伏隔核的外壳部和核心部毁损对大鼠吗啡觅药行为的影响

背景：伏隔核对吗啡觅药行为的建立起着至关重要的作用，而伏隔核内不同区域在形态学、神经化学和电生理学等方面存在明显差别。目的：分析伏隔核各亚区(外壳、核心)在吗啡觅药行为中的作用，研究定向毁损对大鼠成瘾行为的影响。设计：随机对照实验研究。地点和对象：雄性Sprague-Dawley大鼠，由解放军第四军医大学实验动物中心提供。干预：大鼠通过吗啡强化形成条件性地点偏好，在反应稳定后，使用直流电对大鼠进行外壳部或核心部毁损(或空白对照)。待大鼠恢复后进行吗啡复燃，并测试其地点偏好数据。主要观察指标：位置偏爱箱内最大停留时间。结果：在7d内，所有外壳毁损组和空白对照组动物均重新建立起了与毁损前相同的条件性地点偏好，最大停留时间分别为(647&;#177;46)和(662&;#177;29)s，均达到术前水平。但是，伏隔核核心部毁损却导致觅药行为的明显减退，最大停留时间由术前的(650&;#177;30)s减至术后的(463&;#177;40)s，与其他两组相比差异有显著性意义(q=3．95，4．17；P&;lt;0．05)。结论：在药物相关刺激条件下，伏隔核核心在吗啡觅药行为的建立方面起重要作用。     

毁损伏隔核、腹侧苍白球对大鼠觅药行为的影响

目的探讨伏隔核和腹侧苍白球在药物强化中的作用。方法分别毁损成瘾大鼠伏隔核、腹侧苍白球,利用条件性地点偏好实验测定术前、术后成瘾大鼠对注射吗啡的偏好分,评价伏隔核和腹侧苍白球在药物强化效应的作用。结果毁损大鼠双侧伏隔核能够完全消除大鼠对注射吗啡侧的偏好,毁损腹侧苍白球明显减少成瘾大鼠的地点偏好行为。结论伏隔核和腹侧苍白球是调节强化作用的重要位置,伏隔核－腹侧苍白球通路是药物强化的共同环路。     

伏隔核毁损对应激诱导大鼠吗啡觅药行为的影响

目的:研究戒断后的吗啡依赖大鼠在应激诱导下的位置偏爱行为,并毁损伏隔核(nucleusaccumbens,NAc)观察其对大鼠条件性位置偏爱(conditionedplacepreference,CPP)的影响和NAc在应激诱发复吸中的作用。方法:雄性SD大鼠通过吗啡强化形成CPP后,采用立体定向方法使用直流电选择性毁损NAc犤NAc双侧坐标为:前后(AP)+1.7mm,外侧(L)±1.5mm和背腹(DV)硬膜表面以下7.5mm,毁损电流/时间为2mA/min犦,对照组用相同的过程但不通电流。经过15d的熄灭训练后,给予间断足击应激刺激(电流强度0.5mA,时程0.5s,间隔10～70s,平均40s)诱导大鼠重建位置偏爱行为,测量并比较毁损组与对照组的位置偏爱得分。结果:间断足击应激恢复了对照组大鼠对吗啡的CPP,第25天的CPP得分显著高于第1天犤第25天为(673±53)s;第1天为(446±50)s,q=4.91,P<0.01犦。NAc毁损组大鼠在间断足击应激诱导下未恢复对吗啡的CPP,第25天的CPP得分与第1天差异无显著性意义犤第25天为(471±52)s;第1天为(460±53)s,q=2.82,P>0.05犦。结论:间断足击应激可有效诱导戒断动物复吸,毁损NAc能阻断间断足击应激诱导戒断大鼠重建觅药行为。在应激诱导戒断动物觅药行为中,NAc起重要作用。     

