精神分裂症治疗前后单胺类神经递质分析及疗效评定

目的观察精神分裂症患者治疗前后血浆中单胺类神经递质含量变化及与疗效的相关性。方法采用放免法测定85例精神分裂症患者治疗前后血浆多巴胺(DA)、5-羟色胺(5-HT)、去甲肾上腺素(NE)和生长激素(GH)含量及简明精神病量表(BPRS)的减分率来评定疗效。结果治疗前后5-HT含量分别为(84.93±68.13)和(94.33±68.84)mmol/L,DA(34.14±10.24)和(32.89±9.63)mmol/L,NE(67.94±82.84)和(56.63±29.83)mmol/L,GH(3.69±10.02)和(2.28±4.20)mmol/L,前后对照均无统计学差异(P>0.05)。5-HT、DA、NE和GH含量变化与疗效无明显相关(P>0.05)。结论精神分裂症患者治疗前后血浆中单胺类神经递质未发现明显差异,与疗效是否相关需进一步细化精神症状。     

精神分裂症患者脑内神经递质活动与临床症状的关联分析

目的用脑电超慢涨落分析仪(ET)探讨精神分裂症脑内神经递质变化及其与临床症状的关联性。方法用脑电超慢涨落分析仪提取在脑电中载有脑神经递质调节系统的震荡信息(即S谱线),分析精神分裂症患者和健康对照脑神经递质的活动情况,同时用阳性与阴性症状量表(PANSS)评估患者临床症状。结果与健康对照组相比,精神分裂症患者脑内γ-氨基丁酸(GABA)活动明显减弱(5.7±0.9和8.2±0.6,P<0.01),与兴奋因子呈负相关(r=-0.252,P<0.05);5-羟色胺(5-HT)(21.7±2.2和19.9±1.3,P<0.01)和多巴胺(DA)(10.8±1.2和6.8±1.2,P<0.01)活动明显增强,5-HT活动与阴性因子(r=0.291,P<0.05)、认知因子(r=0.348,P<0.01)呈正相关,DA活动与阳性因子呈正相关(r=0.293,P<0.05)。结论精神分裂症患者脑内GABA、5-HT和DA活动异常,通过复杂的机制导致了其各个特征性症状群。     

双乙酰化左旋千金藤啶碱（l-SPD-A）抗精神分裂症作用的研究

背景与目的：以往的研究发现，双乙酰化左旋千金藤啶碱（l-SPD-A）对脑内多巴胺受体具有D1激动-D2阻滞的双重药理作用，此外对5-HT1A受体也有部分激动作用，提示l-SPD-A可能具有潜在的抗精神分裂症（schizophrenia）作用。方法：我们应用苯环己哌啶（phencyclidine，PCP）诱导的精神分裂症大鼠动物模型，在行为学水平研究l-SPD-A的抗精神分裂症作用。结果：研究表明，     

