毁损双侧伏隔核对大鼠吗啡条件性位置偏爱复燃的影响

目的探讨毁损双侧伏隔核对小剂量吗啡诱导大鼠条件性位置偏爱复燃的影响。方法设置毁损组、假毁损组及空白对照组(n=10),建立大鼠吗啡条件性位置偏爱模型,消退后采用立体定向下直流电(10mA,30s)毁损双侧伏隔核,分别在术后3d、10d、30d给予小剂量吗啡(2.5mg/kg)诱导复燃,观察记录各组大鼠条件性位置偏爱得分,采用方差分析及均数间多重比较进行统计学分析。结果条件性位置偏爱模型建立成功后,经消退各组位置偏爱得分间差异无统计学意义(P>0.05);毁损术后各时间点吗啡诱导复燃时,毁损组均较假毁损组的位置偏爱得分低(P<0.05),而毁损组各时间点间位置偏爱得分差异无统计学意义(P>0.05)。结论毁损双侧伏隔核可以抑制小剂量吗啡诱导的复燃,且此作用至少可维持30d。     

催产素介导氯化锂抑制吗啡诱导的大鼠条件性位置偏爱

应用条件性位置偏爱模型,观察了锂盐对吗啡诱导的大鼠条件性位置偏爱的影响。结果表明,急性锂盐处理可明显抑制吗啡诱导的大鼠条件性位置偏爱,锂盐对吗啡诱导的大鼠条件性位置偏爱的抑制效应可被侧脑室注射催产素抗血清所阻断,提示锂盐对吧啡诱导的大鼠条件性位置偏爱的抑制作用可能是通过中枢催产素发挥作用的。     

深部电刺激伏隔核对吗啡成瘾大鼠复吸后伏隔核内γ-氨基丁酸含量变化的影响

目的研究深部电刺激(deep brain stimulation,DBS)双侧伏隔核对吗啡成瘾大鼠复吸后伏隔核内γ-氨基丁酸(γ-aminobutyric Acid,GABA)含量的影响。方法手术前使用条件性位置偏爱试验(conditionedplace preference,CPP)筛选无自然偏爱大鼠,随机分组后DBS组行电极植入术,术后10天采用固定剂量吗啡皮下注射(10mg.Kg-1)建立吗啡成瘾大鼠模型(使用CPP证实)。通过改进的DBS电路进行电刺激(频率130Hz,电流300uA,电压1V,1h.d-1),在不同的时间点使用CPP证实DBS组大鼠戒断成功后再皮下给予小剂量吗啡(3mg.Kg-1),24h后使用CPP验证吗啡成瘾大鼠复吸模型建立成功。CPP试验结束后于冰台上按大鼠脑立体定位图谱取伏隔核行高效液相色谱法(high performance liquid chromatography,HPLC)测定GABA含量。结果①皮下注射固定剂量吗啡能够使大鼠成瘾,DBS能够有效抑制吗啡复吸行为;②morphine+DBS组大鼠伏隔核内GABA含量与吗啡组,morphine+sham组差异明显。结论 DBS双侧伏隔核使吗啡成瘾大鼠复吸后伏隔核内GABA含量增加。     

电刺激伏核对吗啡成瘾心理依赖大鼠行为学的影响

目的 通过建立脑深部刺激(deep brain stimulation,DBS)SD大鼠双侧伏核的动物模型,探讨DBS伏核对吗啡心理依赖大鼠行为学的影响.方法 40只大鼠同期依大鼠立体定向图谱行双侧伏核刺激电极的植入术,20只为吗啡假刺激组,20只为DBS组.术前(用药后第15天)、术后(刺激后第2～6天)对戒断症状进行评分,术前(用药后第15天)和术后(刺激后第2、4、6天)行条件性位置偏爱实验,研究大鼠的行为学变化40只大鼠成功地同期双侧伏核植入DBS刺激电极, 条件位置偏爱实验结果为吗啡成瘾大鼠在伴药箱平均停留时间长于非伴药箱,与生理盐水组比较具有统计学意义(P<0.01);DBS组与术前及吗啡假刺激组相比在伴药箱平均停留时间均明显缩短,具统计学意义(P<0.01),提示高频电刺激伏核能有效减轻大鼠吗啡心理依赖症状.术前戒断症状评分结果表明吗啡成瘾大鼠模型的成功建立(P<0.01);术后DBS大鼠的戒断症状与术前相比具统计学意义,证实DBS减轻了大鼠的躯体依赖症状.结论 高频刺激吗啡成瘾大鼠双侧伏核,能够有效地减轻大鼠吗啡心理依赖症状,为DBS伏核治疗吗啡等成瘾药物的心理依赖提供了实验依据.     

