合治療精神分裂癥殘留型的臨床療效分析
    利培酮治療精神分裂癥22例臨床觀察
    氨磺必利與利培酮治療精神分裂癥對照研究
    利培酮與阿立哌唑用于精神分裂癥的療效對比
    亚洲国产欧美网| 欧美日韩亚洲高清精品| 男女之事视频高清在线观看| 香蕉久久夜色| 老司机福利观看| 一区二区三区精品91| 一二三四社区在线视频社区8| 天天躁夜夜躁狠狠躁躁| 黑人操中国人逼视频| 自拍欧美九色日韩亚洲蝌蚪91| 国产黄色免费在线视频| 国产在线视频一区二区| 国产精品影院久久| 在线 av 中文字幕| 欧美久久黑人一区二区| 久久香蕉激情| 狠狠婷婷综合久久久久久88av| 亚洲av美国av| 亚洲午夜精品一区,二区,三区| 精品国产乱码久久久久久小说| 十八禁人妻一区二区| 热re99久久精品国产66热6| 国产成人av激情在线播放| 国产精品久久久久久人妻精品电影 | 777米奇影视久久| 丝袜美腿诱惑在线| 久久精品aⅴ一区二区三区四区| 美女视频免费永久观看网站| 国产成+人综合+亚洲专区| 久久午夜综合久久蜜桃| 国产成人一区二区三区免费视频网站| 男女下面插进去视频免费观看| 中文字幕人妻丝袜一区二区| 在线观看人妻少妇| 女同久久另类99精品国产91| 精品少妇内射三级| www.精华液| 精品国产一区二区久久| 亚洲第一青青草原| 亚洲欧美日韩另类电影网站| 久热爱精品视频在线9| 看免费av毛片| 日本一区二区免费在线视频| 国产精品自产拍在线观看55亚洲 | 午夜91福利影院| 真人做人爱边吃奶动态| 久久人妻av系列| 丰满少妇做爰视频| 久久青草综合色| 欧美精品啪啪一区二区三区| 成人国产一区最新在线观看| 欧美+亚洲+日韩+国产| 91字幕亚洲| 亚洲精品久久成人aⅴ小说| 欧美午夜高清在线| 国产91精品成人一区二区三区 | 久久人妻av系列| 日本av手机在线免费观看| 国产精品99久久99久久久不卡| 中文亚洲av片在线观看爽 | 天天影视国产精品| 国产伦理片在线播放av一区| 三上悠亚av全集在线观看| 激情在线观看视频在线高清 | 久久人妻av系列| 亚洲综合色网址| 午夜精品久久久久久毛片777| 亚洲国产欧美一区二区综合| 亚洲人成电影观看| 国产精品国产av在线观看| 男女午夜视频在线观看| 国产视频一区二区在线看| 午夜两性在线视频| 精品国内亚洲2022精品成人 | 国产精品影院久久| 日本黄色视频三级网站网址 | 国产一区二区三区综合在线观看| 免费少妇av软件| 亚洲国产欧美日韩在线播放| 成年版毛片免费区| 91精品国产国语对白视频| 法律面前人人平等表现在哪些方面| 别揉我奶头~嗯~啊~动态视频| 狠狠狠狠99中文字幕| 国产亚洲欧美在线一区二区| 一区二区日韩欧美中文字幕| 丁香六月天网| 999久久久国产精品视频| 中文亚洲av片在线观看爽 | 咕卡用的链子| 亚洲精品久久午夜乱码| 久久国产精品人妻蜜桃| 18禁黄网站禁片午夜丰满| 大型av网站在线播放| 天天操日日干夜夜撸| 亚洲熟妇熟女久久| 国产又爽黄色视频| 亚洲国产成人一精品久久久| 午夜日韩欧美国产| 日本撒尿小便嘘嘘汇集6| 亚洲一区二区三区欧美精品| 欧美日本中文国产一区发布| tube8黄色片| 欧美日韩亚洲高清精品| 国产精品98久久久久久宅男小说| 久久久久网色| 中文字幕色久视频| 国产成人影院久久av| 精品国产一区二区三区久久久樱花| 80岁老熟妇乱子伦牲交| 嫩草影视91久久| 丰满饥渴人妻一区二区三| 无限看片的www在线观看| 黑人欧美特级aaaaaa片| 自拍欧美九色日韩亚洲蝌蚪91| 美女主播在线视频| 亚洲国产欧美一区二区综合| 精品久久久久久久毛片微露脸| 