利血平和对氯苯异丙胺诱发小鼠单胺耗竭模型的建立和比较研究

目的建立利血平和对氯苯异丙胺(PCA)诱发小鼠单胺递质耗竭模型,并从自发活动、体温、单胺递质及代谢产物含量等方面探讨两种单胺耗竭模型的异同。方法①利血平诱发小鼠单胺耗竭模型研究:小鼠腹腔注射利血平5 mg·kg-1,18 h后测定自发活动和肛温,断头取脑,高效液相色谱法检测下丘脑组织匀浆5-HT,NE,DA及5-HIAA含量;②PCA诱发小鼠单胺耗竭模型研究:小鼠腹腔注射PCA20 mg·kg-1,6 h后测定自发活动和肛温,断头取脑,高效液相色谱法检测下丘脑组织匀浆5-HT,NE,DA及5-HIAA含量。结果①利血平诱发小鼠单胺耗竭模型研究:与正常对照组相比,利血平组(5 mg·kg-1,ip)小鼠自发活动和肛温显著降低,下丘脑组织匀浆5-HT,NE,DA含量显著降低(分别降低约80%),5-HIAA含量显著升高;②PCA诱发小鼠单胺耗竭模型研究:与正常对照组相比,PCA组(20 mg·kg-1,ip)小鼠自发活动显著增加,肛温显著降低,下丘脑组织匀浆5-HT,NE含量显著降低(分别降低约50%),但PCA对小鼠下丘脑DA及5-HIAA含量无显著影响。结论①利血平和对氯苯异丙胺诱发小鼠单胺耗竭模型建立成功,可用于单胺重摄取抑制剂类抗抑郁剂的靶标和机制研究;②两种模型的相同点:利血平和PCA均可诱发小鼠肛温降低,可并可耗竭5-HT,NE含量;③两种模型的不同点:利血平可同时引起5-HT,NE和DA三种单胺递质耗竭,而PCA仅引起5-HT和NE的含量,且耗竭程度比利血平弱;利血平可引发5-HT代谢产物5-HIAA含量生高,而PCA对5-HIAA含量无影响;利血平对中枢产生抑制作用,而PCA对中枢产生兴奋作用;上述研究表明利血平和PCA引发单胺递质耗竭的作用机制不同。     

利血平和帕吉林对大鼠脑单胺递质含量的联合作用

大鼠ip利血平2mg/kg后1-24h,NE,DA,5-HT均显著下降(p<0.05-p<0.001),5-HIAA则显著升高(p<0.001)。ip帕吉林60mg/kg后1-24h,NE,DA,5-HT均显著升高(p<0.01-p<0.001),5-HIAA则在1-2h内显著下降(p<0.01),4-24h无明显变化。同时使用两药时,对鼠脑NE和DA的影响均呈拮抗作用,对5-HT仅表现帕吉林的作用。帕吉林对利血平化鼠的NE,DA无影响,但可使5-HT升至正常水平;利血平对帕吉林化鼠递质的变化无影响。两药合用对递质的影响表现为拮抗或单一作用,未见递质翻转现象。     

马来酸三甲氧苯丁氨酯的镇痛作用与单胺类递质的关系

探讨马来酸三甲氧苯丁氨酯 (TM )镇痛作用与单胺类递质的关系 .小鼠扭体法及热板法实验的结果表明 ,利血平和赛庚啶能够减弱TM的镇痛作用 ,L 色氨酸则增强其镇痛作用 .酚妥拉明、普萘洛尔、二乙基二硫代氨基甲酸钠、阿朴吗啡和氟哌啶醇对其镇痛作用无明显影响 .应用荧光法测定小鼠脑内单胺类递质含量 ,结果表明腹腔注射TM 70mg/kg可提高小鼠脑内 5 HT含量 ,对NE和DA含量无明显影响 .说明TM的镇痛作用与中枢 5 HT系统有关     