大鼠伏隔核多巴胺D2受体及转运体与吗啡条件性位置偏爱易感性的关系

目的 探讨吗啡条件性位置偏爱(CPP)不同易感性的大鼠脑伏隔核多巴胺D2受体(D2R)和多巴胺转运体(DAT)水平.方法 将160只雄性Sprague-Dawley大鼠随机抽取30只作为对照组,余130只为吗啡组.对吗啡组在预测试后建立吗啡CPP模型.根据CPP值[以末次CPP测评时大鼠在伴药侧(大鼠注射吗啡后放入该侧,吗啡剂量从5 mg·kg-1·次-1开始逐渐增加,第10天为50 mg·kg-1·次-1)的停留时间减去预测试在该侧停留的时间]将吗啡组大鼠按比例分为高(26只)、中(78只)、低偏爱组(26只),其中高、低偏爱组(每组大鼠死亡各2只)分别于吗啡末次注射(对照组注射『司体积生理盐水)后3 h.3 d和14 d分别处死大鼠(每组各8只),用原位杂交法检测伏隔核D2R和DAT的灰度值(阳性区域的强弱与灰度值呈反比),并与对照组比较.结果 (1)预测试3组CPP值的差异无统计学意义(P>0.05);但在吗啡注射后3 h、戒断后3 d和14 d,高偏爱组CPP值[分别为(507±108)s、(524±113)s、(483±60)s]均长于低偏爱组[分别为(100±74)s、(166±86)s、(149±89)s;P=0.000]和对照组[分别为(97 ±111)s、(39±26)s、(-4.9 ±140.1)s;P=0.000].(2)上述各时点高偏爱组D2R mRNA灰度值(131 ±3、122±5、119±5)均高于低偏爱组(125±4、117±8、114±5)和对照组(11l±6、107±7、106±3;P<0.01);高偏爱组DAT mRNA灰度值(161±5、143±4、134±6)亦高于低偏爱组(156±5、139±3、130±4)和对照组(120±4、126±7、129±4;P<0.01).结论 大鼠吗啡CPP易感性高可能与伏隔核的D2R及DAT表达低下有关.     

大鼠伏隔核多巴胺D2受体及转运体与吗啡条件性位置偏爱易感性的关系

Objective To explore the possible role of the expression of dopamine D2 receptor (D2R)and dopamine transporter(DAT)located in the nucleur accumben(Nac)in rats with difierent CPP susceptibility.Methods Altogether 160 male Sprague-Dawley rats were randomly assigned into experiment group(n=130)and control group(n=30).The experiment rats were re-classified into three groups according to the numerical value of the CPP(conditioned place preference),high preference group(HP group,n=26),moderate preference group(n=78)and low preference group(LP group,n=26).At the time of 3 hours,72 hours and 14 days after the final injection,rats in each group were scarified,and the mRNA levels of D2R and DAT in Nac were estimated with in situ hybridization.Results No significant difference of pretest scores staying at the non-preference chamber exist among the three groups(P=0.470),however.the time stayed at the conditioned preference chamber during the test period minus the time stayed at pretest natural preference was significantly higher in the HP group than the LP group(P＜0.01).In each time-point,the expression of D2R mRNA in HP group,were lower that in LP group[(131±3,122±5,119±5)and(125±4,117±8,114±5),P＜0.01].In each time-point,the expression of DAT mRNA in HP group,were significantly lower than that in LP group[(161±5,143±4,134±6)and(156±5,139±3,130±4),P＜0.01].Conclusions It can be inferred that D2R and DAT may be correlated closely and underlie the difierent susceptibility to morphine induced CPP.     

