• 【多巴胺在抗抑郁药作用机理中的作用。】 复制标题 收藏 收藏
    DOI:10.1016/s0014-2999(00)00566-5 复制DOI
    作者列表:D'Aquila PS,Collu M,Gessa GL,Serra G
    BACKGROUND & AIMS: :The present paper reviews evidence on the effect of antidepressant treatments on dopamine transmission. Chronic treatment with antidepressant drugs potentiates the behavioural stimulant responses elicited by the stimulation of dopamine receptors, including reward-related behaviours. Moreover, antidepressants affect dopamine release in several brain areas. The reviewed literature is discussed in terms of the possible mechanisms underlying antidepressant-induced supersensitivity to dopamine-mediated behavioural responses, and of the possible implications for the therapeutic effect of these drugs. It is concluded that the potentiation of dopaminergic neurotransmission induced by chronic antidepressant treatments might contribute to their therapeutic effect.
    背景与目标: :本文综述了抗抑郁药对多巴胺传播的影响的证据。长期用抗抑郁药治疗可增强多巴胺受体的刺激引起的行为刺激反应,包括与奖励有关的行为。此外,抗抑郁药会影响多个大脑区域的多巴胺释放。就抗抑郁药引起的对多巴胺介导的行为反应的超敏性的潜在机制以及对这些药物的治疗作用的潜在影响进行了讨论。结论是,慢性抗抑郁药诱导的多巴胺能神经传递增强可能有助于其治疗效果。
  • 【萘达必利在体内对D2多巴胺受体的占有率。】 复制标题 收藏 收藏
    DOI:10.1016/S0893-133X(97)00024-9 复制DOI
    作者列表:Levant B,Vansell NR
    BACKGROUND & AIMS: :Nafadotride has been proposed as a selective antagonist for the D3 dopamine receptor. This drug has been shown to exhibit selectivity between D2 and D3 dopamine receptors in in vitro assay systems; however, the in vivo D2/D3 selectivity of the compound has not been determined. In this study, protection against inactivation by EEDQ was used as a measure of in vivo occupancy of D2 receptors by behaviorally relevant doses of nafadotride (0.1-10 mg/kg, s.c. and i.p.) in adult, male Sprague-Dawley rats. Ex vivo [3H]spiperone binding was then determined in striatal membranes, l-Nafadotride (10 mg/kg) protected 71% of D2 receptors after s.c. administration; 40% after i.p. administration. Protection of 13% of D2 receptors was observed at a dose of 3 mg/kg (s.c.). These data suggest that blockade of D2 receptors contributes to the pharmacological effects of nafadotride when administered at doses above 1 mg/kg (s.c.) or 3 mg/kg (i.p.).
    背景与目标: 已经提出:Nafadotride可以作为D3多巴胺受体的选择性拮抗剂。在体外测定系统中,该药物显示出D2和D3多巴胺受体之间的选择性。但是,该化合物的体内D2 / D3选择性尚未确定。在这项研究中,针对成年雄性Sprague-Dawley大鼠,行为相关剂量的萘法地利(0.1-10 mg / kg,s.c.和i.p.)使用EEDQ防止D2受体在体内的占用来衡量D2受体在体内的占有率。然后在纹状体膜中测定离体[3 H]哌咯酮结合,经皮下注射后,1-萘达特利(10 mg / kg)保护了71%的D2受体。行政;在i.p.之后40%行政。以3 mg / kg(s.c.)的剂量观察到13%的D2受体受到保护。这些数据表明,当以高于1 mg / kg(s.c.)或3 mg / kg(i.p.)的剂量给药时,D2受体的阻断有助于萘法地利的药理作用。
  • 【多巴胺以及去甲肾上腺素是去甲肾上腺素能神经末梢与脾细胞之间的联系。】 复制标题 收藏 收藏
    DOI:10.1016/s0006-8993(97)00313-2 复制DOI
    作者列表:Bencsics A,Sershen H,Baranyi M,Hashim A,Lajtha A,Vizi ES
    BACKGROUND & AIMS: The effect of supramaximal electric field stimulation on 3H released from rat spleen strips was studied after loading with either [3H]dopamine ([3H]DA) or [3H]norepinephrine ([3H]NE). In some experiments, [3H]DA and [3H]NE stored in the tissue or released in response to electrical stimulation were separated from their tritiated metabolites using HPLC followed by radiochemical detection. The stimulation-evoked release of 3H after loading with either derivative was subject to negative feedback modulation through alpha2-adrenergic, D2-dopamine and muscarinic acetylcholine receptors, and could be prevented by either calcium removal or tetrodotoxin blocking of Na+ influx, indicating its neuronal and vesicular origin. After the separation of radioactive metabolites by HPLC, both the tissue loaded with [3H]DA and the fractions collected during electrical stimulation contained a considerable amount of [3H]NE, providing evidence that the neurons it originated from were adrenergic in function. [3H]DA was also released during electrical stimulation. Since the spleen does not receive dopaminergic innervation, it was concluded that the noradrenergic axon terminals in the spleen were able to take up DA, convert it in part into NE, and release it as both DA and NE in response to neural activity. The ratio of [3H]DA and [3H]NE in the spleen loaded with [3H]DA was found to be dependent on both temperature and time of loading, and could be modulated by various drugs such as desmethylimipramine, a NE uptake blocker, and disulfiram or fusaric acid, dopamine beta-hydroxylase inhibitors. The phenomenon may reveal a new mechanism by which immunocytes in the spleen can be regulated by the neuroendocrine system.