红毛五加总甙的中枢镇静作用及对吗啡依赖性的影响

目的:研究甘肃红毛五加总甙 (TGA)的中枢镇静作用和机理及对吗啡依赖性的影响。方法··:采用光导管法测小鼠自由活动 ,合用镇静催眠药、中枢兴奋药观察协同和拮抗作用 ,用荧光法测小鼠脑内NE、DA含量 ;用吗啡戒断反应观察对吗啡依赖性的影响。结果··:TGA(100-400mg·kg-1 ,ig)使小鼠自由活动次数减少 ,能协同戊巴比妥钠的镇静催眠作用 ,对抗苯丙胺的兴奋作用 ,使尼可刹米诱发的小鼠惊厥潜伏期延长 ;对印防己毒素诱发的小鼠惊厥无对抗作用 ,使小鼠脑内NE、DA含量明显减少 ;使吗啡依赖动物的戒断反应明显减轻。结论··:TGA具有中枢镇静作用 ,其机制可能与中枢GABA无关 ,而是通过使脑内单胺类递质减少而发挥作用的 ;同时TGA能抑制吗啡依赖动物的戒断反应。     

醒神开郁方抗抑郁作用的实验研究

目的：研究醒神开郁方的抗抑郁作用及其可能的作用机制。方法：采用小鼠悬尾、强迫游泳实验观察小鼠悬尾、游泳不动时间;自主活动实验测定小鼠自主活动次数;利血平诱导小鼠体温下降实验考察小鼠肛温、眼睑下垂度以及脑内单胺类神经递质含量等指标。采用SPSS 13.0软件对上述观察指标进行统计分析。结果：醒神开郁方对小鼠自主活动行为无显著影响;在小鼠悬尾和强迫游泳实验中,醒神开郁方低、中、高剂量组可明显缩短小鼠悬尾和强迫游泳不动时间（P〈0.05,P〈0.01,P〈0.01）。利血平诱导小鼠体温下降实验中,与模型组比较,醒神开郁方中、高剂量组可显著拮抗利血平所致小鼠的体温下降和眼睑下垂（P〈0.05,P〈0.01）;与模型组比较,醒神开郁方中、高剂量组均能显著增加小鼠脑组织内NE、5-HT含量（P〈0.01）以及DA含量（P〈0.05,P〈0.01）。结论：醒神开郁方具有显著的抗抑郁作用,其作用机制与增强脑组织内NE、5-HT、DA调节神经系统作用有关,且醒神开郁方无中枢兴奋作用。     

柴胡对肝郁证中枢神经递质作用的实验研究

目的探索柴胡对肝郁证大鼠中枢神经递质的作用。方法利用中医证候模型,研究柴胡对单胺类神经递质的作用。结果肝郁证模型组大鼠脑内NE与DA水平与对照组比较下降明显(P<0.05);肝郁证模型加逍遥散组大鼠脑内NE与DA水平与对照组比较无显著性差异(P>0.05);肝郁证模型加柴胡组大鼠脑内NE与DA水平与对照组比较也无显著性差异(P>0.05)。结论肝郁证大鼠脑内NE与DA水平明显降低,柴胡舒肝解郁,有增加肝郁证大鼠脑内NE、DA神经递质的作用。     

左旋多巴(L-Dopa)对实验性癲痫影响的研究

L-Dopa对大鼠听源性发作和小鼠电休克惊厥均有明显对抗作用,但对后者的对抗作用较弱。L-Dopa的这种作用,主要与其增加脑内DA水平有关,因其作用与升高脑内DA水平相平行,脑室内直接注射DA或以去水吗啡激动DA-受体均有抗惊厥作用,而以氟哌啶阻断DA-受体,则减弱或对抗L-Dopa的作用。 L-Dopa也升高脑内NE含量,对上述两种惊厥也有一定影响,但不如DA重要,至少对于大鼠听源性发作是如此。因为以双硫醒阻断NE合成,减少其脑内含量,但不能对抗大鼠听源性发作,双硫醒与L-Dopa合用,有协同作用,同样,脑室注射NE或用双羟苯丝氨酸增加大鼠脑内NE含量,对大鼠听源性发作影响不大,但α-阻断剂能减弱L-Dopa的作用。 L-Dopa可作为一种治疗癫痫的辅助药物,用于DA明显减少的病例可能有益。     

