中国药理学通报
中國藥理學通報
중국약이학통보
CHINESE PHARMACOLOGICAL BULLETIN
2015年
4期
487-492
,共6页
沈一维%律峰%黎平%罗洁%谢飞%闵苏
瀋一維%律峰%黎平%囉潔%謝飛%閔囌
침일유%률봉%려평%라길%사비%민소
氯胺酮%氟西汀%抑郁%前额叶%神经型一氧化氮合酶%神经型一氧化氮合酶羧基末端 PDZ 配体
氯胺酮%氟西汀%抑鬱%前額葉%神經型一氧化氮閤酶%神經型一氧化氮閤酶羧基末耑 PDZ 配體
록알동%불서정%억욱%전액협%신경형일양화담합매%신경형일양화담합매최기말단 PDZ 배체
ketamine%fluoxetine%depression%pre-frontal lobe%nitirc oxide synthase%CAPON
目的：探讨氯胺酮联合氟西汀对抑郁大鼠行为学以及对大鼠脑内前额叶神经型一氧化氮合酶（nNOS）羧基末端PDZ 配体（CAPON）的影响。方法健康成年♂ SPF 级 SD大鼠，体质量220～270 g，2.5～3月龄，采用慢性轻度不可预见性应激法建立抑郁模型。选建模成功的大鼠96只，采用随机数字表法，将其随机分为4组（n ＝24）：抑郁对照组（D组）、氯胺酮组（K 组）、氟西汀组（F 组）及氯胺酮联合氟西汀组（KF 组）。再根据给予药物处理时间的不同，各组随机分为2个亚组（n ＝12）：处理3 d 组（D3、K3、F3、KF3）和处理7 d 组（D7、K7、F7、KF7）。D 组行空白对照处理，K 组给予氯胺酮10 mg·kg －1腹腔注射；F 组给予氟西汀1.8 mg·kg －1灌胃；KF 组氯胺酮10 mg·kg －1腹腔注射后，即刻给予氟西汀1.8 mg·kg －1灌胃。根据所在亚组分别给予各组连续3 d或7 d 处理，每天1次。于建模前1 d，建模后1 d 及药物处理结束后1 d 采用旷场实验和糖水偏好实验评价其抑郁状态。所有行为学检测完成后1 d 处死大鼠，分别采用免疫组织化学法和RTPCR 法检测前额叶nNOS、CAPON 蛋白及其mRNA 的表达。结果与建模前比较，各组大鼠建模后水平运动距离、直立次数减少，糖水偏好比下降（P ＜0.05），且各组间差异无统计学意义（P ＞0.05）。在药物处理3 d 后，与D3组比较，K3组和KF3组水平运动距离、直立次数增多，糖水偏好比升高，nNOS 及其mRNA 表达下调，CAPON 蛋白及其mRNA 表达上调（P ＜0.05）。在药物处理7 d 后，与D7组比较，K7组，F7组和KF7组水平运动距离、直立次数增多，糖水偏好比升高，nNOS 及其mRNA 表达下调，CAPON 蛋白及其mRNA 表达上调（P ＜0.05）；与F7组比较，KF7组水平运动距离、直立次数增多，糖水偏好比升高，nNOS 及其mRNA 表达下调，CAPON 蛋白及其mRNA 表达上调（P ＜0.05）。结论氯胺酮联合氟西汀较单独使用氟西汀对抑郁大鼠的抗抑郁作用更强，且抗抑郁起效时间缩短，其机制可能与氯胺酮联合氟西汀可降低大鼠脑内前额叶nNOS 表达及升高其配体CAPON 的表达有关。
目的：探討氯胺酮聯閤氟西汀對抑鬱大鼠行為學以及對大鼠腦內前額葉神經型一氧化氮閤酶（nNOS）羧基末耑PDZ 配體（CAPON）的影響。方法健康成年♂ SPF 級 SD大鼠，體質量220～270 g，2.5～3月齡，採用慢性輕度不可預見性應激法建立抑鬱模型。選建模成功的大鼠96隻，採用隨機數字錶法，將其隨機分為4組（n ＝24）：抑鬱對照組（D組）、氯胺酮組（K 組）、氟西汀組（F 組）及氯胺酮聯閤氟西汀組（KF 組）。再根據給予藥物處理時間的不同，各組隨機分為2箇亞組（n ＝12）：處理3 d 組（D3、K3、F3、KF3）和處理7 d 組（D7、K7、F7、KF7）。D 組行空白對照處理，K 組給予氯胺酮10 mg·kg －1腹腔註射；F 組給予氟西汀1.8 mg·kg －1灌胃；KF 組氯胺酮10 mg·kg －1腹腔註射後，即刻給予氟西汀1.8 mg·kg －1灌胃。根據所在亞組分彆給予各組連續3 d或7 d 處理，每天1次。于建模前1 d，建模後1 d 及藥物處理結束後1 d 採用曠場實驗和糖水偏好實驗評價其抑鬱狀態。所有行為學檢測完成後1 d 處死大鼠，分彆採用免疫組織化學法和RTPCR 法檢測前額葉nNOS、CAPON 蛋白及其mRNA 的錶達。結果與建模前比較，各組大鼠建模後水平運動距離、直立次數減少，糖水偏好比下降（P ＜0.05），且各組間差異無統計學意義（P ＞0.05）。在藥物處理3 d 後，與D3組比較，K3組和KF3組水平運動距離、直立次數增多，糖水偏好比升高，nNOS 及其mRNA 錶達下調，CAPON 蛋白及其mRNA 錶達上調（P ＜0.05）。在藥物處理7 d 後，與D7組比較，K7組，F7組和KF7組水平運動距離、直立次數增多，糖水偏好比升高，nNOS 及其mRNA 錶達下調，CAPON 蛋白及其mRNA 錶達上調（P ＜0.05）；與F7組比較，KF7組水平運動距離、直立次數增多，糖水偏好比升高，nNOS 及其mRNA 錶達下調，CAPON 蛋白及其mRNA 錶達上調（P ＜0.05）。結論氯胺酮聯閤氟西汀較單獨使用氟西汀對抑鬱大鼠的抗抑鬱作用更彊，且抗抑鬱起效時間縮短，其機製可能與氯胺酮聯閤氟西汀可降低大鼠腦內前額葉nNOS 錶達及升高其配體CAPON 的錶達有關。