大鼠伏隔核多巴胺D2受体及转运体与吗啡条件性位置偏爱易感性的关系

Objective To explore the possible role of the expression of dopamine D2 receptor (D2R)and dopamine transporter(DAT)located in the nucleur accumben(Nac)in rats with difierent CPP susceptibility.Methods Altogether 160 male Sprague-Dawley rats were randomly assigned into experiment group(n=130)and control group(n=30).The experiment rats were re-classified into three groups according to the numerical value of the CPP(conditioned place preference),high preference group(HP group,n=26),moderate preference group(n=78)and low preference group(LP group,n=26).At the time of 3 hours,72 hours and 14 days after the final injection,rats in each group were scarified,and the mRNA levels of D2R and DAT in Nac were estimated with in situ hybridization.Results No significant difference of pretest scores staying at the non-preference chamber exist among the three groups(P=0.470),however.the time stayed at the conditioned preference chamber during the test period minus the time stayed at pretest natural preference was significantly higher in the HP group than the LP group(P＜0.01).In each time-point,the expression of D2R mRNA in HP group,were lower that in LP group[(131±3,122±5,119±5)and(125±4,117±8,114±5),P＜0.01].In each time-point,the expression of DAT mRNA in HP group,were significantly lower than that in LP group[(161±5,143±4,134±6)and(156±5,139±3,130±4),P＜0.01].Conclusions It can be inferred that D2R and DAT may be correlated closely and underlie the difierent susceptibility to morphine induced CPP.     

大鼠伏隔核多巴胺D2受体及转运体与吗啡条件性位置偏爱易感性的关系

Objective To explore the possible role of the expression of dopamine D2 receptor (D2R)and dopamine transporter(DAT)located in the nucleur accumben(Nac)in rats with difierent CPP susceptibility.Methods Altogether 160 male Sprague-Dawley rats were randomly assigned into experiment group(n=130)and control group(n=30).The experiment rats were re-classified into three groups according to the numerical value of the CPP(conditioned place preference),high preference group(HP group,n=26),moderate preference group(n=78)and low preference group(LP group,n=26).At the time of 3 hours,72 hours and 14 days after the final injection,rats in each group were scarified,and the mRNA levels of D2R and DAT in Nac were estimated with in situ hybridization.Results No significant difference of pretest scores staying at the non-preference chamber exist among the three groups(P=0.470),however.the time stayed at the conditioned preference chamber during the test period minus the time stayed at pretest natural preference was significantly higher in the HP group than the LP group(P＜0.01).In each time-point,the expression of D2R mRNA in HP group,were lower that in LP group[(131±3,122±5,119±5)and(125±4,117±8,114±5),P＜0.01].In each time-point,the expression of DAT mRNA in HP group,were significantly lower than that in LP group[(161±5,143±4,134±6)and(156±5,139±3,130±4),P＜0.01].Conclusions It can be inferred that D2R and DAT may be correlated closely and underlie the difierent susceptibility to morphine induced CPP.     

大鼠伏隔核多巴胺D2受体及转运体与吗啡条件性位置偏爱易感性的关系

Objective To explore the possible role of the expression of dopamine D2 receptor (D2R)and dopamine transporter(DAT)located in the nucleur accumben(Nac)in rats with difierent CPP susceptibility.Methods Altogether 160 male Sprague-Dawley rats were randomly assigned into experiment group(n=130)and control group(n=30).The experiment rats were re-classified into three groups according to the numerical value of the CPP(conditioned place preference),high preference group(HP group,n=26),moderate preference group(n=78)and low preference group(LP group,n=26).At the time of 3 hours,72 hours and 14 days after the final injection,rats in each group were scarified,and the mRNA levels of D2R and DAT in Nac were estimated with in situ hybridization.Results No significant difference of pretest scores staying at the non-preference chamber exist among the three groups(P=0.470),however.the time stayed at the conditioned preference chamber during the test period minus the time stayed at pretest natural preference was significantly higher in the HP group than the LP group(P＜0.01).In each time-point,the expression of D2R mRNA in HP group,were lower that in LP group[(131±3,122±5,119±5)and(125±4,117±8,114±5),P＜0.01].In each time-point,the expression of DAT mRNA in HP group,were significantly lower than that in LP group[(161±5,143±4,134±6)and(156±5,139±3,130±4),P＜0.01].Conclusions It can be inferred that D2R and DAT may be correlated closely and underlie the difierent susceptibility to morphine induced CPP.     

