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。     

东莨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Sco1mg/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。     

戒断对吗啡成瘾大鼠活动性的影响研究

目的：观察戒断对吗啡成瘾大鼠活动性的影响。方法20只大鼠随机分为对照组和吗啡组,每组10只。用条件性位置偏爱实验(CPP)检测大鼠成瘾及活动性的变化。结果经皮下注射吗啡7 d 建立大鼠CPP模型,与对照组比较,吗啡组在伴药箱停留时间增加,差异具有统计学意义(P<0.05)。自然戒断7 d 后,与对照组比较,吗啡组穿梭次数明显增加,差异具有统计学意义(P<0.05)。结论吗啡诱导大鼠CPP模型建立成功,自然戒断7 d后活动性增强,提示吗啡及其运动效应之间的关系,可能是大鼠觅药行为的具体表现之一。     

不同给药时间间隔对吗啡诱导的条件性位置偏爱的影响

目的:比较两种不同给药时间间隔的实验方案对大鼠吗啡条件性位置偏爱(CPP)的影响。方法:采用三箱式非平衡设计的CPP装置,在实验方案1中,吗啡组大鼠注射吗啡(10 mg.kg-1.d-1,ip)后放入伴药箱50 min,间隔6 h后注射同等剂量的生理盐水后放入非伴药箱50 min,共12 d,检测期检测13 d。实验方案2中,奇数天给吗啡组大鼠注射吗啡(10 mg.kg-1,ip),偶数天注射同等剂量的生理盐水,共8 d,在检测期不定期地把大鼠放入到CPP箱中进行检测。结果:两种实验方案的吗啡组大鼠在伴药箱停留的时间均明显多于生理盐水对照组(P<0.01,P<0.01);自然戒断后,实验方案1和实验方案2中吗啡组大鼠的CPP维持分别为5 d和42 d。结论:两种实验方案均能有效建立大鼠吗啡CPP模型,而实验方案2更经济、省时,可提高实验效率。     

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...     

延胡索和左旋延胡索乙素的条件性位置偏爱效应

目的:观察延胡索和左旋延胡索乙素(l-THP)是否具有精神依赖性。方法:80只大鼠随机分为延胡索高、中、低剂量组,l-THP高、中、低剂量组,生理盐水对照组,吗啡组。前6组大鼠每天分别灌胃(ig)延胡索生药0.5、1.0、2.0g·kg-1,l-THP1.0、2.0、4.0mg·kg-1,吗啡组每天皮下注射(sc)吗啡(10mg·kg-1),生理盐水对照组给予等体积生理盐水,进行条件性位置偏爱(conditioned place preference,CPP)训练,时间10d。结果:高、中、低剂量延胡索和l-THP组大鼠在伴药箱中的停留时间均无明显延长,且同一组大鼠在伴药箱中的停留时间与训练前比,差异也无显著性,未形成CPP;而吗啡组对伴药箱明显形成CPP。结论:延胡索和l-THP不具有精神依赖性,无成瘾性。     

α-芋螺毒素TxIB抗药物依赖的初步探索

目的 探究作用于α6/α3β2β3烟碱型乙酰胆碱受体(nAChRs)的α-芋螺毒素TxIB对吗啡/尼古丁诱导条件性位置偏爱(CPP)的影响,为进一步设计筛选抗药物依赖的芋螺毒素提供理论和实验依据。方法 选用SPF级雄性C57BL/6小鼠,采用皮下注射吗啡(5 mg/kg)或尼古丁(0.5 mg/kg)建立CPP模型。侧脑室注射不同剂量的α-芋螺毒素TxIB,记录小鼠在伴药箱的停留时间。结果 皮下注射吗啡(5 mg/kg)或尼古丁(0.5 mg/kg)均可成功建立CPP模型,经侧脑室注射不同剂量的TxIB后测值,发现TxIB能显著性抑制吗啡/尼古丁诱导小鼠CPP的表达(P<0.05),且存在剂量依赖性效果。侧脑室注射最高剂量TxIB(10 nmol)对生理盐水对照组小鼠在伴药箱停留时间无影响(P>0.05)。结论 α-芋螺毒素TxIB可以抑制吗啡/尼古丁诱导小鼠CPP的表达,有望进一步开发成为戒烟戒毒的候选新药。     