多次应用氟西汀对苯环己哌啶诱导的青年大鼠自主运动增多行为的长期影响

目的：考察用苯环己哌啶（phencyclidine,PCP）建立的精神分裂症青年大鼠模型,在连续5天接受氟西汀（fluoxetine,FLX）后,对大鼠成年后再次暴露于FLX时对该药的长期反应的变化。方法：通过检测与精神分裂症相关的自主运动行为和考察感觉门控（sensory gating,SG）功能的前脉冲抑制（prepulse inhibition,PPI）,来评价大鼠青年时期使用FLX是否会对其成年后的行为产生影响,以及FLX是否具有抗精神分裂症药物的活性作用。青年雄性SD大鼠（postnatal day,第40天）随机分为空白对照组（vehicle+vehicle）、PCP造模组（VEH+PCP）、FLX 5.0 mg·kg-1给药组（FLX5+PCP）和FLX 10.0 mg·kg-1给药组（FLX10+PCP）。从第42天起连续5天每天先接受分组药物处理,后在自主运动（locomotor activity,LA）行为检测仪器中观察30 min,再分别接受PCP或VEH的处理,继续进行60 min的LA测试。在大鼠第47、66、77、94天时,所有大鼠进行PPI测试。成年时期（第76、91天）,对所有大鼠再次给予FLX并检测90 min（30 min+60 min）的LA行为。结果：（1）4组大鼠连续5天在给予VEH或FLX后的30 min的平均LA次数统计显示：空白对照组大鼠的平均LA次数显著高于其他3个组（Ps<0.05）。而给予VEH或PCP后的60 min的平均LA次数统计分析显示：空白对照组大鼠LA次数显著低于其他3个组（Ps<0.05）,空白对照组大鼠LA次数与FLX给药组2组比较无统计学差异（Ps>0.05）。（2）大鼠成年后再次接受FLX处理,青年时期接受过FLX处理的2组大鼠的LA次数与模型组无统计学差异：第76天 Ps>0.05;第91天 Ps>0.05。（3）在大鼠青年、成年时即第47、66、77、94天时的PPI测试结果各组间均无统计学差异（Ps>0.05）。结论：青年大鼠经FLX（5.0 mg·kg-1或10.0 mg·kg-1）5天给药,未见抑制或增强PCP诱导的LA增多作用,大鼠成年后再次接触FLX时的LA行为未见统计学意义的改变及中枢的SG通道功能。即FLX在由PCP建立的大鼠LA行为增多模型中没有抗精神分裂症的药理作用。     

齐拉西酮对精神分裂症患者生活质量的影响

目的比较齐拉西酮与氟哌啶醇对精神分裂症患者生活质量的影响。方法对门诊74例服用氟哌啶醇及72例服用齐拉西酮的精神分裂症患者用生活质量综合评定问卷(GQOLI),阳性症状及阴性症状量表(PANSS),副反应量表(TESS)进行调查、分析。结果齐拉西酮组患者的生活质量优于氟哌啶醇组。结论齐拉西酮治疗精神分裂症更有利于患者提高生活质量和适应社会。     

齐拉西酮治疗女性精神分裂症的疗效观察

目的观察齐拉西酮治疗女性精神分裂症的临床效果。方法选取牡丹江神经精神病医院自2008年3月至2009年8月收治的142例女性精神分裂症患者随机分为观察组(齐拉西酮治疗组)和对照组(氟哌啶醇治疗组)各71例,比较两组患者的治疗效果。结果观察组显效40例,有效26例,总有效率为92.9%;对照组显效29例,有效27例,总有效率为78.9%。两组患者比较差异显著(P<0.01),具有统计学意义。观察组出现头痛2例,体重增加1例,肌肉强直1例,血压降低1例,不良反应发生率为7.0%;对照组出现静坐不能4例,震颤3例,头痛3例,嗜睡2例,体重增加2例,肌肉强直1例,闭经1例,泌乳1例,不良反应发生率为23.9%。两组患者比较差异显著(P<0.01),具有统计学意义。结论齐拉西酮治疗女性精神分裂症临床效果理想,且安全性较高,值得临床推广使用。     

蝎毒耐热蛋白对大鼠海马内前脑啡肽原表达的影响

癫痫是常见的神经系统变性疾病,其在临床上顽固难治的原因是癫痫敏感性的形成.国内外文献报道[1～4]阿片肽可能是癫痫敏感性形成的机制之一.脑啡肽(enkephalin,ENK)是脑内含量最高的阿片肽,广泛存在于所有的脑区.蝎毒是传统的抗癫痫药物,蝎毒耐热蛋白是通过特殊工艺从蝎毒中提取的抗癫痫组分,本工作旨在探讨蝎毒耐热蛋白对抗癫痫敏感性形成的作用及其可能的阿片肽机制.     