伏隔核毁损对应激诱导大鼠吗啡觅药行为的影响

目的：研究戒断后的吗啡依赖大鼠在应激诱导下的位置偏爱行为，并毁损伏隔核(nuc1eus acct1mbens，NAc)观察其对大鼠条件性位置偏爱(conditioned p1acepre ference,CPP)的影响和NAc在应激诱发复吸中的作用。方法：雄性SD大鼠通过吗啡强化形成CPF后，采用立体定向方法使用直流电选择性毁损NAc[NAc双侧坐标为：前后(AP)+1．7mm，外侧(L)&;#177;1．5mm和背腹(DV)硬膜表面以下7．5mm，毁损电流／时间为2mA／min]，对照组用相同的过程但不通电流。经过15d的熄灭训练后，给予间断足击应激刺激(电流强度0．5mA，时程0．5s，间隔10～70s。平均40s)诱导大鼠重建位置偏爱行为，测量并比较毁损组与对照组的位置偏爱得分。结果：间断足击应激恢复了对照组大鼠对吗啡的CPP，第25天的CPP得分显著高于第1天[第25天为(673&;#177;53)s；第1天为(446&;#177;50)s，q=4．91，P&;lt;0．01]。NAc毁损组大鼠在间断足击应激诱导下未恢复对吗啡的CPF，第25天的CPP得分与第1天差异无显著性意义[第25天为(471&;#177;52)s；第1天为(460&;#177;53)s，q=2．82，P&;gt;0．05]。结论：间断足击应激可有效诱导戒断动物复吸，毁损NAc能阻断间断足击应激诱导戒断大鼠重建觅药行为。在应激诱导戒断动物觅药行为中，NAc起重要作用。     

构建吗啡依赖条件性位置厌恶模型大鼠伏隔核壳区相关基因的表达

背景：腺苷酸环化酶Ⅷ涉及促进吗啡耐受、戒断和强化性能,对晚期长时程增强效应、长时程记忆和对应激的适应等可塑性变化中发挥重要的作用.目的：基于慢性吗啡依赖大鼠纳洛酮催瘾戒断建立的条件性位置厌恶动物模型,观察在条件性位置厌恶建立前后,与成瘾密切相关脑区伏隔核壳区内腺苷酸环化酶Ⅷ基因表达的适应性变化.方法：选用清洁级雄性S D大鼠,设模型组（吗啡＋纳洛酮组）、吗啡＋盐水组和盐水＋纳洛酮组.模型组采用连续6.5 d慢性吗啡腹腔注射10 mg/kg,纳洛酮一次催瘾注射0.3 mg/kg,同时与条件性位置训练箱搭配建立大鼠条件性位置厌恶模型,对照组依模型组对照注射等体积生理盐水.在条件性位置厌恶建立前后,采用免疫组织化学方法检测伏隔核壳区内腺苷酸环化酶Ⅷ基因的表达水平.结果与结论：条件性位置厌恶建立前,3组腺苷酸环化酶Ⅷ在伏隔核壳区表达水平差异无显著性意义（F=4.651,P=0.052）;条件性位置厌恶建立后,吗啡＋纳洛酮组腺苷酸环化酶Ⅷ在伏隔核壳区（F=4.874, P=0.028）内表达水平显著高于吗啡＋盐水组和盐水＋纳洛酮组.结果提示,伏隔核壳区内腺苷酸环化酶Ⅷ水平可能是调节阿片类物质戒断所致厌恶动机的关键因子之一;腺苷酸环化酶Ⅷ基因表达水平的变化可能是条件性位置厌恶建立相关的神经适应性变化的重要分子基础之一.     

吗啡对大鼠伏隔核及内侧隔-斜角带核神经元放电的影响

吗啡成瘾包括躯体依赖和精神依赖两方面,其最显著的特征为强迫性觅药及用药。而精神依赖则为戒断躯体依赖后高复吸率的主要原因。目前国内外实验证明,吗啡通过激活大脑中的奖赏中枢-中脑边缘多巴胺系统而引起吗啡的精神依赖。本实验从大鼠中脑边缘多巴胺系统的伏隔核以及内侧隔     