褪黑素对吗啡依赖大鼠复吸行为的抑制作用

目的 :研究褪黑素对吗啡依赖大鼠复吸行为的抑制作用。方法 :以剂量递增法连续皮下注射 (sc)吗啡 6d建立吗啡诱导的大鼠条件性位置偏爱 (CPP)模型 ,d7用生理盐水替代吗啡训练大鼠 10d ,以使形成的CPP逐渐消退。单次sc 4mg·kg- 1 吗啡以唤起消退的CPP的恢复。部分大鼠在注射吗啡前 30min分别腹腔注射 (ip)褪黑素 2 0、4 0和 80mg·kg- 1 进行治疗。结果 :与吗啡依赖组相比 ,在sc 4mg·kg- 1 吗啡引燃刺激前 30min应用褪黑素 4 0和 80mg·kg- 1 急性治疗 ,可以使大鼠在伴药箱的停留时间明显缩短 ,(P <0 0 5、P <0 0 1) ;而褪黑素 2 0mg·kg- 1 急性治疗亦使大鼠在伴药箱的停留时间缩短 ,但无统计学意义 ,P >0 0 5。结论 :褪黑素在一定程度上可以抑制吗啡引燃的吗啡依赖大鼠的复吸行为     

黄芪总皂苷对小鼠吗啡条件性位置偏爱及NO水平的影响

目的：观察黄芪总皂苷对吗啡诱导的小鼠条件性位置偏爱（CPP）效应的影响及其与中枢NO水平的关系。方法：建立小鼠吗啡CPP模型，观察黄芪总皂苷对CPP的影响，采用硝酸还原酶法检测小鼠脑中NO含量。结果：吗啡（6mg／kg，SC）可诱导小鼠对伴药箱产生显的CPP（P〈0．01），小鼠脑组织NO水平亦显升高（P〈0．01）；训练阶段于每次给予吗啡前30min给予黄芪总皂苷（40～160mg／kg）可拮抗小鼠对吗啡的CPP效应的（P〈0．05，P〈0．01，P〈0．01），并能降低脑内NO含量（P〈0．05，P〈0．01，P〈0．01）；仅在测试前30min一次给予黄芪总皂苷160mg／kg可抑制小鼠已形成的CPP（P〈0．01），并降低脑内NO含量（P〈0．05），而黄芪总皂苷40和80mg／kg组则不影响其效应（P〉0．05）。结论：黄芪总皂苷可抑制吗啡诱导的小鼠CPP效应的形成和表达，其作用机制可能与降低中枢NO水平有关。     

大鼠相关脑区p—CREB和c—Fos在吗啡点燃条件性位置偏爱条件下的变化

目的：研究磷酸化cAMP反应元件结合蛋白（phospho—cAMP response element binding protein,p-CREB）和c-Fos在吗啡点燃条件性位置偏爱激活大鼠海马、杏仁核表达的变化。方法：以剂量递增连续皮下（s．c．）注射吗啡6d建立吗啡诱导大鼠条件位置性偏爱（conditionedplacepreference,CPP）模型,第7天用生理盐水替代吗啡训练大鼠10d,使CPP消退,单次s．c．吗啡（4mg／kg）激发已消退的CPP。采用免疫组化技术测定吗啡激发CPP重现时大鼠海马、杏仁核p-CREB和c—Fos的变化。结果：吗啡可使大鼠产生CPP效应,吗啡4mg／kg可使已消失的CPP效应激活;吗啡诱发CPP激活时大鼠海马、杏仁核p-CREB和c—Fos的表达增加。结论：海马、杏仁核p-CREB和c—Fos蛋白的表达参与了吗啡点燃CPP重现。     

东莨菪碱对吗啡诱发条件位置性偏爱重现大鼠杏仁核p-CREB及c-Fos表达的影响

目的：探讨东莨菪碱对吗啡诱发条件位置性偏爱（conditioned place preference,CPP）重现大鼠杏仁核（amygdala nucleus,Amy）cAMP反应元件结合蛋白（phospho-cAMP response element binding protein,p-CREB）和c-Fos表达的变化。方法：以剂量递增法建立大鼠CPP模型,生理盐水替代吗啡训练大鼠,使形成的CPP逐渐消退,小剂量吗啡激活已消退的CPP。采用免疫组化技术测定不同剂量东莨菪碱对吗啡诱发CPP重现时大鼠杏仁核p-CREB和c-Fos的变化。结果：东莨菪碱可抑制吗啡点燃诱发大鼠CPP重现行为;并可减少吗啡诱发的CPP重现时大鼠杏仁核p-CREB和c-Fos的表达。结论：东莨菪碱对小剂量吗啡诱发吗啡依赖大鼠CPP重现行为的抑制作用可能与其抑制大鼠杏仁核p-CREB和c-Fos蛋白表达有关。     

Role of the cholinergic system in the rat basolateral amygdala on morphine-induced conditioned place preference

