侧脑室注射东莨菪碱对大鼠吗啡条件性位置偏爱效应的影响

长期应用阿片类药物会导致阿片成瘾,主要表现为产生躯体和精神依赖。我室研究发现应用非选择性毒蕈碱(Ｍ)受体拮抗剂东莨菪碱能阻断吗啡依赖大鼠纳洛酮激发的戒断症状,也可减轻对吗啡耐受［１］。在东莨菪碱对猕猴吗啡静脉自身给药及反应恢复影响实验中发现东莨菪碱能降低吗啡静脉自身给药猕猴的踏板反应率和总强化次数［２］。这些表明东莨菪碱能降低吗啡的躯体和精神依赖性。条件性位置偏爱实验是一种评价药物精神依赖性的方法,本实验通过侧脑室微量注射不同剂量东莨菪碱,观察其对吗啡的条件性位置偏爱的影响,以探讨东莨菪碱在治疗阿片精…     

酸枣仁提取物对小鼠吗啡条件性位置偏爱的影响

目的:观察酸枣仁提取物对吗啡(MOR)诱导建立小鼠条件性位置偏爱(CPP)行为的影响。方法:连续给予吗啡(6mg·kg-1,sc)5d,引起小鼠产生显著的CPP效应,观察酸枣仁提取物对CPP效应的影响。结果:吗啡可诱导小鼠对伴药箱产生显著的位置偏爱;训练阶段于每次给予吗啡前30min给予酸枣仁醇提物800mg·kg-1可拮抗小鼠对吗啡产生的CPP效应(与吗啡对照组比较P<0.05),但酸枣仁醇提物200和400mg·kg-1不影响其效应(P>0.05);酸枣仁乙酸乙酯提取物13mg·kg-1、20mg·kg-1,正丁醇提取物160mg·kg-1可拮抗小鼠对吗啡产生的CPP效应(P<0.05),但酸枣仁石油醚提取物、乙醚提取物、水提物均不影响其效应(P>0.05)。结论:酸枣仁醇提物及其乙酸乙酯提取物、正丁醇提取物能在一定程度上抑制吗啡诱导小鼠建立的CPP行为。     

吗啡不同剂量和给药时程对建立大鼠条件性位置偏爱模型的影响

目的：比较吗啡不同给药剂量及不同给药时程对建立大鼠条件性位置偏爱（cPP）模型的影响，用于建立满意的CPP模型。方法：分别采用15mg／kg吗啡连续颈背部皮下注射（SC）6d，10mg／kg吗啡连续颈背部皮下注射（SC）6d、8d、10d进行CPP训练，测定大鼠在伴药箱停留的时间。结果：与对照组比较，15mg／kg吗啡6d组、10mg／kg吗啡8d组和10mg／kg吗啡10d组大鼠在伴药箱停留的时间均明显延长（P〈0．05），诱导大鼠CPP建立，三组大鼠在伴药箱停留时间比较差异无统计学意义；10mg／kg吗啡训练大鼠6d后，与相应的生理盐水对照组比较，大鼠在伴药箱停留时间差异无统计学意义，未能诱导CPP形成。结论：大鼠在用10mg／kg吗啡训练8d、10d及15mg／kg吗啡训练6d后，均可诱导大鼠CPP形成，但10mg／kg吗啡训练8d建立的CPP模型较满意。     

归元片对吗啡条件性位置偏爱的影响

目的:探讨不同剂量的戒毒中药归元片对吗啡诱导的条件性位置偏爱(conditionedplacepreference ,CPP)的影响及其自身是否引起CPP。方法:(1)♂Wistar大鼠sc吗啡(5mg·kg-1)训练7d ,干预组于每次给吗啡前15min注射不同剂量的归元片(12 . 5 - 37 .5mg·kg-1,sc) ,观察其对吗啡CPP效应的干预作用;(2 )♂Wistar大鼠sc归元片(2 5mg·kg-1及5 0mg·kg-1)训练7d ,d8测定大鼠对伴药侧的偏爱效应。结果:(1) 5mg·kg-1吗啡可以诱导大鼠对伴药侧产生显著的CPP ;而两个剂量的归元片均不能使大鼠形成CPP ;(2 ) 2. 5mg·kg-1和37 .5mg·kg-1的归元片可剂量依赖性地降低吗啡诱导的CPP的形成。结论:一定剂量的归元片可拮抗大鼠对吗啡偏爱效应的获得,且自身不引起CPP ,提示该药有治疗阿片类药物精神依赖性的潜力。     