左旋多巴(L-Dopa)对实验性癲痫影响的研究

L-Dopa对大鼠听源性发作和小鼠电休克惊厥均有明显对抗作用,但对后者的对抗作用较弱。L-Dopa的这种作用,主要与其增加脑内DA水平有关,因其作用与升高脑内DA水平相平行,脑室内直接注射DA或以去水吗啡激动DA-受体均有抗惊厥作用,而以氟哌啶阻断DA-受体,则减弱或对抗L-Dopa的作用。L-Dopa也升高脑内NE含量,对上述两种惊厥也有一定影响,但不如DA重要,至少对于大鼠听源性发作是如此。因为以双硫醒阻断NE合成,减少其脑内含量,但不能对抗大鼠听源性发作,双硫醒与L-Dopa合用,有协同作用,同样,脑室注射NE或用双羟苯丝氨酸增加大鼠脑内NE含量,对大鼠听源性发作影响不大,但α-阻断剂能减弱L-Dopa的作用。L-Dopa可作为一种治疗癫痫的辅助药物,用于DA明显减少的病例可能有益。     

茶色素对吗啡成瘾小鼠脑内去甲肾上腺素、多巴胺、5-羟色胺和β-内啡肽的影响

目的:探索茶色素对吗啡依赖小鼠脑内去甲肾上腺素(NE)、多巴胺(DA)、5-羟色胺(5-HT)和β-内啡肽(β-EP)的影响。方法:建立吗啡依赖模型,采用催促戒断治疗实验测定小鼠跳跃反应次数。运用高效液相法测定下丘脑,脑干和大脑皮质内NE、DA、5-HT含量,采用放射免疫法测定大脑皮质内β-EP含量。结果:茶色素12.5,25,50,100 mg.kg-1组均显著降低吗啡依赖小鼠的跳跃次数。降低吗啡依赖小鼠下丘脑中NE和DA的含量。降低吗啡依赖小鼠大脑皮质内β-EP含量。但对下丘脑,脑干和大脑皮质内的5-HT含量没有明显影响。结论:茶色素能降低吗啡依赖小鼠的跳跃次数,其机制可能与茶色素降低吗啡依赖小鼠下丘脑中NE和DA及大脑皮质β-EP含量相关。     

“心悦“对抑郁模型小鼠中枢神经递质的影响

目的研究"心悦"对抑郁小鼠中枢神经递质的影响.方法选择经典抗抑郁剂评价模型-强迫游泳观察"心悦"对抑郁小鼠治疗作用.同时利用高效液相色谱法测定小鼠大脑NE、DA、5-HT、5-HIAA含量的变化.结果"心悦"可提高NE、5-HT、5-HIAA含量,且5-HT/5-HIAA比值下降.对DA未见显著影响.结论"心悦"对小鼠大脑中5-HT神经元有激活作用,从而起抗抑郁作用.由于本实验未对DA、NE的代谢产物的含量进行测定,因此有关"心悦"对NE、DA系统的影响尚需进一步探讨.     

Facilitation of retention performance in mice by posttraining diethyldithiocarbamate.

These experiments examined the effects in mice of posttraining injections of diethyldithiocarbamate (DDC) upon retention (7 days after training) of active avoidance learning and upon whole brain catecholamine levels. When administered immediately following training, DDC enhanced retention performance. The degree of enhancement varied directly with dose. DDC did not significantly affect retention performance if the injections were delayed 1 or 4 hours after training. Also, DDC administered 30 min prior to training did not affect retention performance. DDC (900 mg/kg) produced a large but transient increase in whole brain dopamine (DA) levels while norepinephrine (NE) levels were lowered.     