    背景与目标: 在装载[3H]多巴胺([3H] DA)或[3H]去甲肾上腺素([3H] NE)后,研究了超最大电场刺激对大鼠脾脏条带释放的3H的影响。在某些实验中,使用HPLC随后进行放射化学检测,将stored 3] DA和[3 H] NE存储在组织中或响应电刺激释放而从tri化代谢产物中分离出来。装载任何一种衍生物后,刺激诱发的3H释放均通过α2-肾上腺素,D2-多巴胺和毒蕈碱型乙酰胆碱受体受到负反馈调节,并且可以通过除钙或河豚毒素对Na流入的阻滞来阻止,表明其神经元和水泡起源。通过HPLC分离放射性代谢物后,装载有[3H] DA的组织和在电刺激过程中收集的馏分均含有大量的[3H] NE,这提供了其起源的神经元在功能上具有肾上腺素能的证据。在电刺激过程中也释放了[3H] DA。由于脾脏不接受多巴胺能神经支配,因此得出的结论是,脾脏中的去甲肾上腺素能轴突末端能够吸收DA,将其部分转化为NE,并将其作为DA和NE释放,以响应神经活动。发现负载有[3H] DA的脾脏中[3H] DA和[3H] NE的比例取决于温度和加载时间,并且可以通过各种药物(例如去甲丙咪嗪,一种NE吸收阻断剂,和双硫仑或富马酸,多巴胺β-羟化酶抑制剂。这种现象可能揭示了一种新的机制,脾脏中的免疫细胞可以被神经内分泌系统调节。

  • 【胎儿内侧中脑:多巴胺神经元移植的首选来源。】 复制标题 收藏 收藏
    DOI:10.1097/00001756-199707070-00032 复制DOI
    作者列表:Costantini LC,Lin L,Isacson O
    BACKGROUND & AIMS: Currently, fetal tissue transplantation into patients with Parkinson's disease utilizes the entire ventral mesencephalon (VM) as donor tissue. However, the resulting mixture of cell types contains a relatively low proportion of therapeutically relevant dopamine (DA) neurons. We show that differential dissection of a medial region of embryonic day 14 rat VM yields a significantly higher proportion of DA neurons (8-10%) than is found in lateral VM (2%) or whole VM (4-5%). Medial VM also contained a larger number of the specific subpopulation of DA neurons (aldehyde dehydrogenase-positive; AHD) that project to dorsolateral motor region of the striatum. Selective dissection of fetal medial VM selectively enriches DA neurons in cell preparations useful for transplantation in Parkinson's disease.

    背景与目标: 当前,将胎儿组织移植到帕金森氏病患者中是利用整个腹侧中脑(VM)作为供体组织。但是,所得的细胞类型混合物包含相对较低比例的治疗相关多巴胺(DA)神经元。我们显示胚胎第14天大鼠VM内侧区域的差异解剖产生的DA神经元比例(8-10%)比外侧VM(2%)或整个VM(4-5%)高得多。内侧VM还包含大量投射到纹状体背外侧运动区的DA神经元的特定亚群(醛脱氢酶阳性; AHD)。胎儿内侧VM的选择性解剖在可用于帕金森氏病移植的细胞制剂中选择性富集DA神经元。

  • 【可卡因敏化过程中,Alpha-1肾上腺素受体调节谷氨酸和GABA神经传递到腹侧被膜多巴胺神经元上。】 复制标题 收藏 收藏
    DOI:10.3390/ijms21030790 复制DOI
    作者列表:Velasquez-Martinez MC,Santos-Vera B,Velez-Hernandez ME,Vazquez-Torres R,Jimenez-Rivera CA
    BACKGROUND & AIMS: :The ventral tegmental area (VTA) plays an important role in the reward and motivational processes that facilitate the development of drug addiction. Presynaptic α1-AR activation modulates glutamate and Gamma-aminobutyric acid (GABA) release. This work elucidates the role of VTA presynaptic α1-ARs and their modulation on glutamatergic and GABAergic neurotransmission during cocaine sensitization. Excitatory and inhibitory currents (EPSCs and IPSCs) measured by a whole cell voltage clamp show that α1-ARs activation increases EPSCs amplitude after 1 day of cocaine treatment but not after 5 days of cocaine injections. The absence of a pharmacological response to an α1-ARs agonist highlights the desensitization of the receptor after repeated cocaine administration. The desensitization of α1-ARs persists after a 7-day withdrawal period. In contrast, the modulation of α1-ARs on GABA neurotransmission, shown by decreases in IPSCs' amplitude, is not affected by acute or chronic cocaine injections. Taken together, these data suggest that α1-ARs may enhance DA neuronal excitability after repeated cocaine administration through the reduction of GABA inhibition onto VTA dopamine (DA) neurons even in the absence of α1-ARs' function on glutamate release and protein kinase C (PKC) activation. α1-AR modulatory changes in cocaine sensitization increase our knowledge of the role of the noradrenergic system in cocaine addiction and may provide possible avenues for therapeutics.