东茛菪碱对吗啡依赖大鼠条件位置性偏爱激活的抑制作用

目的：观察东莨菪碱（Scopolamine，Sco）对吗啡（Morphine，Mor）依赖大鼠条件位置性偏爱激活的抑制作用。方法：以剂量递增连续皮下（SC）给吗啡6天建立吗啡诱导大鼠条件位置性偏爱（CPP）模型，第7天用生理盐水替代吗啡训练大鼠10天，使形成的CPP逐渐消退，单次SC4mg／kg吗啡激发消退的CPP。部分大鼠在注射吗啡前30分钟分别腹腔注射（ip）Sco（1mg／kg、2mg／kg、3mg／kg）。观察东莨菪碱对吗啡依赖大鼠在伴药箱停留时间的变化。结果：与Mor依赖组相比在SC4mg／kgMor引燃刺激前30min应用Sco 1mg／kg、2mg／kg、3mg／kg均可以使大鼠在伴药箱停留时间缩短（P〈0．05）。结论：Sco一定程度上抑制Mor引燃的Mor依赖大鼠的条件位置性偏爱激活。     

甲氧氯普胺对吗啡依赖性的影响

目的:观察甲氧氯普胺对离体豚鼠回肠吗啡戒断收缩和吗啡精神依赖性的影响。方法:离休豚鼠回肠吗啡戒断收缩实验和吗啡诱导小鼠位置偏爱实验。结果:(1)离休豚鼠回肠吗啡依赖实验显示:250-500μmol·L~(-1)甲氧氯普胺可显著抑制离体豚鼠回肠吗啡依赖的形成和纳洛酮促发的戒断收缩,作用呈剂量依赖性;(2)甲氧氯普胺的剂量大于10(10-40)mg·kg~(-1)(ip),可有效抑制吗啡诱导的小鼠条件性位置偏爱的形成,而其本身并不造成位置厌恶。结论:甲氧氯普胺对吗啡身体依赖的形成、戒断症状以及精神依赖的形成均有一定的抑制作用。     

吗啡依赖对大鼠不同脑区内神经甾体水平的影响

目的建立大鼠条件性位置偏爱(CPP)模型，探讨吗啡精神依赖对大鼠脑内神经甾体水平的影响。方法 大鼠连续10 d腹腔注射吗啡5 mg·kg^-1，诱导CPP形成。高效液相色谱-质谱法测定大鼠伏隔核、杏仁核、下丘脑和血浆中脱氢表雄酮、孕烯醇酮、别孕烯醇酮、脱氢表雄酮硫酸酯及孕烯醇酮硫酸酯的含量。结果经10 d吗啡训练后，吗啡组大鼠在伴药侧的停留时间显著长于对照组，吗啡诱导的大鼠CPP形成。与对照组相比，吗啡组大鼠下丘脑内孕烯醇酮明显降低，伏隔核和血浆中的脱氢表雄酮明显降低。结论吗啡诱导CPP形成，吗啡处理影响大鼠脑内某些神经甾体的水平，表明内源性神经甾体可能参与吗啡依赖的形成。     

奥丹西隆对小鼠吗啡条件性位置偏爱效应的影响

目的 :探讨 5 -HT3 型受体特异性拮抗剂奥丹西隆对吗啡诱导的条件性位置偏爱 (CPP)效应的影响。方法 :建立小鼠吗啡CPP模型 ,观察奥丹西隆对CPP的影响。结果 :吗啡 (5mg·kg-1,sc)可诱导小鼠对伴药箱产生显著的CPP ;测试前 30min注射奥丹西隆 (0 0 1- 1mg·kg-1,sc)不影响小鼠已形成的对吗啡的位置偏爱 ;而训练阶段于每次注射吗啡同时注射奥丹西隆 (0 0 1- 0 1mg·kg-1,ip)可拮抗小鼠对吗啡的CPP效应 ,但较大剂量奥丹西隆 (1mg·kg-1,ip)则不影响其效应 ,而且此剂量单独给药亦表现出自身的CPP潜力。结论 :一定剂量的奥丹西隆可拮抗小鼠对吗啡的偏爱效应的获得 ,但不影响其表达 ,提示该类药物有治疗阿片类依赖的潜力。     

