尼古丁对帕金森病大鼠纹状体多巴胺及黑质自由基含量的影响

目的 :研究尼古丁对帕金森病大鼠的影响 ,探讨其对 PD的作用机制。方法 :通过 6 - OHDA脑立体定向注射术建立大鼠帕金森病模型。采用生化方法观察不同剂量尼古丁对帕金森病大鼠的作用 ,检测黑质自由基、抗氧化剂及多巴胺含量的变化。结果 :造模前及造模后皮下注射尼古丁的 PD大鼠 ,黑质自由基及抗自由基酶及多巴胺含量较PD组有明显改善 (P<0 .0 5 )。结论 :尼古丁可减轻 6 - OHDA对黑质 DA能神经元的损伤 ,对 PD大鼠具有保护作用     

蛋白酶在偏头痛中枢敏感化形成过程中的作用分析

目的：探讨蛋白酶在偏头痛中枢敏感化形成过程中的作用。方法选择60只200～300 g雄性SD大鼠,平均随机分为3个组,常规组、蛋白酶抑制组及偏头痛组,每组20只,偏头痛组与抑制组采用Moskowitz法建立起硬脑膜神经源性炎症偏头痛模型,并给予侧脑室注射,随后采用激光多普勒血流量图像仪和多导电生理记录仪测试出3组SD大鼠的硬脑膜血流量变化％和放电频率变化％进行对比。结果偏头痛组与抑制组的SD大鼠建立起偏头痛模型和注射药物后对比常规组发现,偏头痛组的硬脑膜血流量变化％较常规组明显,抑制组的硬脑膜血流量变化％较常规组明显降低,偏头痛组和抑制组的放电频率变化％较常规组明显提高,差异具有统计学意义。结论蛋白酶可能参与偏头痛中枢敏感化的形成。     

尼古丁对帕金森病大鼠纹状体GDNF和多巴胺含量的影响

目的 研究尼古丁对帕金森病（PD）大鼠纹状体脑胶质细胞源性神经营养因子(GDNF)和多巴胺（DA）含量的影响。方法 将6－羟多巴胺（6－OHDA）立体定向注射到大鼠右侧中脑腹侧背盖部（VTA）和黑质致密部（SNpc)，建立PD大鼠模型。采用生化、免疫组织化学方法观察不同剂量尼古丁对PD大鼠的作用，检测纹状体GDNF表达及DA含量的变化。结果 造模前及造模后皮下注射尼古丁的PD大鼠，纹状体GDNF表达及DA含量较PD组有明显改善（P＜0．05）。结论 尼古丁可减轻6－OHDA对黑质DA能神经元的损伤，对PD大鼠具有保护作用。     

神经节苷脂对帕金林病鼠旋转行为,纹状体多巴胺浓度及黑质…

观察神经节苷脂对帕金森病鼠模型旋转行为、纹状体多巴胺浓度及黑质病理的影响。方法将６－羟基多巴胺用立体定地注入大鼠－－侧中脑被盖腹侧区制作ＰＤ大鼠模型，并于同侧侧脑室注射混合型神经节苷脂，观察ＧＭ对由阿朴吗啡所诱发的旋转行为、受损侧纹状全多巴胺浓度及黑质病理的影响。结果 ＧＭ能减轻ＰＤ大鼠模型的旋转行为，、受损侧纹状体多巴胺浓度下降和黑质神经细胞减少。结论ＧＭ可减轻６－羟基多巴胺对黑质多巴胺了的听凭     

PKC在角叉菜胶致炎引起的脊髓背角神经元敏感化中的作用

组织损伤或炎症引起的脊髓背角神经元兴奋性的变化同痛觉过敏、痛觉超敏、自发痛等病理过程密切相关.本实验大鼠足底注射角叉菜胶后,脊髓背角神经元发生敏感化,自发放电及对伤害性刺激的诱发反应明显增强.背角局部经微透析给予蛋白激酶C(PKC)非特异性抑制剂氯丙嗪(CPZ)或特异性抑制剂H-7后,自发及诱发反应均明显回降,提示PKC激活参与中枢敏感化的形成与维持.     

