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.     

铝神经毒性的小鼠行为学研究

目的研究铝对小鼠神经行为学的影响,探讨其神经毒性及相关机制.方法运用脑立体定位仪,将三氯化铝直接注入小鼠脑室,观测注射后3d、5d、1w、2w及3w小鼠自主活动次数及水迷宫潜伏期的变化.结果①与对照组比较,老年组水迷宫潜伏期明显延长,5d、1w及2wP值均小于0.01,3d及3wP＜0.05.②与生理盐水组及假手术组比较,成年组仅1w时自主活动次数增加（P＜0.05）.结论脑室内注射三氯化铝能明显降低老年小鼠的学习记忆功能.     

强迫游泳和糖皮质激素促进小鼠对吗啡的条件性位置偏爱

目的　探讨应激和糖皮质激素在发生药物依赖行为中的作用机制。方法　 (1)将 30只雄性昆明品系小鼠随机分为盐水组、糖皮质激素组 (2 0mg- 1 ·kg- 1 ,皮下注射 )、强迫游泳组 (2 5℃强迫游泳 10min) ,每组 10只 ,观察 3种措施对小鼠条件性位置偏爱形成的影响 ;将 30只雄性昆明品系小鼠先进行吗啡条件性位置偏爱实验 ,再随机分为盐水组、糖皮质激组和强迫游泳组 ,每组 10只 ,处理条件同前 ,持续 6天 ,观察 3种措施对小鼠条件性位置偏爱消退的影响。结果　 (1)强迫游泳组和糖皮质激素组在吗啡搭配箱体中停留时间 [分别为 (9 6± 1 0 )min ,(9 4± 1 3)min]均分别高于盐水组[(7 3± 0 8)min];t1 =4 5 6 ,P1 <0 0 1;t2 =4 5 8,P2 <0 0 1,而强迫游泳组和糖皮质激素组之间差异无显著性 (t=0 41,P >0 0 5 ) ;(2 )经过 6天消退期后 ,强迫游泳组和糖皮质激素组在吗啡搭配箱体中停留时间 [分别为 (7 6± 1 1)min ,(7 4± 0 8)min]亦均分别高于盐水组 [(7 3± 1 0 )min];t1 =4 15 ,P1 <0 0 1;t2 =3 38,P2 <0 0 1。结论　强迫游泳和注射糖皮质激素均能促进小鼠对吗啡的条件性位置偏爱 ,并能延缓条件性位置偏爱的消退。     

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。     

高频电刺激伏隔核对吗啡诱导大鼠条件性位置偏爱行为的影响

目的研究高频电刺激伏隔核(nucleus accumbens,NAc)对吗啡诱导戒断大鼠觅药行为的影响,分析NAc在大鼠成瘾行为中的作用。方法26只雄性SD大鼠通过吗啡强化形成条件性位置偏爱后,13只予以120Hz高频电刺激伏隔核(吗啡刺激组),另13只予以假刺激(吗啡假刺激组)。15d后给予注射吗啡,诱导大鼠恢复位置偏爱行为,测量并比较两组的位置偏爱得分。结果吗啡电刺激组大鼠在注射吗啡诱导下不易恢复对吗啡的条件性位置偏爱,位置偏爱得分为(237.59±79.89)s,吗啡假刺激组为(441.29±212.68)s,两组比较,差异有统计学意义(P<0.01)。结论电刺激NAc能阻断注射吗啡诱导戒断大鼠恢复觅药行为。在成瘾药物诱导戒断动物觅药行为的过程中,NAc起重要作用。     

吗啡相关环境线索调节腹侧海马下托区谷氨酸和γ-氨基丁酸的释放(英文)

目的研究吗啡相关环境线索能否调节腹侧海马下托区谷氨酸和γ-氨基丁酸的释放。方法采用条件性位置偏爱和条件性位置厌恶模型分别建立与吗啡奖赏、厌恶相关的环境线索。采用微透析和高效液相荧光检测法测定上述环境线索下大鼠腹侧海马下托区细胞外谷氨酸和γ-氨基丁酸的浓度。结果吗啡奖赏相关环境线索引起腹侧海马下托区细胞外γ-氨基丁酸浓度下降了约11%,吗啡厌恶相关的环境线索引起腹侧海马下托区细胞外的谷氨酸浓度增加了约230%。结论吗啡相关的环境线索可能通过不同的神经环路调节腹侧海马下托区神经递质的释放。     