齐拉西酮注射液治疗精神分裂症急性期的对照研究

目的了解齐拉西酮注射液治疗精神分裂症急性期的疗效和不良反应。方法将80例患者随机分为研究组（40例）和对照组（40例）,研究组给予齐拉西酮注射液肌肉注射治疗,对照组给予氟哌啶醇注射液肌肉注射,两组疗程均为7 d。分别于治疗前、治疗第1、3、5、7 d进行阳性和阴性症状量表（PANSS量表）评定,以PANSS量表兴奋因子条目减分率为疗效判定标准,副反应采用不良反应量表（TESS量表）评定。结果研究组有效率为85.0%;对照组有效率为80.0%。研究组有效率与对照组相比无统计学差异（2χ=0.35,P〉0.05）,研究组不良反应在锥体外系、心电图异常等方面发生率比氟哌啶醇低。结论精神分裂症急性期使用齐拉西酮注射液治疗,疗效和氟哌啶醇注射液相似,不良反应更少。     

健脑通络胶囊对血管性痴呆大鼠大脑神经递质的影响

目的：观察健脑通络方（ＪＮＴＬ）对血管性痴呆大鼠大脑神经递质的影响,探讨其治疗血管性痴呆的作用机理。方法：以颈内动脉暂时夹闭加颈外动脉注射栓子方法造成多发性脑梗塞,加注山莨菪碱,以记忆力检测模型,测量各组大鼠脑内去甲肾上腺素、乙酰胆碱、多巴胺、５－羟色胺的含量。结果：给药组大脑皮层的各种递质含量明显增加。结论：ＴＮＴＬ具有提高血管性痴呆动物大脑皮层的神经递质含量,具有一定的健脑益智的实验室基础。     

Cocaine: acute effects on reinforcement thresholds for self-stimulation behavior to the medial forebrain bundle.

Reinforcing thresholds for self-stimulation behavior to the medial forebrain bundle were determined in rats by means of rate-free psychophysical method. The acute administration of cocaine lowered the reinforcing thresholds independent of motor stimulatory effects. These results indicate that cocaine affects the sensitivity of the reward pathways in the brain, and further demonstrate the utility of rate-independent methods in the assessment of drug effects on self-stimulation behavior.     

Evaluation of the non-specific effects of catecholamine and serotonin neurotoxins by injection into the medial forebrain bundle of the rat.

Low doses of 6-hydroxydopamine (6-OHDA), 5,6-dihydroxytryptamine (5,6-DHT) and 5,7-dihydroxytryptamine (5,7-DHT) that have previously been shown to produce behavioral change following intracerebral infusion were injected into the medial forebrain bundle of the rat. This site contains serotonin (5-HT), norepinephrine (NE), and dopamine (DA) fibers whose anatomical locations have been described. Damage to these fiber systems was quantified by measuring depletion of telencephalic 5-HT, NE and DA. The effects of infusions of 6-OHDA, 5,6-DHT and 5,7-DHT were compared to the effects of unequivocally non-specific electrolytic lesions and copper sulfate infusions. Survival time was varied to evaluate the amount of regeneration that could be expected over periods from 8 to 60 days. Amine levels were found to be stable over the time period examined. With the doses used, evidence was found to support the position that non-specific damage caused by general cytotoxic effects of 6-OHDA and 5,7-DHT is minimized sufficiently to permit the acquisition of useful data on the function of central catecholamine and indoleamine systems.     

Circling behaviour induced by electrical stimulation of the medial forebrain bundle, importance of stimulus parameters and dopaminergic processes

Unilateral electrical stimulation of the substantia nigra or the ventral tegmental area produced postural asymmetry and increased locomotor activity respectively. Concurrent stimulation of the efferent pathways of these two areas (medial forebrain bundle) resulted in contraversive circling behaviour that was dependent upon the current intensity and frequency of the stimuli. The application of biphasic electrical pulses minimised the damage to the brain site stimulated; no decrease in circling intensity over time, nor spontaneous circling after administration of amphetamine or apomorphine without stimulation was observed. The contraversive circling behaviour was induced by activation of the ascending dopaminergic pathways as revealed by the close correlation between the site of stimulation and the localisation of this pathway, its antagonism by haloperidol and its abolishment by pretreatment with reserpine and alpha-methyl-p-tyrosine. Apomorphine likewise inhibited the electrical stimulation-induced circling behaviour. These results are discussed with regard to the influence of the stimulation parameters and the dopaminergic processes involved.     