孕酮对吗啡精神依赖大鼠相关脑区中强啡肽A水平的影响

目的:观察孕酮对于吗啡所致奖赏效应及相关脑区中强啡肽A水平的影响。方法:建立吗啡条件性位置偏爱(CPP)模型,采用放射免疫法测定大鼠不同脑区中强啡肽A(dynorphinA,DynA)的含量。结果:与生理盐水对照组比较,5mg·kg-1吗啡可诱导大鼠产生稳定的CPP效应(P<0·01),15mg·kg-1孕酮本身不产生CPP效应,但能抑制吗啡CPP效应的获得。与生理盐水对照组比较,吗啡CPP形成时,下丘脑和额叶皮质中的DynA水平显著降低(P<0·05)。与吗啡组比较,合用15mg·kg-1孕酮可使下丘脑和额叶皮质中DynA水平显著升高(P<0·05),而在海马、伏隔核和中脑内未见显著性变化。结论:孕酮可以有效抑制吗啡CPP效应,其机制可能与其逆转吗啡诱导的相关脑区中的DynA水平的变化有关。     

条件性位置偏爱形成对小鼠吗啡行为敏化的影响

目的研究条件性位置偏爱对小鼠吗啡行为敏化的影响。方法应用计算机视频分析系统观察吗啡和氟哌啶醇对雄性小鼠单位时间内的总活动度的影响。同时观察条件性位置偏爱形成后,小鼠单位时间内的总活动度、平均速度和穿梭次数的改变。结果吗啡给药后显著增加小鼠单位时间内的总活动度,氟哌啶醇使小鼠总活动度减少,并且对抗吗啡引起的总活动度的增加。条件性位置偏爱形成后,吗啡组小鼠在白箱停留的时间显著增加,但总活动度、平均速度和穿梭次数与训练前相比显著减少。结论氟哌啶醇可抑制吗啡诱导的行为敏化,条件性位置偏爱形成后可能引起多巴胺系统功能降低。     

Effects of contextual or olfactory cues previously paired with morphine withdrawal on behavior and pain sensitivity in the rat

RATIONALE: Pavlovian conditioning processes have been accorded an important role in maintaining persistent opiate administration. At least one locus for this contribution is during opiate withdrawal. These experiments studied the contribution of Pavlovian conditioning processes to morphine withdrawal. OBJECTIVES: To determine whether exposure to a distinctive context or odor paired with morphine withdrawal would provoke a withdrawal syndrome, defensive behaviors (e.g., freezing) and pain modulatory (e.g., hypoalgesia) responses similar to those produced by exposure to stimuli signaling other sources of aversive stimulation (e.g., footshock), or whether both withdrawal and fear-like responses would be provoked. METHODS: Rats were used in four experiments to study the effects on defensive behavior and pain sensitivity of naloxone-precipitated morphine withdrawal or exposure to a distinctive context or odor previously paired with such withdrawal. RESULTS: Injection of 2.5 mg/kg naloxone in morphine-dependent rats precipitated a withdrawal syndrome characterized by whole body shaking, diarrhea, ptosis, and postural abnormalities (experiment 1). Exposure to either a distinctive context (experiment 2) or odor (experiments 3) previously paired with morphine withdrawal provoked the species-typical defense response of freezing but not signs of withdrawal. Exposure to an odor previously paired with morphine withdrawal also provoked hypoalgesia in the formalin test, which was mediated by activity at opioid receptors (experiment 4). CONCLUSIONS: These results show that opiate withdrawal supports the conditioning of defensive and hypoalgesic responses consistent with the arousal of a fear motivational system. The emergence of fear in these experiments, and the relationship between the freezing observed here and the learned avoidance and suppression observed in other withdrawal conditioning preparations, is discussed with reference to dual representation accounts of Pavlovian conditioning.     

吗啡依赖大鼠皮质内BDNF和即早基因c-fos的表达

目的 建立大鼠条件性位置偏爱(CPP)模型,探讨脑源性神经营养因子(BDNF)和即早基因c-fos在大鼠吗啡精神依赖中所起的作用.方法 大鼠连续6d腹腔注射吗啡mg/kg·d-1,诱导吗啡CPP形成.免疫组化法测定大鼠皮质内BDNF和C-fos的表达.结果 经6d吗啡训练后,吗啡组在伴药侧的停留时间较对照组显著增加(P...     