女性生殖器流出的白浆| 精品一区二区三卡| 乱人伦中国视频| 老司机靠b影院| 国产精品久久久久久精品古装| 天堂8中文在线网| 狂野欧美激情性xxxx| 精品国产乱码久久久久久小说| 免费女性裸体啪啪无遮挡网站| 99精国产麻豆久久婷婷| 国产亚洲欧美在线一区二区| 国产一区有黄有色的免费视频| 国产日韩欧美视频二区| 在线 av 中文字幕| 天天躁日日躁夜夜躁夜夜| 免费av中文字幕在线| 国产97色在线日韩免费| 老鸭窝网址在线观看| 性高湖久久久久久久久免费观看| 久久中文看片网| kizo精华| 国产精品98久久久久久宅男小说| 国产成人免费无遮挡视频| 91精品国产国语对白视频| 精品国产国语对白av| 成人18禁高潮啪啪吃奶动态图| 久久久久久久久免费视频了| 老司机午夜福利在线观看视频 | 欧美中文综合在线视频| 国产成人啪精品午夜网站| av一本久久久久| 国精品久久久久久国模美| 91九色精品人成在线观看| 色视频在线一区二区三区| 国产精品一区二区免费欧美| 高潮久久久久久久久久久不卡| 日本av手机在线免费观看| 国产成人免费无遮挡视频| 咕卡用的链子| 五月天丁香电影| 一级黄色大片毛片| 欧美 日韩 精品 国产| 黄色 视频免费看| 久久久久久久大尺度免费视频| 午夜福利视频在线观看免费| 国产主播在线观看一区二区| 色在线成人网| 99re在线观看精品视频| 男女无遮挡免费网站观看| 久久ye,这里只有精品| 一级毛片电影观看| 伦理电影免费视频| 50天的宝宝边吃奶边哭怎么回事| 欧美国产精品一级二级三级| 欧美国产精品一级二级三级| 国产一区二区 视频在线| 美国免费a级毛片| 亚洲欧美日韩另类电影网站| 女人被躁到高潮嗷嗷叫费观| tube8黄色片| 亚洲熟妇熟女久久| 精品免费久久久久久久清纯 | 叶爱在线成人免费视频播放| 99riav亚洲国产免费| 免费不卡黄色视频| 亚洲欧洲精品一区二区精品久久久| 精品高清国产在线一区| 国产亚洲av高清不卡| 久久久久久久国产电影| 精品一品国产午夜福利视频| 成年人免费黄色播放视频| 亚洲av第一区精品v没综合| 久久精品91无色码中文字幕| 老司机午夜十八禁免费视频| 久久国产精品人妻蜜桃| 国产精品久久久久久精品电影小说| 日本欧美视频一区| 香蕉丝袜av| 桃花免费在线播放| 夜夜骑夜夜射夜夜干| 在线观看人妻少妇| 在线观看免费视频日本深夜| 热re99久久精品国产66热6| 欧美黄色片欧美黄色片| 黄片大片在线免费观看| 欧美成人免费av一区二区三区 | 精品福利永久在线观看| 亚洲第一欧美日韩一区二区三区 | 日本五十路高清| 国产av精品麻豆| 日本vs欧美在线观看视频| 午夜91福利影院| 丝袜喷水一区| 香蕉丝袜av| 亚洲人成电影免费在线| 久久99热这里只频精品6学生| 久久久久久久大尺度免费视频| 亚洲精品美女久久久久99蜜臀| 亚洲国产欧美一区二区综合| 亚洲欧洲日产国产| 亚洲午夜理论影院| 男女午夜视频在线观看| 国产精品九九99| 91国产中文字幕| 免费av中文字幕在线| 欧美成人午夜精品| 亚洲,欧美精品.| 丝袜人妻中文字幕| 一级毛片电影观看| 国产精品免费视频内射| 日韩精品免费视频一区二区三区| 最近最新中文字幕大全免费视频| 日韩大片免费观看网站| 欧美人与性动交α欧美软件| 国产不卡一卡二| 亚洲黑人精品在线| 女人精品久久久久毛片| 欧美乱码精品一区二区三区| www.