목적：탐토록알동연합불서정대억욱대서행위학이급대대서뇌내전액협신경형일양화담합매（nNOS）최기말단PDZ 배체（CAPON）적영향。방법건강성년♂ SPF 급 SD대서，체질량220～270 g，2.5～3월령，채용만성경도불가예견성응격법건립억욱모형。선건모성공적대서96지，채용수궤수자표법，장기수궤분위4조（n ＝24）：억욱대조조（D조）、록알동조（K 조）、불서정조（F 조）급록알동연합불서정조（KF 조）。재근거급여약물처리시간적불동，각조수궤분위2개아조（n ＝12）：처리3 d 조（D3、K3、F3、KF3）화처리7 d 조（D7、K7、F7、KF7）。D 조행공백대조처리，K 조급여록알동10 mg·kg －1복강주사；F 조급여불서정1.8 mg·kg －1관위；KF 조록알동10 mg·kg －1복강주사후，즉각급여불서정1.8 mg·kg －1관위。근거소재아조분별급여각조련속3 d혹7 d 처리，매천1차。우건모전1 d，건모후1 d 급약물처리결속후1 d 채용광장실험화당수편호실험평개기억욱상태。소유행위학검측완성후1 d 처사대서，분별채용면역조직화학법화RTPCR 법검측전액협nNOS、CAPON 단백급기mRNA 적표체。결과여건모전비교，각조대서건모후수평운동거리、직립차수감소，당수편호비하강（P ＜0.05），차각조간차이무통계학의의（P ＞0.05）。재약물처리3 d 후，여D3조비교，K3조화KF3조수평운동거리、직립차수증다，당수편호비승고，nNOS 급기mRNA 표체하조，CAPON 단백급기mRNA 표체상조（P ＜0.05）。재약물처리7 d 후，여D7조비교，K7조，F7조화KF7조수평운동거리、직립차수증다，당수편호비승고，nNOS 급기mRNA 표체하조，CAPON 단백급기mRNA 표체상조（P ＜0.05）；여F7조비교，KF7조수평운동거리、직립차수증다，당수편호비승고，nNOS 급기mRNA 표체하조，CAPON 단백급기mRNA 표체상조（P ＜0.05）。결론록알동연합불서정교단독사용불서정대억욱대서적항억욱작용경강，차항억욱기효시간축단，기궤제가능여록알동연합불서정가강저대서뇌내전액협nNOS 표체급승고기배체CAPON 적표체유관。
Aim To investigate the effect of ketamine plus fluoxetine on depressed behavior and the expres-sion of neuronal nitric oxide synthase (nNOS)and CA-PON in prefrontal lobe of mentally depressed rats at different time points,so as to study the possible mecha-nism of ketamine plus fluoxetine inducing antidepres-sant behavior.Methods Healthy adult male Sprague-Dawley rats,aged 2.5 ~3 months,weighing 220 ~270 g,were induced as the rodent model of depression by chronic unpredictable mild stress (CUMS).After the models of depression were established,96 of CUMS modeling successfully depressed rats were selected. Then they were randomly divided into four groups (n =24 each):the depressed group (group D,untreated group),ketamine group (group K,treated with intrap-eritoneal injection of ketamine 1 0 mg·kg -1 once a day for 3 days or 7 days),fluoxetine group (group F,trea-ted with gavage of fluoxetine 1 .8 mg·kg -1 once