Morphine dependence in rats with medial forebrain bundle lesions

Rats with posterior medial forebrain bundle (PMFB) lesions and control rats were administered morphine chronically for 4 or 5 days via implanted subcutaneous silicone reservoirs. Following cessation of morphine administration after five days, PMFB rats showed less withdrawal-induced weight loss than control rats. Other PMFB and control rats were subjected to forced drinking of morphine solution for 9 days. PMFB rats consumed the morphine solution much more readliy than control rats, whereas intake of a quinine solution was similar in two other PMFB and control groups. These results suggest that the addictive and dependence properties of morphine may have separate mechanisms and based on previously reported neurochemical effects of PMFB lesions, that biogenic amines may be differentially involved in such mechanisms.This research was supported by NIMH grants MH 70082 and DA 00535 to S. D. Glick. The authors thank Stuart Greenstein for indispensable technical assistance.     

Medial forebrain bundle stimulation evokes endocannabinoid-mediated modulation of ventral tegmental area dopamine neuron firing in vivo

Rationale Endocannabinoid-mediated forms of transient synaptic depression have been described in several brain structures, including the dopaminergic ventral tegmental area (VTA). However, their functional and/or behavioural correlates are yet to be determined. Objectives The present study was designed to investigate whether back-propagating action potentials in dopamine (DA) neurons, evoked by the stimulation of the medial forebrain bundle (MFB), could trigger endocannabinoid-mediated forms of synaptic modulation. The MFB contains axons ascending from DA neurons to the nucleus accumbens and other forebrain structures, and its stimulation is rewarding because it elicits intra-cranial self-stimulation. Materials and methods Single cell extracellular recordings were carried out from anti-dromically identified VTA DA neurons in chloral hydrate anesthetized rats. Results DA neurons responded to MFB stimulation (1 s, 20–80 Hz) with a frequency-dependent increase in spontaneous firing rate, which was enhanced by the cannabinoid type-1 receptor antagonist SR141716A (1 mg/kg) and depressed by the agonist WIN55212-2 (0.125 mg/kg). Increasing brain levels of the endocannabinoid anandamide by blocking its major hydrolysing enzyme, fatty-acid amide hydrolase, with URB597 (0.1 mg/kg) was ineffective, whereas blockade of the endocannabinoid membrane transporter with UCM707 (1 mg/kg) enhanced post-stimulus firing rate. Conclusions Our study indicates that stimulation of the MFB evokes an endocannabinoid-mediated short-term modulation of DA neuron activity. Thus, endocannabinoids might play an important role in the mechanisms underlying the rewarding properties of MFB stimulation.     

The effect of 6-aminodopamine on electrical self-stimulation in rats

The compound 6-aminodopamine is a powerful CNS catecholaminergic neurotoxin. Small dosages of 6-aminodopamine injected intraventricularly markedly depress electrical self-stimulation rates in rats. This 6-aminodopamine treatment produced whole brain lowering of norepinephrine to ca. 50% of normal while the dopamine content was unchanged The possible use of 6-aminodopamine treatment to elucidate the relative roles of norepinephrine and dopamine pathways is discussed.     

Effect of cholecystokinin on self-stimulation behavior in rats

Experiments were performed to examine the effects of intracerebroventricularly administered cholecystokinin octapeptide sulfate ester (CCK-8-SE) and unsulfated cholecystokinin octapeptide (CCK-8-NS) on electrical self-stimulation behavior elicited from the medial forebrain bundle. CCK-8-SE and CCK-8-NS in 80 pmol doses reduced the response rate of self-stimulation behavior 22-30 min following injection, while 400 pmol doses of these peptides attenuated self-stimulation behavior between 13 and 36 min. It is suggested that CCK-8-SE and CCK-8-NS interact with central rather than peripheral nervous mechanisms.     