自偷自拍.com| 午夜福利免费观看在线| 亚洲国产av新网站| 在线播放国产精品三级| 水蜜桃什么品种好| 久久精品aⅴ一区二区三区四区| 满18在线观看网站| 久久久精品国产亚洲av高清涩受| 在线观看免费高清a一片| 韩国精品一区二区三区| 90打野战视频偷拍视频| 老司机午夜十八禁免费视频| 精品卡一卡二卡四卡免费| 老司机靠b影院| 亚洲精品美女久久av网站| 69精品国产乱码久久久| 午夜福利视频精品| 99久久人妻综合| 亚洲性夜色夜夜综合| 在线av久久热| 又黄又粗又硬又大视频| 波多野结衣av一区二区av| 天堂中文最新版在线下载| 久久久久国产一级毛片高清牌| 欧美激情久久久久久爽电影 | 欧美黄色片欧美黄色片| 在线观看免费午夜福利视频| 精品少妇久久久久久888优播| 欧美日韩黄片免| 深夜精品福利| 国产精品久久久久久人妻精品电影 | 国产高清国产精品国产三级| 侵犯人妻中文字幕一二三四区| 精品人妻在线不人妻| 视频在线观看一区二区三区| 国产精品 欧美亚洲| 成年版毛片免费区| 国产av一区二区精品久久| 亚洲人成电影观看| 久久久久久久久免费视频了| 久久久久久久大尺度免费视频| 精品少妇黑人巨大在线播放| 99精品久久久久人妻精品| 国产99久久九九免费精品| 欧美 日韩 精品 国产| 99在线人妻在线中文字幕 | 国产一区二区 视频在线| 欧美日韩国产mv在线观看视频| av天堂在线播放| 狠狠婷婷综合久久久久久88av| 成人三级做爰电影| 97人妻天天添夜夜摸| 精品一品国产午夜福利视频| 亚洲av国产av综合av卡| 精品国产乱子伦一区二区三区| 黄色 视频免费看| 精品久久久久久久毛片微露脸| 亚洲免费av在线视频| 色老头精品视频在线观看| 国产xxxxx性猛交| 日韩人妻精品一区2区三区| 国产人伦9x9x在线观看| 麻豆乱淫一区二区| 国产不卡av网站在线观看| 两性夫妻黄色片| 国产片内射在线| 欧美成人午夜精品| 日韩三级视频一区二区三区| 最黄视频免费看| 亚洲av成人一区二区三| 久久久国产欧美日韩av| 午夜福利在线观看吧| 50天的宝宝边吃奶边哭怎么回事| 亚洲全国av大片| 人人妻人人澡人人爽人人夜夜| 精品久久蜜臀av无| 国产精品98久久久久久宅男小说| 日韩欧美三级三区| 波多野结衣一区麻豆| 亚洲成人手机| 搡老岳熟女国产| 久久久久国内视频| 50天的宝宝边吃奶边哭怎么回事| 久久人人97超碰香蕉20202| 久久人妻福利社区极品人妻图片| 国产成人啪精品午夜网站| 成人av一区二区三区在线看| 国产精品.久久久| 久久久久国产一级毛片高清牌| 亚洲三区欧美一区| 人人妻人人澡人人爽人人夜夜| 91麻豆av在线| 超碰97精品在线观看| 叶爱在线成人免费视频播放| 久久久久精品国产欧美久久久| 妹子高潮喷水视频| 亚洲精品国产精品久久久不卡| 中文字幕另类日韩欧美亚洲嫩草| 一级片'在线观看视频| 丰满饥渴人妻一区二区三| 国产免费现黄频在线看| 欧美一级毛片孕妇| 在线观看66精品国产| 老汉色av国产亚洲站长工具| 十分钟在线观看高清视频www| 国产日韩欧美视频二区| av有码第一页| 日韩中文字幕视频在线看片| 精品国产超薄肉色丝袜足j| 久久99一区二区三区| 亚洲色图综合在线观看| 国产主播在线观看一区二区| 无人区码免费观看不卡 | 黄频高清免费视频| 久久影院123| 午夜福利视频在线观看免费| 香蕉国产在线看| 欧美人与性动交α欧美软件| 成年人免费黄色播放视频| 欧美日韩亚洲国产一区二区在线观看 | 欧美日韩视频精品一区| 亚洲自偷自拍图片 自拍| 久久中文看片网| 极品人妻少妇av视频| av不卡在线播放| 精品人妻熟女毛片av久久网站| 老司机午夜福利在线观看视频 | 1024香蕉在线观看| 午夜精品久久久久久毛片777| 日韩免费高清中文字幕av| 他把我摸到了高潮在线观看 | 老司机靠b影院| 成在线人永久免费视频| 