The effects of intra-basolateral amygdala (intra-BLA) injections of physostigmine, atropine, nicotine and/or mecamylamine on morphine-induced conditioned place preference (CPP) in rats was investigated by using an unbiased 3-day schedule of place conditioning design. Animals that received 3 daily injections of morphine (0.5-10 mg/kg) subcutaneously (s.c.) or saline (1.0 ml/kg, s.c.) showed a significant preference for compartment paired with morphine. The maximum response was observed with 7.5 mg/kg of the opioid. Administration of the anticholinesterase drug, physostigmine (1, 3 and 5 microg/rat) with an ineffective dose of morphine (0.5 mg/kg) elicited a significant CPP. Injections of antimuscarinic receptor agent, atropine (1, 4 and 7 microg/rat) dose-dependently inhibited the morphine (7.5 mg/kg)-induced place preference. The injections of nicotine (0.75, 1 and 2 microg/rat) potentiated the morphine (0.5 mg/kg)-induced place preference, while the nicotinic receptor antagonist, mecamylamine (1, 3 and 6 microg/rat) dose-dependently inhibited the morphine (7.5 mg/kg)-induced place preference. Furthermore, administration of atropine (7 microg/rat) but not mecamylamine (6 microg/rat) reduced the response induced by different doses of physostigmine plus morphine. Moreover, mecamylamine (6 microg/rat) but not atropine (7 microg/rat) reduced the response induced by different doses of nicotine plus morphine. It is concluded that the muscarinic and nicotinic receptor mechanisms in the BLA may be involved in the acquisition of morphine-induced place preference.     

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.     

The effect of L-stepholidine, a novel extract of Chinese herb, on the acquisition, expression, maintenance, and re-acquisition of morphine conditioned place preference in rats

The effect of L-stepholidine (SPD), a novel alkaloid extract of the Chinese herb Stephania with partial dopamine D1 receptor agonistic and D2 receptor antagonistic dual actions, on morphine conditioned place preference (CPP) was studied. Daily injection of morphine (10 mg/kg, i.p.) for 6 days induced CPP in rats, and daily treatment with SPD at 10 or 20 mg/kg before morphine injection dose-dependently attenuated morphine-induced CPP. On the day following acquisition of morphine CPP, a single administration of SPD at 10 or 20 mg/kg failed to block the expression of CPP. However, daily administration of SPD at 20 mg/kg for 7 days attenuated the maintenance of CPP. Morphine-induced CPP extinguished after a 21-day saline training and then a single injection of morphine (3 mg/kg, i.p.) induced re-acquisition of morphine CPP; however, pretreatment with SPD at 10 or 20 mg/kg 30 min before morphine injection dose-dependently blocked morphine (3 mg/kg, i.p.)-induced re-acquisition of morphine CPP. Furthermore, our data indicate that SPD had no effect on food-induced CPP or state-dependent learning, suggesting that the observed effect of SPD does not result from an inhibition of general learning ability. These results demonstrate that SPD can inhibit acquisition, maintenance, and re-acquisition of morphine conditioned place preference and suggest its potential for treatment of opioid addiction.     

Repeated administration of dopaminergic agents in the dorsal hippocampus and morphine-induced place preference

The aim of the present experiments was to investigate whether repeated intra-hippocampal CA1 (intra-CA1) administration of dopaminergic agents can affect morphine-induced conditioned place preference (CPP). Effects of repeated intra-CA1 injections of dopamine (DA) receptor agonists and antagonists on morphine-induced CPP in rats were investigated using an unbiased 3-day schedule of place conditioning. Animals receiving once-daily subcutaneous (s.c.) injections of morphine (1-9 mg/kg) or saline (1.0 ml/kg, s.c.) showed a significant place preference in a dose-dependent manner: the maximum response was observed with 3 mg/kg morphine. Three days' intra-CA1 injections of apomorphine (0.25-1 microg/rat) followed by 5 days free of the drug, significantly decreased morphine CPP (1 and 3 mg/kg, s.c.). Moreover, pre-treatment with the highest dose of apomorphine (1 microg/rat) altered the effect of morphine to an aversive response. The morphine (1 and 3 mg/kg) CPP was also significantly decreased in animals that previously received three intra-CA1 injections of SKF 38393 (2-9 microg/rat), quinpirole (1-3 microg/rat) or sulpiride (1-3 microg/rat), and significantly increased in animals that had previously received three intra-CA1 injections of SCH 23390 (0.02 microg/rat). The 3-day pre-treatment with apomorphine, SKF 38393 or quinpirole reduced locomotor activity in the test session, while SCH 23390 and sulpiride did not have any influence on locomotor activity. It is concluded that repeated injections of DA receptor agents in the dorsal hippocampus, followed by 5 days free of the drugs, can affect morphine reward.     