PKC在角叉菜胶致炎引起的脊髓背角神经元敏感化中的作用

组织损伤或炎症引起的脊髓背角神经元兴奋性的变化同痛觉过敏、痛觉超敏、自发痛等病理过程密切相关。本实验大鼠足底注射角叉菜胶后 ,脊髓背角神经元发生敏感化 ,自发放电及对伤害性刺激的诱发反应明显增强。背角局部经微透析给予蛋白激酶 C(PKC)非特异性抑制剂氯丙嗪 (CPZ)或特异性抑制剂 H- 7后 ,自发及诱发反应均明显回降 ,提示 PKC激活参与中枢敏感化的形成与维持     

异体颈动脉体球细胞脑内移植对帕金森病大鼠行为及纹状体多巴胺含量的改善

帕金森病（Parkinson disease,PD)是一种好发于中老年人的中枢神经系统退行性疾病,细胞移植治疗是一项重要的手段,近年来,有研究表明颈动脉体球细胞在低氧状态下生长良好,且具有旺盛的分泌多巴胺（DA）的特性,为此,我们利用颈动脉体球细胞作为移植组织来源,系统观察移植治疗偏侧PD大鼠行为及DA的改善情况。     

左旋多巴对帕金森病大鼠黑质多巴胺能神经元及纹状体多巴胺递质的影响

目的　研究长期应用左旋多巴对帕金森病 (PD)大鼠黑质多巴胺 (DA)能神经元和DA递质的影响。方法　采用 6 羟基多巴胺 (6 OHDA)制备部分损毁和严重损毁的PD大鼠模型 ,给两种模型口服不同剂量左旋多巴 /苄丝肼 3个月 ,通过观察大鼠旋转行为、酪氨酸羟化酶 (TH)免疫组化染色和高效液相色谱 电化学检测仪 (HPLC ECD)检测纹状体单胺类递质 ,研究左旋多巴对PD大鼠残存的黑质DA能神经元的影响。结果　 (1)左旋多巴对PD大鼠的旋转行为无明显影响 ;(2 )TH阳性细胞数损毁侧 /非损毁侧比值在左旋多巴喂药组和不喂药对照组的差异无显著意义 (P >0 0 5 ) ;(3)在严重损毁组 ,大剂量左旋多巴使PD大鼠损毁侧DA和 3,4二羟基苯乙酸 (DOPAC)水平明显升高(P <0 0 1)。结论　长期使用左旋多巴对 6 OHDA单侧损毁的PD大鼠残存的黑质DA能神经元无毒性作用。     

酸枣仁汤对失眠症疗效及血浆褪黑素水平的影响

目的探讨酸枣仁汤对失眠症的疗效及对血浆褪黑素水平的影响。方法选用酸枣仁汤治疗失眠症,采用匹兹堡睡眠质量指数（PSQI）量表评定睡眠状况,采用放射免疫法测定血浆褪黑素水平,观察其治疗前后的变化,并与正常对照进行比较,统计分析分别采用t检验、F检验和直线相关分析。结果治疗前患者PSQI总分明显高于正常对照组（f=3．282,P=0．002）,治疗后患者PSQI总分下降（r=2．371,P=0．007）;患者组治疗前、治疗后和正常对照组血浆MT水平分别为（45．81±13．23）pg／ml、（49．01±16．53）pg／ml和（54．86±18．35）pg／ml,组间比较有差异显著意义（F=5．004．P=0．009）,治疗前明显低于正常对照组和治疗后MT水平;治疗前MT水平与PSQI总分、睡眠质量因子分、入睡时间因子分分剐呈负相关关系（P〈0．05或P〈0．01）。结论酸枣仁汤治疗失眠有明显的疗效,其作用机制可能与MT水平调节有关。     

酸枣仁汤对抑郁模型大鼠海马Wnt-1 基因和蛋白 表达的影响

目的 观察酸枣仁汤对抑郁模型大鼠海马Wnt-1 基因和蛋白表达的影响。方法 制作慢 性轻度不可预见性应激抑郁大鼠模型,实验分成对照组、模型组、氟西汀组、酸枣仁汤低、中、高剂量 组,分别采用酸枣仁汤和氟西汀治疗抑郁模型大鼠,测定其体重、糖水消耗、旷场实验行为活动前后得 分变化情况,以及Western blot 和Real-time PCR 分别检测大鼠海马中Wnt-1 蛋白和基因的表达情况。结 果 抑郁模型大鼠体重增长速度减慢,糖水消耗和旷场实验行为活动得分减少,海马内Wnt-1 蛋白和基 因表达也减少;酸枣仁汤治疗后,大鼠体重增长明显,糖水消耗量明显增多,旷场实验行为活动得分也 增加明显,Wnt-1 蛋白和基因表达上调。结论 酸枣仁汤可增加大鼠抑郁模型海马Wnt-1 基因和蛋白的 表达,减少神经元细胞凋亡,具有抗抑郁作用。     

Loss of nicotine-induced behavioral sensitization in micro-opioid receptor knockout mice