大鼠伏隔核多巴胺D2受体及转运体与吗啡条件性位置偏爱易感性的关系

Objective To explore the possible role of the expression of dopamine D2 receptor (D2R)and dopamine transporter(DAT)located in the nucleur accumben(Nac)in rats with difierent CPP susceptibility.Methods Altogether 160 male Sprague-Dawley rats were randomly assigned into experiment group(n=130)and control group(n=30).The experiment rats were re-classified into three groups according to the numerical value of the CPP(conditioned place preference),high preference group(HP group,n=26),moderate preference group(n=78)and low preference group(LP group,n=26).At the time of 3 hours,72 hours and 14 days after the final injection,rats in each group were scarified,and the mRNA levels of D2R and DAT in Nac were estimated with in situ hybridization.Results No significant difference of pretest scores staying at the non-preference chamber exist among the three groups(P=0.470),however.the time stayed at the conditioned preference chamber during the test period minus the time stayed at pretest natural preference was significantly higher in the HP group than the LP group(P＜0.01).In each time-point,the expression of D2R mRNA in HP group,were lower that in LP group[(131±3,122±5,119±5)and(125±4,117±8,114±5),P＜0.01].In each time-point,the expression of DAT mRNA in HP group,were significantly lower than that in LP group[(161±5,143±4,134±6)and(156±5,139±3,130±4),P＜0.01].Conclusions It can be inferred that D2R and DAT may be correlated closely and underlie the difierent susceptibility to morphine induced CPP.     

Morphine conditioned place preference depends on glucocorticoid receptors in both hippocampus and nucleus accumbens

Learned association between drugs of abuse and context is essential for the formation of drug conditioned place preference (CPP), which is believed to engage many brain regions including hippocampus and nucleus accumbens (NAc). The underlying mechanisms are not fully understood. Here, we examined whether glucocorticoid receptors (GRs) of hippocampus and NAc influenced the formation of morphine CPP in Sprague Dawley rats. We found that systemic or intrahippocampal infused DMSO vehicle (DMSO 20% in saline) 30 min before daily morphine (10 mg/kg, s.c.) conditioning did not affect the formation of morphine CPP. In contrast, systemic administration (5 mg/kg, s.c.) or intrahippocampal infusion (0, 0.1, 1.0, 10, 20 microg per side) of the GR antagonist RU38486 blocked or impaired the formation of CPP in a dose-dependent manner, respectively. Furthermore, intra-NAc infused RU38486 (10 microg per side) but not DMSO vehicle also prevented the formation of CPP. These results demonstrate that both the GRs of hippocampus and NAc are necessary for the formation of morphine CPP, suggesting a neural network function of the GRs in forming the opiate-associated memory.     

The caudal part of the posterior insula of rats participates in the maintenance but not the acquisition of morphine conditioned place preference

The heterogeneous insular cortex plays an interoceptive role in drug addiction by signaling the availability of drugs of abuse. Here, we tested whether the caudal part of the multisensory posterior insula (PI) stores somatosensory‐associated rewarding memories. Using Sprague Dawley rats as subjects, we first established a morphine‐induced conditioned place preference (CPP) paradigm, mainly based on somatic cues. Secondly, an electrolytic lesion of the caudal portion of the PI was carried out before and after the establishment of CPP, respectively. Our data demonstrated that the caudal PI lesions disrupted the maintenance, but not the acquisition of morphine‐induced CPP. Lesion or subtle disruption of the PI had no major impact on locomotor activity. These findings indicate that the caudal portion of the PI might be involved in either the storage or the retrieval of morphine CPP memory.     