Vesicular accumulation of dopamine following L-DOPA administration

In this study, the accumulations of dopamine (DA) and norepinephrine (NE) were measured in the brain tissues and in the synaptic vesicle fractions prepared from whole brain of control rats and rats injected with L-DOPA. In the normal rat brain, a 3-fold increase in DA following L-DOPA administration was followed by a small, but not significant increase in vesicular DA, indicating a restricted vesicular uptake of exogenous DA. At the same time, NE in the vesicular fraction and in the whole brain tissue did not change, suggesting a possible link between DA vesicular uptake of DA and brain NE. However, in rats pretreated with alpha-methyl-p-tyrosine, which significantly (P less than 0.05) reduced DA and NE levels in brain tissues and in the synaptic vesicles, L-DOPA administration led to a significant increase in vesicular DA (P less than 0.05), suggesting that catecholamine depletion may result in greater vesicular uptake of cytoplasmic DA. The increase in vesicular DA was accompanied by increases in tissue and vesicular NE, underscoring again the existence of a link between vesicular uptake of DA and brain NE following L-DOPA administration. The results also demonstrated a large increase in 3,4-dihydroxyphenylacetic acid (DOPAC) following L-DOPA, in the brain tissues but not in the synaptic vesicle, indicating that monoamine oxidase activity is confined to the cytoplasm.     

Alteration of catecholamines in pheochromocytoma (PC12) cells in vitro by the metabolites of chlorotriazine herbicide.

The effects of four major chlorotriazine metabolites on the constitutive synthesis of the catecholamines dopamine (DA) and norepinephrine (NE) were examined, using undifferentiated PC12 cells. NE release and intracellular DA and NE concentrations were quantified, for up to 24 h after initiation of treatment with different concentrations, ranging from 0 to 400 microM, of the metabolites hydroxyatrazine (HA), 2-amino-4-chloro-6-isopropylamino-s-triazine (deethylchlorotriazine), 2-amino-4-chloro-6-ethylamino-s-triazine (deisopropylchlorotriazine), and diaminochlorotriazine (DACT). Hydroxyatrazine significantly decreased intracellular DA and NE concentrations in a dose- and time-dependent manner. This metabolite also caused a significant inhibition of NE release from the cells. In contrast, deethylchlorotriazine and deisopropylchlorotriazine significantly increased intracellular DA concentration following exposure to 50-200 microM from 12 to 24 h. Intracellular NE was significantly reduced at these same concentrations of deethylchlorotriazine at 24 h while the concentration of NE in PC12 cells exposed to deisopropylchlorotriazine was not altered at any dosage or time point measured. NE release was decreased at 18 (200 microM) and 24 h (100 and 200 microM) following exposure to deethylchlorotriazine and at 24 h (100 and 200 microM) following deisopropylchlorotriazine. DACT, at the highest concentration (160 microM), significantly increased intracellular DA and NE concentrations at 18 and 24 h. NE release was also increased at 40-160 microM at 24 h. The viability of the PC12 cells was tested using the trypan blue exclusion method. Following 18 to 24 h of treatments with HA, cell viability was reduced 10-12% at the two higher concentrations (200 and 400 microM), but, with other metabolites, the viability was reduced by only 2 to 5% at the highest concentrations. These data indicate that HA affects catecholamine synthesis and release in PC12 cells in a manner that is similar to synthesis of atrazine and simazine. On the other hand, deethylchlorotriazine and deisopropylchlorotriazine altered catecholamine synthesis in a manner similar to that observed in the rat brain following in vivo exposure (i.e., increased DA and decreased NE concentration), whereas DACT appeared to produce an increase in NE release as well as in the intracellular DA and NE concentrations. Overall, these findings suggest that the catecholamine neurons may be a target for the chlorotriazines and/or their metabolites, that the metabolites produce a unique pattern of catecholamine response, and that all of the changes were seen within the same range of doses.     

Monosodium L-glutamate-induced convulsions--II. Changes in catecholamine concentrations in various brain areas of adult rats

Norepinephrine (NE) and dopamine (DA) levels in various brain regions were measured in a model of experimentally produced convulsions by monosodium L-glutamate (MSG) administration to adult rats. Stress by injection of all solutions produced a 60% decrease in NE level in forebrain, recovering its basal value at 15 min after injection. A significant reduction of brain NE and DA levels of MSG-injected animals was found in the preconvulsive stage, particularly in the forebrain. No significant variations in catecholamine levels were seen in brain stem and cerebellum as a result of MSG injection. It is suggested that the changes found in endogenous catecholamine concentration in the forebrain may play a physiological role in the mechanisms of production of convulsions in the MSG model.     