Repeated administration of nicotine produces behavioral sensitization. However, the possible mechanism of behavioral sensitization to nicotine remains unclear. The present study was undertaken in micro-opioid receptor knockout mice, to examine the hypothesis that micro-opioid receptors play a crucial role in behavioral sensitization to nicotine. All mice received saline or nicotine (0.05 mg/kg, s.c) twice a day for 7 consecutive days. The mice remained drug free for 3 days and on day 11 each group was challenged with saline or nicotine (0.05 mg/kg, s.c.). On day 1, it was observed that the single injection of nicotine (0.05 mg/kg, s.c.) did not influence locomotor activity in either micro-opioid receptor knockout or in wildtype mice. On day 7 (24 h after mice had been treated twice daily for 6 consecutive days with an injection of 0.05 mg/kg of nicotine), the mice were challenged with a single injection of nicotine, which produced behavioral sensitization in the wildtype but not in micro-opioid receptor knockout mice. On day 11, following 3 days of withdrawal after the second injection of nicotine on day 7, nicotine-treated mice were challenged with a single injection of nicotine and showed the behavioral sensitization of wildtype. However, nicotine challenge did not induce behavioral sensitization in micro-opioid receptor knockout mice. Our data indicate that a lack of micro-opioid receptors can inhibit the effects of nicotine-induced behavioral sensitization. This result strongly suggests that the micro-opioid receptor plays an important role in behavioral sensitization to nicotine.     

Clozapine inhibits development and expression of nicotine-induced locomotor sensitization in rats

It has been shown that clozapine, the prototype of atypical antipsychotics, significantly reduces daily cigarette use and alcohol consumption in schizophrenic patients. However, our knowledge about the effect of clozapine on nicotine abuse is limited. Aim of this study was to determine whether clozapine would inhibit the development and expression of nicotine-induced locomotor sensitization in rats. To investigate the effect of clozapine on the development of nicotine-induced locomotor sensitization, rats were pretreated with clozapine (2.5-10 mg/kg) 30 min before the nicotine (0.5 mg/kg), and locomotor activity was recorded for 15 min. This procedure was repeated every day for eight sessions. After a 3-day drug-free period, rats were challenged with nicotine (0.5 mg/kg). To reveal effect of clozapine on the expression of nicotine-induced locomotor sensitization, rats were injected with nicotine for eight sessions. After a 3-day drug-free period, rats were pretreated with clozapine (2.5-10 mg/kg) or vehicle 30 min before the nicotine (0.5 mg/kg) challenge injection. Repeated administration of nicotine generated robust locomotor sensitization in rats. Clozapine pretreatment (2.5-10 mg/kg) blocked the development and the expression of nicotine-induced locomotor sensitization in rats. Our results suggest that atypical antipsychotic clozapine can prevent the effects of nicotine in an animal model of dependence, which represents early adaptations in initiation and continuation of addictive behavior.     

Effects of risperidone on development and expression of nicotine-induced locomotor sensitization in rats

It has been shown that atypical antipsychotics significantly reduce smoking and alcohol consumption in schizophrenic patients. However, our knowledge about the effect of risperidone, especially on nicotine abuse is limited. We aimed to test the effects of risperidone in an animal model of nicotine‐induced locomotor sensitization, which represents initial neuroadaptations and continued behavioral changes in nicotine‐type dependence. To investigate the effect of risperidone on the development of nicotine‐induced locomotor sensitization, rats were pretreated with risperidone (0.025 and 0.050 mg kg^?1) 30 min before the nicotine (0.5 mg kg^?1, base) treatment, and locomotor activity was recorded for 30 min. This procedure was repeated every day for eight sessions. After a 6‐day drug‐free period, rats were challenged with nicotine (0.5 mg kg^?1). To reveal the effect of risperidone on the expression of nicotine‐induced locomotor sensitization, rats were injected with nicotine for eight sessions. After a 6‐day drug‐free period, rats were pretreated with risperidone (0.025 and 0.050 mg kg^?1) or vehicle 30 min before the nicotine (0.5 mg kg^?1) challenge injection. Repeated administration of nicotine generated robust locomotor sensitization in rats. Risperidone pretreatment (0.050 mg kg^?1) blocked the expression but not the development of nicotine‐induced locomotor sensitization in rats. Our results suggest that risperidone blocks the continuation of nicotine‐type addictive behavior, but it is ineffective on early adaptations in the initiation of nicotine addiction. Thus, this drug may have a limited beneficial effect in treatment of nicotine dependence. Synapse, 2011. © 2010 Wiley‐Liss, Inc.     