Conditioned place preference with morphine: the effect of extinction training on the reinforcing CR

Rats were injected with either morphine (5 mg/kg) or saline in association with one set of distinct environmental stimuli, and injected with saline in association with a different set of stimuli. After four conditioning trials, animals were given a 15-minute free-choice test to determine which stimulus environment was preferred. Animals displayed CPP as a significant increase in duration spent within the morphine-associated environment, but did not display any change in number of entries into that environment. In contrast, when extinction training was given following CPP, animals displayed a significant decrease in duration spent per entry into the morphine-associated environment, but did not display any change in total duration spent in that environment. These results suggest that assessment of the reinforcing conditioned response (CR) in the CPP model may require measurement of both duration spent in and number of entries into the drug-associated environment.     

Effects of diazepam on conditioned place preference induced by morphine or amphetamine in the rat

RATIONALE: The drug-abuse literature suggests that benzodiazepines may be preferentially abused in conjunction with opioids rather than stimulants. OBJECTIVE: To investigate possible effects of diazepam on the reinforcing effects of morphine and amphetamine. METHODS: The effects of diazepam (0.5, 1 or 2 mg/kg) on the formation and expression of conditioned place preferences (CPP) induced by morphine sulphate (0.3, 0.8, 2 and 8 mg/kg) or D-amphetamine (0.4, 0.8, 2 or 2.5 mg/kg) were studied in an unbiased CPP paradigm. The action of diazepam (1 mg/kg) on conditioned and unconditioned locomotion induced by morphine (2 mg/kg) or amphetamine (2 mg/kg) was assessed. RESULTS: Rats that received conditioning injections of morphine in one environment displayed a preference for this environment. Pre-testing injections of diazepam did not alter the magnitude of this CPP. When diazepam was given with morphine during training, rats displayed a CPP for the environment paired with the two drugs. Injections of amphetamine in one environment also induced a preference for this environment. However, pre-testing injections of diazepam blocked the expression of amphetamine-induced CPP, and co-injections of diazepam blocked the formation of amphetamine CPP. Diazepam itself did not produce a CPP nor did it alter spontaneous place preferences. Diazepam equally blocked both morphine and amphetamine unconditioned and conditioned locomotor hyperactivity. This indicates that its effects on morphine and amphetamine CPP were not due to a differential effect on locomotion. CONCLUSIONS: Diazepam interferes with the reinforcing properties of amphetamines but not of morphine. The reinforcing effects of morphine and amphetamine are pharmacologically dissociable.     

Conditioned locomotion and place preference elicited by tactile cues paired exclusively with morphine in an open field

A novel version of the conditioned place preference (CPP) technique was used in an attempt to determine whether tactile stimuli previously associated with morphine elicit approach and sustained contact. Empirical support for this view has been equivocal, prompting some to question the validity of the CPP technique. In the present study, rats received, during conditioning, morphine (10 mg/kg, IP) paired exclusively with an open field floor made of four quadrants of one texture (CS+) and saline with another floor made of four quadrants of a different texture (CS–). On the test for CPP, rats were given saline and placed in an open field containing either 1, 2, or 4 quadrants of the CS+ (with 3, 2, 0 quadrants of the CS–, respectively). These animals showed high absolute CPP scores on the test, spending, on average, as much as 83% and 75% of their time on the CS+ when two and one CS+ quadrants, respectively, were present. Concurrent measures of activity indicated that animals were most active when all four quadrants were CS+ and least active when zero or one CS+ quadrant was present. Thus, once an animal approached and made contact with the CS+ it tended to maintain contact with this stimulus and to reduce its approach to and contact with other stimuli. The differentiating features of this version of the CPP technique, as well as the relationship between morphine-induced conditioned locomotion and CPP, are discussed.     

Effects of ritanserin on the rewarding properties of d-amphetamine, morphine and diazepam revealed by conditioned place preference in rats

The possibility that 5-HT₂ receptors mediate the reinforcing properties of d-amphetamine, morphine and diazepam was investigated in rats, using ritanserin, a 5-HT₂ antagonist, and the conditioned place preference paradigm. Ritanserin 1 or 2.5 mg/kg did not cause place conditioning. Place preference induced by 1.5 mg/kg d-amphetamine and 2 mg/kg morphine was inhibited and attenuated respectively by pretreatment with 2.5 mg/kg ritanserin. Diazepam- (1 mg/kg) induced place preference was completely blocked by both doses of ritanserin. Ritanserin pretreatment failed to influence amphetamine-induced hyperlocomotion, morphine-induced analgesia and diazepam-induced increased open arm exploration of rats on the elevated plus maze. These data are discussed in terms of (a) the possibility that serotoninergic mechanisms have a role in mediating reinforcement and (b) the relationship between appetitive properties and specific behavioral effects of psycho-stimulants, opiates and anxiolytics.     