Neurobiochemical alterations induced by the artificial sweetener aspartame (NutraSweet)

The dipeptide aspartame (NutraSweet) is a newly approved and widely used artificial sweetener in foods and beverages. Consumption of aspartame (ASM) has been reported to be responsible for neurologic and behavioral disturbances in sensitive individuals. Unfasted male CD-1 mice were dosed orally with 13, 130, or 650 mg/kg ASM in corn oil, while control animals received corn oil alone. Three hours after dosing, the animals were killed, and the concentrations of the catecholamines norepinephrine (NE) and dopamine (DA), catecholamine metabolites 3-methoxy-4-hydroxymandelic acid (VMA), homovanillic acid (HVA), and dihydroxyphenylacetic acid (DOPAC), the indoleamine serotonin (5-HT), and its metabolite 5-hydroxyindoleacetic acid (5-HIAA) were determined by electrochemical high-performance liquid chromatography in six brain regions. ASM exerted its primary effect on adrenergic neurotransmitters in various brain regions. In the hypothalamus, the region richest in NE, increases in NE concentrations of 12, 49, and 47% were found in the low, medium, and high dose groups, respectively, relative to control. Significant increases of NE in the medulla oblongata and corpus striatum were also observed. Increases of the catecholamine DA and catecholamine metabolites VMA, HVA, and DOPAC were seen in various regions. The indoleamine serotonin and its metabolite 5-HIAA were unaffected by ASM treatment. These findings are consistent with ASM-induced increases in the brain catecholamine precursor amino acids phenylalanine and tyrosine, as reported earlier. Such observed alterations in brain neurotransmitter concentrations may be responsible for the reported clinical and behavioral effects associated with ASM ingestion.     

Ginkgo biloba normalises stress-elevated alterations in brain catecholamines, serotonin and plasma corticosterone levels.

Stress and depression and associated mental health problems have increased tremendously in modern times. The search for effective and safe alternatives from natural sources especially plant products should, therefore, continue. Forced immobilization is one of the best explored models of stress in rats and the role of corticosterone, serotonin and catecholamines, i.e. norepinephrine (NE), dopamine (DA) is well documented. Numerous studies have shown that Ginkgo biloba has antioxidant and neuroprotective properties and utility in cerebrovascular insufficiency and impaired cerebral performance. We investigated the effect of G. biloba on whole brain catecholamine, serotonin and plasma corticosterone levels following 1, 2 and 4 h restraint stress using HPLC and also plasma corticosterone using luminescence spectrophotometry. G. biloba extract (14 mg/kg p.o.) restored restraint stress-induced elevation in whole brain levels of catecholamines (NE, DA), 5-HT and plasma corticosterone to near normal levels. Further studies are warranted to explore the clinical potential of this encouraging lead in the management of stress and to elucidate the mechanisms involved.     

Effects of dietary vanadium exposure on levels of regional brain neurotransmitters and their metabolites

Adult male CD-1 mice were treated with various levels of vanadate in drinking water for 30 days. The levels of catecholamine and indoleamine neurotransmitters and their major metabolites were measured in six different brain regions. Vanadium caused a dose-related decrease in norepinephrine (NE) levels in hypothalamus, the region rich in this biogenic amine. Levels of the NE metabolite, vanillylmandelic acid (VMA), correspondingly decreased in the same region. Although hypothalamic dopamine (DA) also showed a significant decline, vanadium had little effect on DA metabolites. Levels of 5-hydroxytryptamine (5-HT) and its metabolite, 5-hydroxyindoleacetic acid (5-HIAA), were not influenced. Levels of DA were not affected in the corpus striatum, where the highest levels of this amine are observed. Effects of vanadium on various biogenic amines and their metabolites were only marginal in other brain regions. Results suggest that vanadium has a selective effect on adrenergic pathways, and effects on other hypothalamic amines appear to be secondary. These observations support the pro-oxidant potential of vanadate ion on catecholamines suggested earlier.     