亚洲国产欧美在线一区| 日本黄色视频三级网站网址 | 免费女性裸体啪啪无遮挡网站| 黄色丝袜av网址大全| 美女视频免费永久观看网站| 香蕉丝袜av| 丰满迷人的少妇在线观看| 少妇精品久久久久久久| 国产精品偷伦视频观看了| 亚洲欧美一区二区三区久久| 午夜福利乱码中文字幕| 久9热在线精品视频| 中文字幕精品免费在线观看视频| kizo精华| 日韩中文字幕视频在线看片| 久久久久久久大尺度免费视频| cao死你这个sao货| 欧美久久黑人一区二区| 亚洲av成人不卡在线观看播放网| 最近最新免费中文字幕在线| 久久99热这里只频精品6学生| 欧美变态另类bdsm刘玥| av片东京热男人的天堂| 免费在线观看影片大全网站| av网站免费在线观看视频| 精品国内亚洲2022精品成人 | 国产精品99久久99久久久不卡| 深夜精品福利| 国产成人免费观看mmmm| 悠悠久久av| 欧美激情高清一区二区三区| 亚洲欧洲日产国产| 嫩草影视91久久| 免费看十八禁软件| 精品国产国语对白av| 一区福利在线观看| 久9热在线精品视频| 免费在线观看视频国产中文字幕亚洲| 欧美午夜高清在线| 黄色片一级片一级黄色片| 精品少妇一区二区三区视频日本电影| 日韩欧美免费精品| 我的亚洲天堂| avwww免费| 最黄视频免费看| 丰满饥渴人妻一区二区三| 男女免费视频国产| 国精品久久久久久国模美| 热99久久久久精品小说推荐| 夜夜夜夜夜久久久久| 老汉色∧v一级毛片| 纵有疾风起免费观看全集完整版| 窝窝影院91人妻| 久久精品aⅴ一区二区三区四区| 午夜精品久久久久久毛片777| 老司机亚洲免费影院| 性高湖久久久久久久久免费观看| av网站在线播放免费| 狂野欧美激情性xxxx| 男人舔女人的私密视频| 午夜福利在线免费观看网站| 色视频在线一区二区三区| 午夜福利乱码中文字幕| 久久久久久亚洲精品国产蜜桃av| 精品国产超薄肉色丝袜足j| 啪啪无遮挡十八禁网站| 9191精品国产免费久久| 亚洲精品美女久久久久99蜜臀| 久久久久国产一级毛片高清牌| 乱人伦中国视频| 欧美成狂野欧美在线观看| 一本大道久久a久久精品| 欧美午夜高清在线| 99久久精品国产亚洲精品| 热re99久久精品国产66热6| 久久久久久久久久久久大奶| 人妻久久中文字幕网| 久久久精品区二区三区| 女人久久www免费人成看片| 久久国产精品人妻蜜桃| 一个人免费看片子| 日本av免费视频播放| 两性午夜刺激爽爽歪歪视频在线观看 | 久久久久久久大尺度免费视频| 一边摸一边抽搐一进一小说 | 欧美人与性动交α欧美软件| 久久久精品免费免费高清| 后天国语完整版免费观看| 美女国产高潮福利片在线看| 女性生殖器流出的白浆| 一级毛片电影观看| 国产亚洲精品第一综合不卡| 黄色片一级片一级黄色片| 国产亚洲一区二区精品| 精品国产一区二区三区久久久樱花| 国产精品免费大片| 伊人久久大香线蕉亚洲五| 最近最新免费中文字幕在线| 欧美 亚洲 国产 日韩一| 日本黄色日本黄色录像| 高清av免费在线| 波多野结衣av一区二区av| 久久这里只有精品19| 12—13女人毛片做爰片一| 视频在线观看一区二区三区| 欧美国产精品va在线观看不卡| 99在线人妻在线中文字幕 | 国产成人免费观看mmmm| 纯流量卡能插随身wifi吗| 视频在线观看一区二区三区| 免费在线观看视频国产中文字幕亚洲| 中文字幕人妻丝袜一区二区| 人妻久久中文字幕网| 在线观看人妻少妇| 欧美日韩福利视频一区二区| 亚洲国产欧美日韩在线播放| 欧美人与性动交α欧美精品济南到| 亚洲熟女毛片儿| 国产av又大| 亚洲熟女毛片儿| 久久天躁狠狠躁夜夜2o2o| 欧美 亚洲 国产 日韩一| 欧美激情极品国产一区二区三区| 高清av免费在线| 精品亚洲乱码少妇综合久久| 国产色视频综合| 一边摸一边抽搐一进一出视频| 免费高清在线观看日韩| av国产精品久久久久影院| 久久毛片免费看一区二区三区| 狂野欧美激情性xxxx| www.