Ritanserin reverses repeated methamphetamine-induced behavioral and neurochemical sensitization in mice

Chronic administration of methamphetamine (METH) elicits progressive enhancement of locomotor activity known as behavioral sensitization. We have recently shown that chronic METH enhanced METH challenge-induced increase in 5-HT levels in the prefrontal cortex and that 5-HT(1A) receptor activation attenuated this neurochemical sensitization as well as behavioral sensitization. This study examined whether the nonselective 5-HT(2) receptor antagonist, ritanserin affects METH-induced behavioral and neurochemical sensitization in mice. Ritanserin at doses of 1 and 3 mg/kg inhibited the development and expression of METH-induced behavioral sensitization in a dose-dependent manner. Furthermore, chronic administration of ritanserin for a week attenuated the maintenance of behavioral sensitization, indicating the improvement of established behavioral sensitization. Microdialysis analysis showed that chronic ritanserin inhibited the neurochemical sensitization that chronic METH enhanced METH challenge-induced increase in extracellular 5-HT levels in the prefrontal cortex. Furthermore, acute ritanserin inhibited METH challenge-induced increase in extracellular 5-HT but not DA levels in the prefrontal cortex. These results suggest that 5-HT(2) receptors are involved in METH-induced hyperactivity and behavioral sensitization in mice.     

Enhancement of sensitization to nicotine-induced ambulatory stimulation by psychological stress in rats.

1. The authors investigated the influence of psychological stress (PSY-stress) on sensitization to nicotine (0.5 mg/kg, s.c.)-induced ambulatory stimulation. 2. Rats were exposed to the emotional responses of animals which received foot-shock (FS), which they, themselves, did not receive. Ten daily exposures to PSY-stress for 20 min enhanced sensitization to the nicotine-induced ambulatory stimulation compared to that in non-stress rats. 3. However, the increased serum corticosterone levels following nicotine (0.5 mg/kg, s.c.) administered 24 hr after the tenth injection of nicotine in the behavioral study was almost the same in the rats exposed to PSY-stress as compared to non-stress rats. 4. These results suggest that PSY-stress may promote sensitization to nicotine-induced ambulatory stimulation and that the combined effect of PSY-stress and nicotine would facilitate the development of sensitization to nicotine.     

Post-treatment of dextromethorphan on methamphetamine-induced drug-seeking and behavioral sensitization in rats

In our previous study, we first demonstrated a significant effect of dextromethorphan (DM) on morphine‐seeking behavior in morphine‐dependent rats, when DM was given during morphine withdrawal. Using the same conditioned place preference (CPP) paradigm modified for measuring drug‐seeking‐related behavior, we further investigated the possible effect of DM on methamphetamine (MA)‐seeking in MA‐dependent rats. Our data showed that DM could also effectively suppress the drug‐seeking behavior for MA, when administered during MA withdrawal. This suggests that DM may possess a pharmacological property to prevent drug‐seeking behavior for addictive drugs in general. To examine the action sites of DM in the brain, DM was microinjected into the VTA or the NAc, and tested for its effect on MA‐seeking during withdrawal. Both intra‐VTA and intra‐NAc injections of DM were able to block the MA‐seeking, suggesting that DM has a dual action sites. In our neurochemical results, intra‐NAc injection of DM showed a clear reduction of DA turnover rate at the NAc and the mPFC in response to MA challenge during withdrawal, which matched with the behavioral results. However, intra‐VTA injection of DM reduced the DA turnover rate at the mPFC but did not have effect on the DA turnover rate at the NAc. Although further investigations may be needed to verify the connection between our neurochemical and behavioral results, the present study highlights the therapeutic potential of DM in antidrug‐seeking behavior of MA and that the mechanism could be related to its effect on the mesolimbic and mesocortical dopaminergic pathways. Synapse 2012. © 2012 Wiley Periodicals, Inc.     

MK-801 prevents the development of behavioral sensitization during repeated morphine administration

Acute administration of morphine (10 mg/kg) to rats elicited an increase in locomotion that became sensitized upon repeated treatment over 14 days. Administration of the noncompetitive N-methyl-D-aspartate receptor (NMDA) antagonist MK-801 (0.1 or 0.25 mg/kg) prior to each morphine injection prevented the development of behavioral sensitization to morphine, an effect that persisted even after a 7-day withdrawal from repeated treatment. Sensitization was also prevented by coadministration of the competitive NMDA receptor antagonist CGS 19755 (10 mg/kg). In contrast, acute pretreatment with MK-801 did not alter the response of sensitized rats to morphine challenge, indicating that MK-801 does not prevent the expression of sensitization. When administered alone, MK-801 produced stereotyped movements at moderate doses (0.25 rng/kg) and horizontal locomotion at higher- doses, (0.5 mg/kg). Repeated administration of 0.25 mg/kg MK-801 elicited sensitization to its own locomotor stimulatory effects, such that this dose became capable of eliciting horizontal locomotion. Sensitization was not seen during repeated administration of 0.1 mg/kg MK-801 or 10 mg/kg CGS 19755, although both of these pretreatments did produce a sensitized response to subsequent challenge with 0.25 mg/kg MK-801. This effect was enhanced by coadministration of morphine, even though repeated administration of morphine alone failed to sensitize rats to MK-801 challenge. These results suggest a complex interplay between NMDA and opioid receptors, such that NMDA antagonists prevent morphine sensitization while morphine enhances the ability of NMDA antagonists to elicit sensitization to their own locomotor stimulatory effects. © 1994 Wiley-Liss, Inc.     