Different effects of GABAergic receptors located in the ventral tegmental area on the expression of morphine-induced conditioned place preference in rat

In the present study, an unbiased conditioned place preference paradigm was used to study the effects of intra-ventral tegmental area injections of Gama-amino-butyric acid (GABA)-A and B (GABA(A) and GABA(B)) receptor agonists and antagonists on the expression of morphine-induced conditioned place preference (CPP) in rats. Subcutaneous (s.c.) injections of morphine sulfate (5 mg/kg) induced CPP. Intra-ventral tegmental area administration of the GABA(A) receptor agonist, muscimol (6 microg/rat) reduced the expression of morphine-induced CPP. Muscimol (25 microg/rat) increased the expression of CPP induced by morphine. A reduction of the expression of morphine-induced CPP was observed on intra-ventral tegmental area injection of GABA(A) receptor antagonist bicuculline (25 microg/rat). Bicuculline (10 microg/rat) increased the expression of CPP induced by morphine. Baclofen (12 microg/rat) increased where as (19 and 25 microg/rat) reduced the expression of morphine-induced CPP. Injection of CGP38345 (10, 19, 25 and 50 microg/rat) into the ventral tegmental area significantly reduced the expression of CPP induced by morphine. It is concluded that GABA(A) and GABA(B) receptor subtypes within the ventral tegmental area may have different effects on the expression of morphine-induced CPP.     

Agmatine potentiates morphine-induced conditioned place preference in mice: modulation by alpha2-adrenoceptors.

The effects of agmatine, an endogenous polyamine metabolite formed by decarboxylation of L-arginine, and its combination with morphine on conditioned place preference (CPP) has been investigated in male mice. Our data show that subcutaneous administration of morphine (1-7.5 mg/kg) significantly increases the time spent in the drug-paired compartment in a dose-dependent manner. Intraperitoneal administration of agmatine (1-40 mg/kg) alone does not induce either CPP or conditioned place aversion, while combination of agmatine and subeffective doses of morphine leads to potent rewarding effects. Lower doses of morphine (0.1, 0.05, and 0.01 mg/kg) are able to induce CPP in mice pretreated with agmatine 1, 5, and 10 mg/kg, respectively. Concomitant intraperitoneal administration of UK 14 304 (0.5 mg/kg), a highly selective alpha2-agonist, with per se noneffective dose of morphine (0.5 mg/kg) and also its combination with noneffective doses of agmatine (1 mg/kg) plus morphine (0.05 mg/kg) produces significant CPP. UK 14 304 (0.05, 0.5 mg/kg) alone, or in combination with agmatine (1, 5 mg/kg) have had no effect. We have further investigated the possible involvement of the alpha2-adrenoceptors in the potentiating effect of agmatine on morphine-induced place preference. Selective alpha2-antagonists, yohimbine (0.005 mg/kg) and RX821002 (0.1, 0.5 mg/kg), block the CPP induced by concomitant administration of agmatine (5 mg/kg) and morphine (0.05 mg/kg). Yohimbine (0.001-0.05 mg/kg) or RX821002 (0.05-0.5 mg/kg) alone or in combination with morphine (0.05 mg/kg) or agmatine (5 mg/kg) fail to show any significant place preference or aversion. Our results indicate that pretreatment of animals with agmatine enhances the rewarding properties of morphine via a mechanism which may involve alpha2-adrenergic receptors.     

Conditioned place preference: no tolerance to the rewarding properties of morphine

The effect of repeated morphine administration on conditioned place preference (CPP) using a novel treatment schedule, i.e., drug treatment was always contingent with the conditioned environmental stimuli, was investigated. We also examined whether changes in the μ- and κ-opioid receptor binding occurred in the brain of morphine-treated animals. Intraperitoneal (i.p.) administration of morphine (2 and 10 mg/kg) induced a place preference after 8 daily conditioning trials (4 morphine injections on alternate trials), the level of preference being the same with the two doses of the opiate. No change in place preference was observed in the morphine-treated rats at 2 mg/kg, when animals were further trained up to a total of 32 conditioning trials (16 morphine injections). Conversely, after 20 conditioning trials (10 morphine injections), a stronger CPP response developed in the morphine-treated rats at 10 mg/kg. Signs of morphine withdrawal were never detected in morphine-treated rats during the experiment. Loss of body weight (index of opiate dependence) was not observed either 24 h or 48 h after the last morphine administration. μ- and κ-opioid receptor density and affinity were not affected by repeated morphine administrations at either dose. The results demonstrate that no tolerance develops to the rewarding properties of morphine. Indeed, a sensitisation effect may occur at increasing doses of the opiate. Furthermore, changes in the rewarding effect of morphine are not dependent upon alterations in opioid receptors involved in the reinforcing mechanisms. Received: 31 October 1996 / Accepted: 7 February 1997