吗啡相关环境线索调节腹侧海马下托区谷氨酸和γ-氨基丁酸的释放

目的 研究吗啡相关环境线索能否调节腹侧海马下托区谷氨酸和γ-氨基丁酸的释放。方法 采用条件性位置偏爱和条件性位置厌恶模型分别建立与吗啡奖赏、厌恶相关的环境线索。采用微透析和高效液相荧光检测法测定上述环境线索下大鼠腹侧海马下托区细胞外谷氨酸和γ-氨基丁酸的浓度。结果 吗啡奖赏相关环境线索引起腹侧海马下托区细胞外γ-氨基丁酸浓度下降了约11％,吗啡厌恶相关的环境线索引起腹侧海马下托区细胞外的谷氨酸浓度增加了约230％。结论 吗啡相关的环境线索可能通过不同的神经环路调节腹侧海马下托区神经递质的释放。     

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。     

锂-匹罗卡品致癎幼鼠海马结构损伤的形态学及苔藓纤维发芽研究

目的 :观察幼鼠致后海马的组织病理学改变。方法 :采用氯化锂 匹罗卡品腹腔注射制成幼鼠癫持续状态模型 ,应用常规病理及电镜观察海马结构的形态学改变 ,同时应用Timm组织化学染色方法进行苔藓纤维发芽的研究。结果 :海马区神经元可见变性、坏死的改变 ,以CA1区、CA3区为重。Timm染色见齿状回内分子层和CA3区下锥体层苔藓纤维发芽增加。结论 :①氯化锂 匹罗卡品诱导的幼鼠癫持续状态可造成海马区神经元损伤 ;②幼鼠癫持续状态后海马CA1、CA3区神经元损伤较重 ;③幼鼠癫持续状态后可致苔藓纤维发芽增加。     

2′－甲基甲苯氢啶对小鼠不同脑区单胺类神经递质含量的影响

为了评价１－甲基－４－苯基－１，２，３，６四氢吡啶（２′－甲基甲苯氢啶或２′－ＣＨ３－ＭＰＴＰ）的作用，提供新的帕金森病模型的工具药，通过高效液相色谱电化学检测法对２′－甲基甲苯氢啶在小鼠不同脑区去甲肾上腺素、多巴胺（ＤＡ）、５－羟色胺（５－ＨＴ）、多巴酸和高香草酸的作用进行了研究测定。结果表明：２′－甲基甲苯氢啶对纹状体多巴胺能神经有选择性破坏作用。１０ｍｇ／ｋｇ组给药１５天，１５ｍｇ／ｋｇ组给药５天，２０ｍｇ／ｋｇ组给药１天，均能使小鼠纹状体多巴胺及其代谢产物的含量明显降低，第２天尤为显著。随着时间的延长，有一定程度的恢复，但至２０天仍处于较低水平；而对５－ＨＴ及其代谢产物无明显影响；能明显降低额叶皮层内的去甲肾上腺素含量；低剂量给药，对ＤＡ的抑制强度仍明显强于甲苯氢啶（ＭＰＴＰ），差异有显著意义（Ｐ均＜０．００１）。结果显示：２′－甲基甲苯氢啶对多巴胺神经元的抑制作用特异且较为持久，作用明显强于ＭＰＴＰ，可作为帕金森病动物模型的工具药应用     

Intrinsic membrane plasticity via increased persistent sodium conductance of cholinergic neurons in the rat laterodorsal tegmental nucleus contributes to cocaine‐induced addictive behavior

The laterodorsal tegmental nucleus (LDT) is a brainstem nucleus implicated in reward processing and is one of the main sources of cholinergic afferents to the ventral tegmental area (VTA). Neuroplasticity in this structure may affect the excitability of VTA dopamine neurons and mesocorticolimbic circuitry. Here, we provide evidence that cocaine‐induced intrinsic membrane plasticity in LDT cholinergic neurons is involved in addictive behaviors. After repeated experimenter‐delivered cocaine exposure, ex vivo whole‐cell recordings obtained from LDT cholinergic neurons revealed an induction of intrinsic membrane plasticity in regular‐ but not burst‐type neurons, resulting in increased firing activity. Pharmacological examinations showed that increased riluzole‐sensitive persistent sodium currents, but not changes in Ca²⁺‐activated BK, SK or voltage‐dependent A‐type potassium conductance, mediated this plasticity. In addition, bilateral microinjection of riluzole into the LDT immediately before the test session in a cocaine‐induced conditioned place preference (CPP) paradigm inhibited the expression of cocaine‐induced CPP. These findings suggest that intrinsic membrane plasticity in LDT cholinergic neurons is causally involved in the development of cocaine‐induced addictive behaviors.     