Exposure to nicotine and sensitization of nicotine-induced behaviors

Evidence for an important link between sensitization of midbrain dopamine (DA) neuron reactivity and enhanced self-administration of amphetamine and cocaine has been reported. To the extent that exposure to nicotine also sensitizes nucleus accumbens DA reactivity, it is likely that it will also impact subsequent drug taking. It is thus necessary to gain an understanding of the long-term effects of exposure to nicotine on nicotinic acetylcholine receptors (nAChRs), neuronal excitability and behavior. A review of the literature is presented in which different regimens of nicotine exposure are assessed for their effects on upregulation of nAChRs, induction of LTP in interconnected midbrain nuclei and development of long-lasting locomotor and DA sensitization. Exposure to nicotine upregulates nAChRs and nAChR currents and produces LTP of excitatory inputs to midbrain DA neurons. These effects appear in the hours to days following exposure. Exposure to nicotine also leads to long-lasting sensitization of nicotine's nucleus accumbens DA and locomotor activating effects. These effects appear days to weeks after drug exposure. A model is proposed in which nicotine exposure regimens that produce transient nAChR upregulation and LTP consequently produce long-lasting sensitization of midbrain DA neuron reactivity and nicotine-induced behaviors. These neuroadaptations are proposed to constitute critical components of the mechanisms underlying the initiation, maintenance and escalation of drug use.     

Neonatal exposure to lipopolysaccharide enhances methamphetamine-induced reinstated behavioral sensitization in adult rats

Our previous studies have shown that neonatal exposure to lipopolysaccharide (LPS) resulted in long-lasting dopaminergic injury and enhanced methamphetamine (METH)-induced increase of locomotion in the adult male rat. To further investigate the effect of neonatal LPS exposure-induced dopaminergic injury, we used our neonatal rat model of LPS exposure (1 mg/kg, intracerebral injection in postnatal day 5, P5, rats) to examine the METH sensitization as an indicator of drug addiction in the adult rats. On P70, animals began a treatment schedule of 5 daily subcutaneous (s.c.) administration of METH (0.5 mg/kg) or saline (P70-P74) to induce behavioral sensitization. Ninety-six hours after the 5th treatment with METH or saline (P78), animals received a single dose of 0.5 mg/kg METH (s.c.) or saline. Neonatal LPS exposure enhanced the level of development of behavioral sensitization including distance traveled, rearing events and stereotypy to METH administration in both male and female rats. Neonatal LPS exposure also enhanced the reinstated behavioral sensitization in both male and female rats after the administration had ceased for 96 h. However, neonatal LPS exposure induced alteration in the reinstated behaviors sensitization of distance traveled and rearing events to METH administration appears to be greater in male than in female rats. These results indicate that neonatal brain LPS exposure produces a persistent lesion in the dopaminergic system, as indicated by enhanced METH-induced locomotor and stereotyped behavioral sensitization in later life. These findings show that early-life brain inflammation may enhance susceptibility to the development of drug addiction in later life.     

Effect of melatonin on cocaine-induced behavioral sensitization

Melatonin, a pineal hormone and a potent free radical scavenger with neuroprotective actions, has been reported to act as an inhibitor of nitric oxide synthase (NOS). We have earlier shown that inhibitors of NOS (N(omega)-nitro-L-arginine methyl ester [L-NAME], 7-nitroindazole [7-NI]) block cocaine-induced behavioral sensitization. In the present study, the effects of melatonin on cocaine behavior were studied. A single injection of melatonin markedly augmented cocaine-induced locomotor activity. Rats injected daily with melatonin prior to cocaine injections failed to elicit cocaine sensitization. These behavioral effects of melatonin do not completely mimic those of other NOS inhibitors, suggesting that the effects of melatonin on cocaine behavior are mediated by both NOS-dependent as well as NOS-independent mechanisms.