神经生长因子对大鼠视神经损伤的保护作用

背景神经生长因子(nerve growth factor,NGF)对神经元的存活、神经纤维的生长和分化以及再生起重要作用,是维持中枢神经和周围神经功能的重要活性因子,对许多疾病如神经系统变性疾病、老年性痴呆、脊髓损伤、脑卒中致瘫痪等均有潜在的治疗价值.目的测定经二硫化碳所致视神经损害的大鼠在治疗前后视觉诱发电位的变化,来证实神经生长因子对受损视神经的治疗效果.设计完全随机设计,对照实验研究.地点和材料研究地点为解放军上海第二军医大学基础部.材料为Wistar健康成年大鼠,体质量240～340g,雌雄各半,由第二军医大学实验动物中心提供.方法与主要观察指标将大鼠随机分成4组NGF 5 000 U/kg组、NGF1 000 U/kg组、NGF 200 U/kg组和空白对照组.将清醒已埋好电极的大鼠进行固定,测定其视觉诱发电位及模式翻转诱发电位.结果大鼠视神经损伤模型经神经生长因子治疗20 d后,模式反转诱发电位潜伏期[NGF 5000 U/kg组N1为(42.9±5.3)s,P1为(59.9±5.6)s,N2(93.8±5.9)s]和闪光诱发电位的潜伏期[NGF 5 000 U/kg组P1为(31.2±2.6)s,N1为(37.9±4.0)s,P2为(54.7±4.9)s,N2为(85.1±5.2)s]与对照组相比均有明显的缩短.结论神经生长因子能明显改善视神经传导功能,并有量-效关系,提示神经生长因子对视神经损伤有一定的治疗作用.     

NMDA受体在慢性吗啡处理大鼠伏隔核神经元突触可塑性改变中的作用

目的：探讨N-甲基-D-天冬氨酸(N-methyl-D-aspartic acid，NMDA)受体在慢性吗啡处理大鼠伏隔核神经元突触可塑性中的作用。方法：将15只雄性Sprague-Dawley大鼠随机等分为吗啡组(腹腔注射吗啡，起始剂量5mg／kg，2次／d，逐日递增5mg,至第10天为50mg／kg)、干预组(每次注射吗啡前30min腹腔注射NMDA受体拮抗剂地卓西平0．075mg／kg)及对照组(注射同体积的生理盐水)。末次注射后6d处死取伏隔核并制作电镜标本，日立H-600透射电镜下测量神经元突触界面结构参数。结果：吗啡组大鼠伏隔核神经元突触活性区长度[(226.46&;#177;21．10)nm]及突触后致密物厚度[(43．50&;#177;5．44)nm]显著小于对照组[(319．30&;#177;13．40)nm，(58．70&;#177;4．95)nm](F=49.528，6．725；P均&;lt;0．01)；干预组大鼠突触后致密物厚度[(57．30&;#177;1.02)nm]显著大于吗啡组[(43．50&;#177;5.44)nm](P&;lt;0．05)，与对照组差异无显著性。结论：NMDA受体在慢性吗啡处理所导致的伏隔核神经元突触可塑性改变中有重要作用。     

慢性酒精暴露对不同性别Wistar大鼠前额叶皮质htr3a mRNA表达水平及觅药行为的影响

目的 探讨慢性酒精暴露对不同性别Wistar大鼠前额叶皮质htr3a mRNA表达水平及觅药行为的影响.方法 将24只雄性和24只雌性成年健康Wistar大鼠随机分为4组,雄性酒精组、雄性对照组、雌性酒精组、雌性对照组,每组12只,分别予以酒精或生理盐水处理15 d.采用条件性位置偏爱模型的条件性位置偏爱分值评价大鼠的觅药行为.采用实时荧光定量PCR检测大鼠前额叶皮质htr3a mRNA表达水平.结果 雄性酒精组及雌性酒精组条件性位置偏爱分值、前额叶皮质htr3a mRNA表达水平均显著高于雄性对照组及雌性对照组(P＜0.01),不同性别大鼠酒精组和对照组条件性位置偏爱分值、前额叶皮质htr3a mRNA表达水平比较差异均无显著性(P＞0.05).雄性和雌性酒精组条件性位置偏爱分值与前额叶皮质htr3a mRNA表达水平呈显著正相关(r=0.441,P＜0.05).结论 Wistar大鼠慢性酒精暴露后前额叶皮质htr3amRNA表达水平升高,且与酒精觅药行为呈正相关;雄性与雌性Wistar大鼠慢性酒精暴露诱导的觅药行为、前额叶皮质htr3a mRNA的表达水平无显著差异.     