Influence of formamidines on biogenic amine levels in rat brain and plasma

Biogenic amine levels in samples of whole brain and plasma following treatment of rats with chlordimeform (CDF), its two N-demethyl metabolites (DMC and DDC), p-chloroamphetamine (PCA), and harmaline were separated by high performance liquid chromatography equipped with fluorescence or electrochemical detection systems. At 1 hr following s.c. injection, CDF (200 mg/kg) caused a reduction in levels of norepinephrine (NE), 5-hydroxytryptamine (5-HT), and tyramine (TRM), an increase in dopamine (DA), and no change in levels of beta-phenethylamine (PEA) in samples of whole rat brain, whereas DMC (100 mg/kg) and DDC (25 mg/kg) effected reductions of brain levels of NE, 5-HT, TRM, and PEA with no change in DA. The effect of DMC (100 mg/kg) on NE and DA levels in brain was followed periodically for 24 hr. Following a significant decrease at 1 hr, NE levels increased to a maximum at 12 hr and remained higher than controls throughout the remainder of the 24 hr test period. DA levels increased during the initial 12 hr and remained significantly higher than controls for the remaining 12 hr. The influence of s.c. vs i.p. administration of DMC (100 mg/kg) on brain amine levels was examined. Intraperitoneal treatment generally resulted in lower amine levels in DMC and vehicle treated animals. Differences in treatment effects were similar for all amines except for 5-HT in which s.c. injection produced a slight reduction, while i.p. injection resulted in a two-fold increase.(ABSTRACT TRUNCATED AT 250 WORDS)     

The effects of chronic administration and withdrawal of (+)-amphetamine on seizure threshold and endogenous catecholamine concentrations and their rates of biosynthesis in mice

The i.v. pentylenetetrazol seizure threshold was increased by 2.5 mg/kg and decreased by 15 mg/kg of a single (+)-amphetamine dose. After 7 consecutive days of amphetamine administration, tolerance developed to the decrease but not to the increase in seizure threshold. At 12–48 h after the last dose of 2.5 mg/kg seizure threshold was decreased, and at 36–48 h after the last dose of 15 mg/kg seizure threshold was increased. After acute and chronic administration of (+)-amphetamine (2.5 mg/kg) endogenous concentrations of whole brain dopamine (DA) were increased and returned to normal levels during the withdrawal period (12–48 h); endogenous norepinephrine (NE) levels were unchanged by acute and chronic drug treatment and during withdrawal. The rates of DA and NE synthesis were increased by chronic amphetamine administration at 24–48 h after drug withdrawal. An acute dose of (+)-amphetamine (15 mg/kg) decreased endogenous levels of DA and NE; normal levels of DA were detected with chronic drug treatment and during withdrawal, with NE remaining slightly depressed. The rates of synthesis of DA and NE were increased by acute and chronic amphetamine treatment and returned to normal 24–48 h after withdrawal. The rebound reversal in seizure threshold after (+)-amphetamine withdrawal suggests an abstinence syndrome that may be interpreted as evidence for the development of physical dependence to (+)-amphetamine after chronic drug administration.     

The role of biogenic amines in the reserpine-induced alteration of minimal electroshock seizure thresholds in the mouse

A single injection of reserpine (1 $\text{mg}\text{kg}$ i.p.) produced an increased susceptibility to minimal electroshock seizures, as well as a decrease in whole brain levels of norepinephrine (NE), dopamine (DA), and serotonin (5-HT). The return to normal seizure susceptibility correlated well with the return of the ability of whole brain tissue to synthesize and retain ³H-amine formed from either ³H-3,5-l-tyrosine or ³H-5-hydroxy-dl-tryptophan. Selective inhibition of catecholamine synthesis with α-methyl-p-tyrosine, following reserpine administration, prevented the return to normal both of seizure susceptibility and NE and DA levels. The combination of disulfiram and reserpine also prevented the return to normal seizure susceptibility. After the latter treatment, levels of DA were elevated while NE remained depressed. Selective inhibition of 5-HT synthesis following reserpine similarly prevented the return of normal seizure susceptibility. Our study suggests that NE and 5-HT, but not DA, are important in regulating minimal electroshock seizure susceptibility.