Strain differences in the rewarding and dopamine-releasing effects of morphine in rats

Studies examining differential sensitivity to psychoactive drugs in mice suggest that genotype may play a critical role. Furthermore, an involvement of genotype in mediating individual differences in sensitivity to the rewarding effects of several drugs of abuse has also been postulated. The aim of this study was to examine the conditioned rewarding and dopamine-releasing effects of morphine in two outbred rat strains commonly used in addiction research. Additionally, the behavioural and neuroendocrine responses of these strains to the stress of novelty were also examined. Basal locomotor activity was higher in Wistar rats than Sprague-Dawley following exposure to a novel environment. In contrast, elevations in plasma corticosteroid levels following novelty exposure did not differ between the two strains. In a counterbalanced place preference conditioning procedure, increasing doses of morphine (1.0–10.0 mg/kg SC) produced significant conditioned place preferences (CPP) in both Wistar and Sprague-Dawley strains. However, Wistar rats required a significantly larger dose of morphine (5.0 mg/kg) to produce a significant CPP than the Sprague-Dawley rats. In the latter strain, CPP occurred with doses of 3.0 mg/kg and greater. In parallel microdialysis experiments, both strains showed significant dose-related increases in dopamine release in the nucleus accumbens following acute morphine challenge (1.0–10.0 mg/kg SC). Again in Wistar rats, a larger dose of morphine was necessary to produce a significant increase in comparison to Sprague-Dawley rats. These results show that genetically distinct rat strains can show differential sensitivity to opioids, more specifically to drug-seeking responses.     

Aripiprazole blocks reinstatement but not expression of morphine conditioned place preference in rats

Aripiprazole is an atypical antipsychotic drug primarily characterized by partial agonist activity at dopamine (DA) D₂ receptors and serotonin-1A (5-hydroxytryptamine, 5-HT_1A) receptors and minimal side effects. Based on its pharmacological profile, including stabilization of mesocorticolimbic DA activity (a pathway implicated in drug addiction), we investigated the effects of aripiprazole on relapse to morphine seeking in rats. In experiment 1, rats underwent morphine-induced conditioned place preference (CPP) training with alternate injections of morphine (5 mg/kg, s.c.) and saline (1 ml/kg, s.c.) for 8 consecutive days. To examine the effect of aripiprazole on the expression of morphine-induced CPP, rats received aripiprazole (0, 0.03, 0.1, and 0.3 mg/kg, i.p.) 30 min before testing for the expression of CPP. In experiment 2, rats underwent the same CPP training as in experiment 1 and subsequent extinction training. To examine the effect of aripiprazole on reinstatement of morphine-induced CPP, rats received aripiprazole 30 min before testing for reinstatement of CPP. In experiment 3, to assess the effects of aripiprazole on locomotor activity, aripiprazole was administered 30 min before testing for locomotor activity. Aripiprazole significantly decreased the reinstatement of CPP induced by a priming injection of morphine but had no effect on the expression of morphine-induced CPP or locomotor activity. The D₂ and 5-HT_1A partial agonist and 5-HT_2A antagonist properties of aripiprazole likely account for the blockade of relapse to drug seeking. These findings suggest that aripiprazole may have therapeutic value for reducing craving and preventing relapse to drug seeking.     

Conditioned flavor aversions for assessing precipitated morphine abstinence in rats.

Rats receiving twice-daily morphine injections acquired aversions to a saccharin solution which had been presented for 1 hr immediately prior to injections of naloxone. The degree of aversion was related to the maintenance dosage of morphine. Rats maintained on a regimen of daily saline injections did not show significant aversion to saccharin paired with naloxone, even at doses as high as 40 mg/kg. The sensitivity of the technique was such that significant aversions could be demonstrated in rats receiving doses of morphine as low as 1 mg/kg twice daily. It is suggested that conditioned flavor aversions provide a useful method for assessing the aversive quality of abstinence precipitated from low doses of morphine.