预先电刺激小脑顶核对缺血心肌神经生长因子基因表达的影响

目的:观察预先电刺激小脑顶核对心肌梗死大鼠心脏神经生长因子mRNA表达的影响。方法:实验于2003-03/06在重庆医科大学附属第一医院心血管疾病研究所完成。选用Wistar大鼠98只。将其中90只随机分为3组,每组30只:①心肌梗死组,结扎左冠状动脉前降支。②电刺激小脑顶核组,预先电刺激小脑顶核1h再予以左冠状动脉前降支结扎。③毁损小脑顶核组,毁损小脑顶核5d后电刺激小脑顶核1h,再行左冠状动脉前降支结扎。又分左冠状动脉前降支结扎后1,7,21d3个时间点,各10只。另设假手术组(n=8)。各组于相应时间点处死大鼠后,取心肌梗死区和非梗死区组织标本,用反转录-聚合酶链反应技术检测标本神经生长因子mRNA表达。结果:去除死亡、心肌未梗死、小脑顶核电刺激或毁损失败的大鼠,最终54只大鼠资料完整,心肌梗死组、电刺激小脑顶核组、毁损小脑顶核组、假手术组分别为13,20,13,8只。①结扎左冠状动脉前降支后1,7,21d,梗死区神经生长因子mRNA表达量:心肌梗死组明显低于假手术组(q=10.047,13.869,7.044,P<0.01);电刺激小脑顶核组明显高于心肌梗死组(0.42±0.07,0.46±0.07,0.51±0.08;0.26±0.08,0.19±0.06,0.36±0.07,q=5.358,9.888,4.822,P<0.01);毁损小脑顶核组与心肌梗死组比较无明显差异(P>0.05)。②心肌非梗死区1,7,21d神经生长因子mRNA表达:心肌梗死组均明显低于假手术组和电刺激小脑顶核组(0.36±0.07,0.30±0.07,0.36±0.07;0.56±0.07,0.56±0.07,0.56±0.07;0.49±0.09,0.46±0.08,0.59±0.09,q=4.099～8.947,P<0.01);毁损小脑顶核组神经生长因子mRNA的表达量与心肌梗死组比较无明显差异(P>0.05)。结论:大鼠心肌梗死后梗死区与非梗死区神经生长因子mRNA表达下调,电刺激小脑顶核可上调神经生长因子mRNA表达,起到神经保护作用。     

The nucleus accumbens core has a more important role in resisting reactivation of extinguished conditioned place preference in morphine-addicted rats

We investigated the roles of the core and shell subfields of the nucleus accumbens (NAc) in drug- or foot-shock-induced reactivation of extinguished conditioned place preference (CPP) in morphine-addicted rats. Rats were given electrolytic lesions to either the core or shell after CPP was established. After surgery, a reduction of CPP scores to morphine was observed in all groups. During the reacquisition of morphine-seeking behaviour, rats in the shell and sham lesion groups regained their CPP, while the CPP in core lesion rats remained severely impaired. Similarly, foot-shock-induced reactivation of CPP in the core lesion group was significantly lower than that of the shell and sham lesion groups, and there was no significant difference between these latter groups. Our results demonstrate that NAc core and shell lesions elicited dissociable effects on reactivation of extinguished CPP in rats, suggesting that the NAc core might play a more important role in resisting reactivation of extinguished CPP in morphine-addicted rats.     

伏核毁损对精神分裂症大鼠行为和纹状体多巴胺含量的影响

目的探讨毁损伏核对精神分裂症大鼠行为及纹状体多巴胺含量的影响,为用神经外科方法治疗精神分裂症提供参考。方法50只Spraqui-Dawlay大鼠随机分为正常对照组、模型组、模型伏核毁损组和模型伏核假毁损组。模型组经腹腔注射苯环己哌啶(PCP)制作精神分裂症动物模型,立体定向电极毁损大鼠伏核,观察精神分裂症模型大鼠社会行为,并对其刻板行为评分,荧光分光光度法测定纹状体多巴胺含量。结果伏核毁损组能减轻精神分裂症模型大鼠刻板行为和社会行为,与假毁损组之间的差别具有非常显著性的意义(P<0.001,t=8.51)。伏核毁损组纹状体多巴胺含量显著低于伏核假毁损组,与假毁损组之间的差别具有显著性的意义(P<0.05,t=2.19)。结论精神分裂症模型大鼠纹状体多巴胺功能亢进,立体定向毁损伏核能够降低纹状体多巴胺含量,改善精神分裂症症状。     

Inflammation and drug idiosyncrasy--is there a connection?