吗啡预处理增强吗啡诱导的条件性位置偏爱的反应恢复但减弱保持

背景：药物相关的条件化刺激在强迫性觅药行为的复发中发挥重要的作用。条件化刺激对药物相关行为所起的作用会受早期用药经历的影响。 目的：本实验考察早期接触吗啡对戒断后吗啡诱发的条件性位置偏爱现象的形成、保持和反应恢复的影响。 构思：随机编组,并设对照组来完成实验。 环境：中国科学院心理研究所 心理健康重点实验室 材料：采用体重范围在240~260克的64只Sprague-Dawley雄鼠,均来自中国北京查理河实验室。所有实验流程都符合动物伦理规范。 方法：本实验使用四种不同的吗啡预处理方案：1）“加强型”（每天两次一共注射五天,使用从10mg/kg到60mg/kg的上升剂量）;2）“适中型”（ 5mg/kg的剂量每天一次一共注射五天）;3）“急性型”（5mg/kg的剂量只注射一次）;4）盐水对照组。在预处理过后,大鼠腹腔注射3mg/kg的吗啡或盐水,训练条件性位置偏爱行为。 主要测量标准：建立条件性位置偏爱模型之后,通过每周一次、持续一个月的反复测试衡量吗啡的CPP保持性。通过在两侧箱体给于盐水使条件化位置偏爱行为消退后,再给于低剂量的（0.05mg/kg,0.15mg/kg）的吗啡再使动物恢复条件性位置偏爱行为。 结果：吗啡诱导的CPP的形成并未受吗啡处理的影响。然而,接受反复的吗啡预处理的老鼠的CPP表现出低持久性,并且能够被较低剂量的吗啡诱发条件性位置偏爱的反应恢复。吗啡诱导的CPP的保持和反应恢复在单次吗啡暴露和对照组老鼠之间没有差别。 结论：前期接触更多药物的个体当再次暴露于成瘾药物时,对药物会有更高的易感性。 关键词：用药史、条件性位置偏爱、吗啡、反应恢复     

高频电刺激伏隔核对大鼠可卡因自身给药行为的影响

目的通过高频电刺激大鼠双侧伏隔核(nucleus accumbens,NAc),研究其对可卡因诱导的大鼠自身给药行为的影响,为临床治疗药物成瘾提供新的思路。方法16只大鼠随机分为假刺激组和刺激组,每组8只,二组均进行15天可卡因固定比率自身给药训练,自第16天起,行熄灭训练直到其触鼻反应率小于15%稳定阶段的触鼻反应率,复燃阶段两组大鼠均腹腔注射20mg/kg的可卡因点燃,刺激组大鼠在整个复燃阶段给予持续伏隔核高频电刺激,假刺激组不施加刺激。大鼠的熄灭阶段和点燃复吸阶段交替进行三次。结果刺激组大鼠在三次复吸期内的触鼻频率与自身给药训练第15天触鼻频率相比明显减少(P<0.01),而假刺激组无明显统计学差异(P>0.05);刺激组大鼠在三次复吸期内触鼻频率与假刺激组相比明显减少(P<0.01)。结论腹腔注射可卡因(20mg/Kg)可引起戒断大鼠的复燃,在这一过程中给予持续伏隔核高频电刺激可抑制大鼠的复燃现象。     

Combined action of MK-801 and ceftriaxone impairs the acquisition and reinstatement of morphine-induced conditioned place preference, and delays morphine extinction in rats

Objective It is well established that glutamate and its receptors, particularly the N-methyl-D-aspartate receptor (NMDAR), play a significant role in addiction and that the inhibition of glutamatergic hyperfunction reduces addictive behaviors in experimental animals. Specifically, NMDAR antagonists such as MK-801, and an inducer of the expression of glutamate transporter subtype-1 (GLT-1) (ceftriaxone) are known to inhibit addictive behavior. The purpose of this study was to determine whether the combined action of a low dose of MK-801 and a low dose of ceftriaxone provides better inhibition of the acquisition, extinction, and reinstatement of morphine-induced conditioned place preference (CPP) than either compound alone. Methods A morphine-paired CPP experiment was used to study the effects of low doses of MK-801, ceftriaxone and a combination of both on reward-related memory (acquisition, extinction, and reinstatement of morphine preference) in rats. Results A low dose of neither MK-801 (0.05 mg/kg, i.p.) nor ceftriaxone (25 mg/kg, i.p.) alone effectively impaired CPP behaviors. However, when applied in combination, they reduced the acquisition of morphine-induced CPP and completely prevented morphine reinstatement. Their combination also notably impaired the extinction of morphine-induced CPP. Conclusion The combined action of a low dose of an NMDAR antagonist (MK-801) and GLT-1 activation by ceftriaxone effectively changed different phases of CPP behavior.     