Stress and opioids: Role of opioids in modulating stress-related behavior and effect of stress on morphine conditioned place preference

Research studies have defined the important role of endogenous opioids in modulating stress-associated behavior. The release of β-endorphins in the amygdala in response to stress helps to cope with a stressor by inhibiting the over-activation of HPA axis. Administration of mu opioid agonists reduces the risk of developing post-traumatic stress disorder (PTSD) following a traumatic event by inhibiting fear-related memory consolidation. Similarly, the release of endogenous enkephalin and nociceptin in the basolateral amygdala and the nucleus accumbens tends to produce the anti-stress effects. An increase in dynorphin levels during prolonged exposure to stress may produce learned helplessness, dysphoria and depression. Stress also influences morphine-induced conditioned place preference (CPP) depending upon the intensity and duration of the stressor. Acute stress inhibits morphine CPP, while chronic stress potentiates CPP. The development of dysphoria due to increased dynorphin levels may contribute to chronic stress-induced potentiation of morphine CPP. The activation of ERK/cyclic AMP responsive element-binding (CREB) signaling in the mesocorticolimbic area, glucocorticoid receptors in the basolateral amygdala, and norepinephrine and galanin system in the nucleus accumbens may decrease the acute stress-induced inhibition of morphine CPP. The increase in dopamine levels in the nucleus accumbens and augmentation of GABAergic transmission in the median prefrontal cortex may contribute in potentiating morphine CPP. Stress exposure reinstates the extinct morphine CPP by activating the orexin receptors in the nucleus accumbens, decreasing the oxytocin levels in the lateral septum and amygdala, and altering the GABAergic transmission (activation of GABA_A and inactivation of GABA_B receptors). The present review describes these varied interactions between opioids and stress along with the possible mechanism.     

Effects of risperidone on the acquisition and reinstatement of the conditioned place preference induced by MDMA

Some users of 3,4-methylenedioxymethylamphetamine (MDMA or ecstasy) abuse this drug and/or become concerned about their use. These individuals would benefit greatly from the development of pharmacological strategies to reduce MDMA consumption. We have previously observed that antipsychotics block acquisition and expression of the conditioned place preference (CPP) induced by MDMA, though they do not modify priming-induced reinstatement of MDMA-induced CPP after extinction. In the present study we have evaluated the capacity of the mixed serotonin (5-HT_2A)/dopamine (DA D₂) antagonist risperidone to block acquisition and reinstatement of MDMA induced-CPP. Adolescent male mice conditioned with 10 mg/kg of MDMA were treated with 0.1 or 0.3 mg/kg of risperidone during acquisition of conditioning (experiment 1) or before the reinstatement test (experiment 2). Risperidone was devoid of motivational effects in the CPP paradigm, but the higher dose blocked acquisition of the MDMA-induced CPP. This behavioural effect was accompanied by an increase in the level of dopamine transporters in the striatum. However, risperidone had no effects on reinstatement of the CPP induced by a priming of MDMA. Our results suggest that risperidone induces the same effects as other antipsychotics, in which case its efficacy for treating MDMA abuse is limited.     

Effects of excitotoxic lesions of the basolateral amygdala on cocaine-seeking behavior and cocaine conditioned place preference in rats