For several decades, it has been suggested that dopamine (DA), especially in nucleus accumbens, mediates the primary reinforcing characteristics of natural stimuli such as food, as well as drugs of abuse. Yet, several fundamental aspects of primary food reinforcement, motivation, and appetite are left intact after interference with accumbens DA transmission. Recent studies have shown that accumbens DA is involved in responsiveness to conditioned stimuli and activational aspects of motivation. In concurrent choice tasks, accumbens DA depletions cause animals to reallocate their choice behavior in the direction of instrumental behaviors that involve less effort. Also, an emerging body of evidence has demonstrated that the effects of accumbens DA depletions on instrumental food-seeking behavior can vary greatly depending upon the task. For example, some schedules of reinforcement are insensitive to the effects of DA depletions, whereas others are highly sensitive (e.g., large fixed ratios). Accumbens DA depletions slow the rate of operant responding, blunt the rate-facilitating effects of moderate-sized ratios, and enhance the rate-suppressing effects of very large ratios (i.e., produce ratio strain). Accumbens DA may be important for enabling rats to overcome behavioral constraints, such as work-related response costs, and may be critical for the behavioral organization and conditioning processes that enable animals to engage in vigorous responses, such as barrier climbing, or to emit large numbers of responses in ratio schedules in the absence of primary reinforcement. The involvement of accumbens DA in activational aspects of motivation has implications for energy-related disorders in psychiatry, as well as aspects of drug-seeking behavior.     

Attenuation of brain response to heroin correlates with the reinstatement of heroin-seeking in rats by fMRI

Thirty male Sprague-Dawley rats were divided into two groups and trained to self-administer either saline (n = 14) or heroin (0.1 mg/kg per injection, n = 16) for 10-12 days until a stable self-administration (SA) behavior was achieved. After 8-9 days of withdrawal, each group was divided into two subgroups for reinstatement tests and functional magnetic resonance image (fMRI) scanning, respectively, to determine the neural correlates of the reinstatement of heroin-seeking behavior. For reinstatement testing, heroin-SA rats (n = 10) displayed robust reinstatement of drug-seeking behavior triggered by an acute heroin priming injection, whereas saline control rats (n = 8) did not show such a behavioral response. Regional positive or negative blood oxygen level-dependent (BOLD) signals, induced by heroin priming injection, were observed in both groups of rats during fMRI scanning. However, such heroin-induced positive BOLD signal primarily in the prefrontal cortex and parietal cortex was significantly attenuated in heroin-SA rats (n = 6) when compared to saline control rats (n = 6). Similarly, the heroin-induced negative BOLD signal in the subcortical regions, such as in the nucleus accumbens and hippocampus, was also significantly attenuated in both signal intensity and number of brain voxels activated in heroin-SA rats. These data demonstrate that heroin-induced reinstatement of drug-seeking behavior coincides with a significant, enduring reduction in opiate-induced brain activity in heroin-SA rats, suggesting a possible role of opiate tolerance in mediating reinstatement of drug-seeking behavior.     