a day for 3 days or 7 days),or ketamine plus fluoxetine group (group KF,treated with intraperitoneal injection of ketamine 1 0 mg·kg -1 plus gavage of fluoxetine 1 .8 mg·kg -1 once a day for 3 days or 7 days).Open field test and sucrose preference test were performed 1 day before depression model was established,and 1 day before and after treatment.The rats were sacrificed 1 day after the last test for determination of the expres-sion of nNOS and CAPON protein (using immuno-his-tochemisity)and mRNA (by RT-PCR)in the prefron-tal lobe.Results After the models of depression were established,the total distance,rearing number and the sucrose preference percentage (SPP)were decreased significantly compared with those before (P <0.05). There was no significant difference among all groups in the total distance,rearing number and the SPP before treatment (P >0.05 ).Compared with groups D and F,the total distance was prolonged,the number of rea-ring and SPP were significantly increased,the expres-sion of nNOS protein and mRNA was down-regulated and the expression of CAPON protein and mRNA was up-regulated in groups K and KF,with 3 days’treat-ment (P <0.05).Compared with group D,the total distance was prolonged,the number of rearing and SPP were significantly increased,the expression of nNOS protein and mRNA was down-regulated and the expres-sion of CAPON protein and mRNA was up-regulated in groups K,F and KF with 7 days’treatment (P <0.05).Compared with group F,the total distance was prolonged,the number of rearing and SPP were signifi-cantly increased,the expression of nNOS protein and mRNA was down-regulated and the expression of CA-PON protein and mRNA was up-regulated in group KF with 7 days’treatment (P <0.05).Conclusion Co-administration of antidepressant fluoxetine with ket-amine may induce a more pronounced antidepressant activity than treatment with each antidepressant alone and it can shorten the time to improve the depressive state through promoting the expression of CAPON and inhibiting nNOS activity in the prefrontal lobe of men-tally depressed rats.