自偷自拍.com| 国产av又大| 又紧又爽又黄一区二区| 高清黄色对白视频在线免费看| 午夜日韩欧美国产| 国产精品九九99| 久久人人爽av亚洲精品天堂| 午夜福利乱码中文字幕| 中文字幕色久视频| 精品人妻1区二区| 视频区图区小说| 蜜桃国产av成人99| 欧美乱妇无乱码| 麻豆成人av在线观看| av超薄肉色丝袜交足视频| 亚洲午夜精品一区,二区,三区| 天堂中文最新版在线下载| 久久精品亚洲熟妇少妇任你| 91av网站免费观看| 国产成人精品久久二区二区免费| 美女高潮到喷水免费观看| 黄色怎么调成土黄色| 他把我摸到了高潮在线观看 | 国产日韩欧美在线精品| 精品久久久久久电影网| 男人舔女人的私密视频| 免费观看a级毛片全部| 另类精品久久| 在线观看免费日韩欧美大片| 久久国产精品影院| 久久免费观看电影| 欧美性长视频在线观看| 精品国产一区二区三区久久久樱花| 中文字幕av电影在线播放| 日本精品一区二区三区蜜桃| 国产高清国产精品国产三级| 考比视频在线观看| 亚洲综合色网址| 日本欧美视频一区| 色综合欧美亚洲国产小说| 国产精品久久久av美女十八| 老司机午夜福利在线观看视频 | 狠狠婷婷综合久久久久久88av| 国产亚洲精品一区二区www | 国产av精品麻豆| 91九色精品人成在线观看| 国产av精品麻豆| 国产在视频线精品| 日韩欧美免费精品| 久久精品亚洲熟妇少妇任你| 满18在线观看网站| 曰老女人黄片| 交换朋友夫妻互换小说| 国产精品亚洲一级av第二区| 大香蕉久久成人网| 亚洲国产欧美日韩在线播放| 一进一出抽搐动态| 纯流量卡能插随身wifi吗| 一区二区av电影网| 久久久久久人人人人人| 18禁黄网站禁片午夜丰满| 在线亚洲精品国产二区图片欧美| 成人黄色视频免费在线看| 中文字幕制服av| 国产精品美女特级片免费视频播放器 | 国产精品自产拍在线观看55亚洲 | 一级毛片精品| 女人久久www免费人成看片| 国精品久久久久久国模美| 一区二区av电影网| 亚洲精品在线美女| 亚洲色图 男人天堂 中文字幕| 中文亚洲av片在线观看爽 | 欧美精品一区二区大全| 两性午夜刺激爽爽歪歪视频在线观看 | 无遮挡黄片免费观看| 国产97色在线日韩免费| 丁香六月天网| 老司机午夜福利在线观看视频 | 黄色视频,在线免费观看| 99九九在线精品视频| 免费观看av网站的网址| 99国产精品一区二区三区| 亚洲精品中文字幕一二三四区 | 国产有黄有色有爽视频| 国产精品久久久久成人av| 欧美激情高清一区二区三区| 高清欧美精品videossex| 国产免费福利视频在线观看| 亚洲va日本ⅴa欧美va伊人久久| 亚洲欧美一区二区三区黑人| 在线 av 中文字幕| 母亲3免费完整高清在线观看| 曰老女人黄片| 亚洲精品自拍成人| 亚洲欧美日韩另类电影网站| 嫁个100分男人电影在线观看| 亚洲三区欧美一区| 欧美日韩视频精品一区| 悠悠久久av| 亚洲国产av新网站| 男女午夜视频在线观看| 国产单亲对白刺激| 国产又爽黄色视频| 免费久久久久久久精品成人欧美视频| 一区福利在线观看| 欧美精品av麻豆av| 人妻一区二区av| 精品国内亚洲2022精品成人 | 国产精品亚洲一级av第二区| 在线观看免费日韩欧美大片| 免费在线观看影片大全网站| 黄色片一级片一级黄色片| 国产亚洲精品第一综合不卡| 久久精品国产99精品国产亚洲性色 |