GABAB receptor-positive modulation-induced blockade of the rewarding properties of nicotine is associated with a reduction in nucleus accumbens DeltaFosB accumulation

There is an increasing demand for a novel non-nicotinic, nondopaminergic therapeutic approach to nicotine addiction. GABAergic mechanisms have been implicated in drug dependence. Recently, a novel GABAB receptor allosteric-positive modulator, GS39783, was characterized. There are no investigations to date on the effects of GABAB receptor-positive modulators in animal models of nicotine reinforcement. Conditioned place preference (CPP) paradigms are based on the principle that animals, like humans, would learn to seek environmental stimuli that have been previously associated with rewarding events. Here we show that nicotine (0.06 mg/kg s.c.) induced a robust CPP response. Furthermore, GS39783 (30-100 mg/kg p.o.) during the conditioning phase blocked the rewarding effects of nicotine in the CPP paradigm in rats. However, GS39783 did not significantly alter the CPP effects of nicotine when given only immediately before the CPP test. A growing body of evidence suggests that repeated administration of drugs of abuse induced long-term molecular changes in brain plasticity, most notably an accumulation of DeltaFosB, in the striatal complex that contribute to the manifestation of dependence. There was a significant accumulation of DeltaFosB in the nucleus accumbens, but not in the dorsal striatum, of rats treated daily for 5 days with nicotine (0.06 mg/kg i.p.). GS39783 completely (30-100 mg/kg p.o.) counteracted these nicotine-induced molecular adaptations when given before the CPP acquisition phase but not when administered immediately before the test phase. Taken together, the behavioral and molecular changes induced by nicotine occur in concert and are concomitantly amenable to reversal by GABAB receptor-positive modulators.     

GABA(B) receptor activation in the ventral tegmental area inhibits the acquisition and expression of opiate-induced motor sensitization

Opiate-induced motor sensitization refers to the progressive and enduring motor response that develops after intermittent drug administration, and results from neuroadaptive changes in ventral tegmental area (VTA) and nucleus accumbens (NAc) neurons. Repeated activation of mu-opioid receptors localized on gamma-aminobutyric acid (GABA) neurons in the VTA enhances dopaminergic cell activity and stimulates dopamine release in the nucleus accumbens. We hypothesize that GABA(B) receptor agonist treatment in the VTA blocks morphine-induced motor stimulation, motor sensitization, and accumbal Fos immunoreactivity by inhibiting the activation of dopaminergic neurons. First, C57BL/6 mice were coadministered a single subcutaneous injection of morphine with intra-VTA baclofen, a GABA(B) receptor agonist. Baclofen produced a dose-dependent inhibition of opiate-induced motor stimulation that was attenuated by 2-hydroxysaclofen, a GABA(B) receptor antagonist. Next, morphine was administered on days 1, 3, 5, and 9 and mice demonstrated sensitization to its motor stimulant effects and concomitant induction of Fos immunoreactivity in the NAc shell (NAcS) but not NAc core. Intra-VTA baclofen administered during morphine pretreatment blocked the acquisition of morphine-induced motor sensitization and Fos activation in the NAcS. Intra-VTA baclofen administered only on day 9 blocked the expression of morphine-induced motor sensitization and Fos activation in the NAcS. A linear relationship was found between morphine-induced motor activity and accumbal Fos in single- and repeated-dose treatment groups. In conclusion, GABA(B) receptor stimulation in the VTA blocked opiate-induced motor stimulation and motor sensitization by inhibiting the activation of NAcS neurons. GABA(B) receptor agonists may be useful pharmacological treatments in altering the behavioral effects of opiates.     

Forebrain sites differentially sensitive to beta-endorphin and morphine for analgesia and release of Met-enkephalin in the pentobarbital-anesthesized rat.

The mapping of the forebrain regions sensitive to beta-endorphin and morphine for antinociception was performed in pentobarbital-anesthetized rats. The antinociception was assessed by the tail-flick test. The sites most sensitive to beta-endorphin (2 micrograms) for inhibition of the tail-flick response were located in the ventromedial regions of the forebrain such as medial posterior nucleus accumbens, medial preoptic area and arcuate hypothalamic nucleus. Other areas such as anterior nucleus accumbens, dorsomedial hypothalamic nucleus, posterior hypothalamus, lateral hypothalamus, caudate nuclei, thalami and cerebral cortex were not sensitive to beta-endorphin for the tail-flick inhibition. The sites sensitive to morphine sulfate (4 micrograms) for inhibition of the tail-flick response were located in regions of medial preoptic nucleus and arcuate hypothalamic nucleus. Posterior nucleus accumbens, which is sensitive to beta-endorphin, was not sensitive to morphine for antinociception. Morphine injected into this site did not produce tail-flick inhibition in both conscious and pentobarbital-anesthetized rats. The inhibition of the tail-flick response induced by beta-endorphin (2 micrograms) from posterior nucleus accumbens, medial preoptic area and arcuate hypothalamic nucleus was blocked by the administration of beta-endorphin-(1-27), an epsilon opioid receptor blocker, but not by D-Phe-Cys-Tyr-D-Try-Orn-Thr-Pen-Thr-NH2, a mu opioid receptor blocker. On the other hand, the inhibition induced by morphine (4 micrograms) from medial preoptic area and arcuate hypothalamic nucleus was blocked by D-Phe-Cys-Tyr-D-Try-Orn-Thr-Pen-Thr-NH2, but not by beta-endorphin-(1-27).(ABSTRACT TRUNCATED AT 250 WORDS)     