Suppression of c-fos induction in the nucleus accumbens prevents acquisition but not expression of morphine-conditioned place preference

The c-fos immediate-early gene is induced by morphine and other drugs of abuse in the nucleus accumbens (NAc), a mesolimbic region implicated in drug abuse and reward. This study examined the role of c-fos in the acquisition and expression of the conditioned place paradigm (CPP) in the rat by suppressing Fos protein expression with c-fos antisense oligodeoxynucleotides (ODNs). CPP was completely prevented by c-fos antisense ODN infused bilaterally into the NAc prior to each systemic morphine injection, whereas sense and missense NAc injections had no effect on CPP. NAc administration of c-fos antisense ODN after the last systemic morphine conditioning session did not affect the expression of morphine-CPP. These results suggest that c-fos expression in NAc is necessary for the acquisition but not expression of morphine-CPP, and they have important implications for understanding conditioned behaviours and drug craving and addiction.     

Brain opioid-receptors are involved in mediating peripheral electric stimulation-induced inhibition of morphine conditioned place preference in rats

Conditioned place preference (CPP) paradigm has been suggested as one of the animal models for drug craving. The present study was performed to examine the effect of 100 Hz peripheral electric stimulation (PES) on the expression of morphine-induced CPP. Rats were trained with morphine for 4 days to establish the CPP paradigm in a three-chamber "unbiased" apparatus. Morphine-induced CPP was maintained up to 4 weeks when tests were given once a week. PES of 100 Hz administered 30 min a day for 3 days significantly attenuated morphine-induced CPP (P<0.01). I.c.v. injection of the delta-opioid receptor antagonist naltrindole (NTI) or the kappa-antagonist norbinaltorphimine (nor-BNI) but not the mu-antagonist cyclic D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH(2) (CTAP), completely blocked the inhibitory effect of 100 Hz PES on the expression of morphine-induced CPP (P<0.05-0.01). These results indicate that the anti-craving effects induced by repeated PES of 100 Hz is mediated by the activation of supra-segmental delta- and kappa-opioid receptors in the central nervous system.     

Modafinil-induced conditioned place preference via dopaminergic system in mice

Modafinil, a psychostimulant, is used in the treatment of narcolepsy, shift work sleep disorder, and excessive daytime sleepiness associated with obstructive sleep apnea. Preclinical and clinical studies suggest that modafinil may have reinforcing effects. However, a possible rewarding property of modafinil has not been fully investigated. In this study, we assessed the potential rewarding property of modafinil using the conditioned place preference (CPP) paradigm in mice. Using radiolabeled ligands, we observed changes in dopamine, glutamate, and GABA receptor binding in the brains of mice after treatment with modafinil. Modafinil produced significant CPP in mice at an intraperitoneal (i.p.) dose of 125 mg kg^?1 and prevented normal body weight gain of mice in a dose‐dependent manner. A significant reduction in normal body weight gain was observed when mice were administrated 125 mg kg^?1 modafinil. In addition, there were widespread changes in receptor binding in the brains of modafinil‐treated mice; Dopamine D₁ binding was increased in the caudate putamen, the accumbens, and the substantia nigra, while dopamine D₂ binding was decreased in the caudate putamen and the accumbens. Dopamine transporter (DAT) binding was increased in the prefrontal cortex, the caudate putamen, and the nucleus accumbens. No changes were observed in NMDA and GABA_A receptor binding. These data indicate that modafinil had a significant rewarding property and could be abused as a recreational drug. Dopamine systems may play a key role in the rewarding property of modafinil. Synapse, 2011. © 2010 Wiley‐Liss, Inc.     

Gamma-vinyl GABA (GVG) blocks expression of the conditioned place preference response to heroin in rats

We examined the effect of gamma-vinyl GABA (GVG) on the expression of the conditioned place preference response to intraperitoneally (i.p.) administered heroin in rats. Heroin, but not vehicle, produced a significant conditioned place preference response. Pretreatment of animals with 300 mg/kg of GVG significantly attenuated the expression of the heroin-induced conditioned place preference response. These results are the first to suggest that systemic GVG may provide an effective alternative to methadone maintenance in the treatment of heroin addiction, since it is without abuse potential and can be used for treatment outside an institutional setting.