Alterations of second messenger systems in the rat brain after 6-hydroxydopamine lesions of the medial forebrain bundle

We studied the sequential changes in second messenger systems in the striatum and substantia nigra (SN) after 6-hydroxydopamine lesions of the medial forebrain bundle in rats. The animals were unilaterally lesioned in the medial forebrain bundle and the brains were analyzed at 1, 2, 4 and 8 weeks postlesion. [³H]Phorbol-12,13-dibutyrate (PDBu), [³H]forskolin and [³H]rolipram were used to label protein kinase C (PKC), adenylyl cyclase and calcium/calmodulin-independent cyclic-AMP phosphodiesterase, respectively. The degeneration of nigrostriatal pathway produced a significant increase in [³H]PDBu binding in the ventromedial part of the ipsilateral striatum from 2 to 8 weeks postlesion. In the contralateral side, [³H]PDBu binding showed a transient increase in the SN only 4 weeks after lesioning. [³H]Forskolin binding showed a significant increase in the ipsilateral and contralateral striatum from 2 to 4 weeks postlesion. In the ipsilateral SN, a significant increase in [³H]forskolin binding was observed at 4 weeks after lesioning. However, no significant change in [³H]forskolin binding was observed in the contralateral SN during postlesion. On the other hand, [³H]rolipram binding showed no conspicuous alteration in the brain during postlesion. These results demonstrate that rats made hemiparkinsonism by unilateral 6-hydroxydopamine injection have a significant increase in [³H]PDBu and [³H]forskolin binding in the striatum and/or SN, whereas no significant change in [³H]rolipram binding is observed in these areas during postlesion. Our findings also suggest that the increase in [³H]forskolin binding is more pronounced than that in [³H]PDBu binding in the brain after unilateral 6-hydroxydopamine injection. Thus, our studies may provide valuable information concerning degeneration of the nigrostriatal pathway such as Parkinson’s disease.     

Hypothalamic adrenaline synthesis after stimulation of the medial forebrain bundle.

1 The problem of whether locally released noradrenaline can be methylated to adrenaline in the hypothalamus has been investigated. 2 During stimulation of the medial forebrain bundle (MFB) the hypothalamic adrenaline content increased somewhat, but the increase was not statistically significant (13%, mean of 10 experiments). 3 After inhibition of the activity of monoamine oxidase and catechol-O-methyltransferase this increase was much larger (80%, mean of 9 experiments). 4 Adrenalectomy did not prevent the rise in hypothalamic adrenaline after stimulation of the MFB. These results suggest that noradrenaline released during activity of noradrenergic hypothalamic structures may be methylated to adrenaline in the hypothalamus.     

Effect of lesions in the striatum. nucleus accumbens and medial raphe on phencyclidine-induced stereotyped behaviors and hyperactivity in rats

The effect of lesioning the striatum, nucleus accumbens and medial raphe on phencyclidine(PCP)-induced stereotyped behaviors and hyperactivity was investigated to determine the site or sites of actions of PCP in rats. Bilateral lesions of the striatum diminished or abolished all the parameters of PCP-induced stereotyped behaviors, including sniffing, backpedalling, turning and head weaving 7 days after the operation. The medial raphe lesion significantly reduced PCP-induced back pedalling and head weaving. Bilateral lesions of the ventral portion of the nucleus accumbens did not affect the PCP-induced stereotyped behaviors. On the contrary, none of the lesions altered the sensitivity to PCP-induced hyperactivity 7 days after the operation. These results that PCP-induced stereotyped behaviors may be mediated in the striatum and the medial raphe but not the nucleus accumbens. Furthermore, PCP-induced hyperactivity may not result from PCP effects on these discrete brain areas.