Differential conditioned place preference responses to endomorphin-1 and endomorphin-2 microinjected into the posterior nucleus accumbens shell and ventral tegmental area in the rat

An unbiased conditioned place preference (CPP) paradigm was used to evaluate the reward effects of endogenous mu-opioid receptor ligands endomorphin-1 (EM-1) and endomorphin-2 (EM-2) from the mesolimbic posterior nucleus accumbens (Acb) shell and the ventral tegmental area (VTA) in CD rats. EM-1 (1.6-8.1 nmol) microinjected into posterior Acb shell produced CPP, whereas EM-2 (8.7-17.5 nmol) given into the same Acb shell produced conditioned place aversion (CPA). EM-1 (1.6-16.3 nmol) microinjected into the VTA produced CPP, whereas EM-2 (8.7 and 17.5 nmol) given into the same VTA site did not produce any effect, but at a high dose (35 nmol) produced CPP. EM-1 (3.3 nmol) or EM-2 (17.5 nmol) microinjected into the nigrostriatal substantia nigra was not significantly different from vehicle-injected groups. D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH(2) (CTOP) at 94.13 pmol or 3-methoxynaltrexone at 0.64 pmol microinjected into the posterior Acb shell blocked EM-1-induced CPP and EM-2-induced CPA. At a higher dose, CTOP (941.3 pmol) and 3-methoxynaltrexone (6.4 pmol) produced CPA and CPP, respectively. Coadministration with antiserum against dynorphin A(1-17) (Dyn) (10 microg) microinjected into the posterior Acb shell blocked EM-2-induced CPA. However, it did not affect EM-1-induced CPP. It is concluded that EM-1 and EM-2 produce site-dependent CPP and CPA, respectively, by stimulation of different subtypes of mu-opioid-receptors; stimulation of one subtype of mu-opioid-receptor at the posterior Acb shell and VTA by EM-1 induces CPP, whereas stimulation of another subtype of mu-opioid receptor at the posterior Acb shell, but not the VTA, by EM-2 induces the release of Dyn to produce CPA.     

Baclofen inhibits heroin self-administration behavior and mesolimbic dopamine release.

An emerging hypothesis to explain the mechanism of heroin-induced positive reinforcement states that opiates inhibit gamma-aminobutyric acid (GABA)-ergic interneurons within the mesocorticolimbic dopamine (DA) system to disinhibit DA neurons. In support of this hypothesis, we report that the development of heroin self-administration (SA) behavior in drug-naive rats and the maintenance of SA behavior in heroin-trained rats were both suppressed when the GABA(B) receptor agonist baclofen was coadministered with heroin. Microinjections of baclofen into the ventral tegmental area (VTA), but not the nucleus accumbens, decreased heroin reinforcement as indicated by a compensatory increase in SA behavior. Additionally, baclofen administered alone or along with heroin dose-dependently reduced heroin-induced DA release. This effect was blocked partially by intra-VTA infusion of the GABA(B) antagonist 2-hydroxysaclofen, suggesting an additional, perhaps GABA(A) receptor-mediated, disinhibitory effect. Taken together, these experiments, for the first time, demonstrate that heroin-reinforced SA behavior and nucleus accumbens DA release are mediated predominantly by GABA(B) receptors in the VTA and suggest that baclofen may be an effective agent in the treatment of opiate abuse.