Incentive motivation for cocaine, elicited by cocaine-associated stimuli, is thought to be involved in craving and relapse. To examine the role of the basolateral amygdala complex (BLC) in this phenomenon, we assessed the effects of post-training BLC lesions on extinction of cocaine-seeking behavior and cocaine-conditioned place preference (CPP) and the effects of pre-training BLC lesions on acquisition of cocaine-CPP. In Experiment 1, rats were first trained to self-administer cocaine and then received bilateral infusions of the excitotoxin, N-methyl-D-aspartic acid (NMDA, 0.12 M; 0.3 microl/side), or vehicle into the BLC. They were then tested repeatedly for extinction of cocaine-seeking behavior (i.e. nonreinforced responses in the presence of cocaine-paired stimuli). Subsequently, they were trained and tested for acquisition of cocaine-CPP (i.e. increased time spent in a previously cocaine-paired, relative to a saline-paired, environment). Locomotion and compartment entries were also measured. In Experiment 2, rats were first trained and tested for cocaine-CPP, and then received NMDA or vehicle infusions into the BLC. Subsequently, they were tested repeatedly for extinction of cocaine-CPP. Post-training BLC lesions retarded extinction of cocaine-seeking behavior and cocaine-CPP, whereas pre-training lesions disrupted acquisition of cocaine-CPP. These effects did not appear to be related to changes in general activity. We suggest that pre-training BLC lesions disrupted acquisition of cocaine-CPP by impairing assignment of incentive value to cocaine-paired stimuli, whereas post-training BLC lesions disrupted extinction of cocaine-conditioned behaviors by impairing the assessment of the current incentive value of cocaine-paired stimuli.     

伏隔核毁损对药物和应激诱导大鼠吗啡觅药行为重建的影响

目的 分析伏隔核(nucleus accumbens，NAc)在药物和应激诱导大鼠吗啡觅药行为中的作用，研究定向毁损NAc对大鼠成瘾行为重建的影响。方法 雄性SD大鼠通过吗啡强化形成条件性位置偏爱(conditioned place preference，CPP)后，使用直流电毁损NAc。15天后给予皮下注射吗啡或间断足击应激诱导CPP，测量并比较毁损组与对照组的CPP得分。结果 无论在注射吗啡诱导还是在间断足击应激诱导中，NAc毁损组的CPP得分均显著低于对照组。结论 NAc毁损能阻断注射吗啡和间断足击应激诱导戒断大鼠重建觅药行为。     

Effects of enriched environment on morphine-induced reward in mice

Drug addiction and abuse have been extremely serious problems in our society. The effect of different environmental conditions on the susceptibility of human to drug addiction and abuse is still not fully understood. It was recently reported that enriched environment can trigger long-term modification in neural functions and might prevent the occurrence of pathogenic behaviors. Here we investigated the effects of enriched environment on morphine-induced reward in mice. We found that the enriched environment attenuated the acute morphine (10 mg/kg)-induced hyperlocomotion and repeated morphine (10 mg/kg)-induced behavioral sensitization. Moreover, the environmental condition blocked the conditioned place preference (CPP) of the mice induced by morphine (5 mg/kg). Associated with behavioral alterations, the expression of FosB-like proteins in the nucleus accumbens of the brain was down-regulated in the mice housed in the enriched environmental condition, but not in the standard environment. Taken together, these results indicate that enriched environmental condition leads to decrease in sensitivity of the mice to morphine-induced reward.     

Distinctive effects of unpredictable subchronic stress on memory, serum corticosterone and hippocampal BDNF levels in high and low exploratory mice

Methamphetamine (MA) is one of the most frequently used illicit drugs worldwide and also one of the most common drugs abused by pregnant women. Repeated administration of psychostimulants induces behavioral sensitization in response to treatment of the same or related drugs in rodents. The effect of prenatal MA exposure on sensitivity to drugs in adulthood is not yet fully determined. Because our most recent studies demonstrated that prenatal MA (5 mg/kg) exposure makes adult rats more sensitive to acute injection of the same drug, we were interested whether the increased sensitivity corresponds with the increased drug-seeking behavior. The aim of the present study was to examine the effect of prenatal MA exposure on drug-seeking behavior of adult male rats tested in the conditioned place preference (CPP). The following psychostimulant drugs were used as a challenge in adulthood: MA (5 mg/kg), amphetamine (5 mg/kg) and cocaine (10 mg/kg). All psychostimulant drugs induced increased drug-seeking behavior in adult male rats. However, while MA and amphetamine-induced increase in drug-seeking behavior did not differ based on the prenatal drug exposure, prenatally MA-exposed rats displayed tolerance effect to cocaine in adulthood. In addition, prenatally MA-exposed rats had decreased weight gain after administration of MA or amphetamine, while the weight of prenatally MA-exposed rats stayed unchanged after cocaine administration. Defecation was increased by all the drugs (MA, amphetamine and cocaine), while only amphetamine increased the tail temperature. In conclusion, our results did not confirm our hypothesis that prenatal MA exposure increases drug-seeking behavior in adulthood in the CPP test.