    背景与目标: :腹侧被盖区(VTA)在促进药物成瘾的奖励和动机过程中起着重要作用。突触前的α1-AR活化调节谷氨酸和γ-氨基丁酸(GABA)的释放。这项工作阐明了可卡因致敏过程中VTA突触前α1-ARs的作用及其对谷氨酸能和GABA能神经传递的调节作用。通过全细胞电压钳测量的兴奋性和抑制性电流(EPSC和IPSC)显示,可卡因治疗1天后注射α1-ARs激活会增加EPSCs幅度,但注射可卡因5天后却不会。对α1-ARs激动剂的药理反应不存在突出了重复可卡因给药后受体的脱敏作用。停药7天后,α1-ARs的脱敏仍然持续。相反,急性或慢性可卡因注射并未影响IPSCs振幅降低所显示的GABA神经传递中α1-ARs的调节。综上所述,这些数据表明,即使在缺乏α1-ARs谷氨酸释放和蛋白激酶C功能的情况下,重复可卡因给药后,α1-ARs仍可通过减少VTA多巴胺(DA)神经元的GABA抑制作用来增强DA神经元的兴奋性( PKC)激活。可卡因敏化中的α1-AR调节性变化增加了我们对去甲肾上腺素能系统在可卡因成瘾中的作用的了解,并可能为治疗提供可能的途径。
  • 【慢性睡眠剥夺过程中SKF38393对海马中多巴胺D1受体信号通路的调节。】 复制标题 收藏 收藏
    DOI:10.1016/j.neulet.2017.05.072 复制DOI
    作者列表:Chen S,Wen X,Liang H,Li Y,Chen X,Zhang D,Shi R,Ma W
    BACKGROUND & AIMS: BACKGROUND:Hippocampal functions are sensitive to sleep deficiency. Dopamine D1 receptor (D1R) in hippocampus can regulate the expression of cAMP response element binding protein (CREB) through PKA, MAPK and phosphoinositide pathway, but which pathway plays the major role in hippocampus during Chronic sleep deprivation (CSD) is unclear. METHODS:The CSD model was created, SKF rats were administered the D1R agonist (SKF38363), and hippocampus from each animal was dissected for following molecular detection. The gene and protein levels of CREB and key molecules in D1R pathways were measured by real-time PCR and western blotting, respectively. RESULTS:Both the gene and protein expression of CREB in hippocampus decreased by CSD and improved significantly by SKF38393 (p<0.05). Both the gene and protein expression of PKA in hippocampus decreased by CSD and improved significantly by SKF38393 (p<0.05). SKF38393 just significantly improved the gene level of CaMK IV and the protein level of p-CaMK IV (p<0.05) in CSD rats, but it cannot improve the protein expression of ERK1/2 and p-ERK1/2. DISCUSSION:CSD significantly decreased the expression of CREB in hippocampus. As the key molecules, PKA and CaMK IV play an important role during the improvement of hippocampus by the activation of D1R, and this process might be improved during CSD through the PKA and phosphoinositide pathway.
    背景与目标: 背景:海马功能对睡眠不足敏感。海马中的多巴胺D1受体(D1R)可以通过PKA,MAPK和磷酸肌醇途径调节cAMP反应元件结合蛋白(CREB)的表达,但是在慢性睡眠剥夺(CSD)期间,该途径在海马中起主要作用尚不清楚。
    方法:建立CSD模型,给SKF大鼠施用D1R激动剂(SKF38363),并解剖每只动物的海马体以进行分子检测。通过实时PCR和蛋白质印迹分别测量CR1和D1R途径中关键分子的基因和蛋白质水平。
    结果:CSD降低海马CREB的基因和蛋白表达,SKF38393显着提高海马CREB的基因和蛋白表达(p <0.05)。 CSD使海马PKA的基因和蛋白表达均降低,而SKF38393则使PKA的基因和蛋白表达均显着提高(p <0.05)。 SKF38393可以显着改善CSD大鼠的CaMK IV基因水平和p-CaMK IV蛋白水平(p <0.05),但不能改善ERK1 / 2和p-ERK1 / 2的蛋白表达。
    讨论:CSD可明显降低海马CREB的表达。作为关键分子,PKA和CaMK IV在D1R活化过程中改善海马过程中起着重要作用,并且在CSD期间可通过PKA和磷酸肌醇途径改善这一过程。
  • 【大鼠前房的正常和移植胰腺组织中的多巴胺-β-羟化酶阳性神经。】 复制标题 收藏 收藏
    DOI:10.1016/0891-0618(91)90004-v 复制DOI
    作者列表:Adeghate E,Donáth T
    BACKGROUND & AIMS: :Dopamine-beta-hydroxylase(DBH)-positive nerves were demonstrated in normal and in pancreatic tissue fragments transplanted for 22 and 32 days into the anterior eye-chamber of rats using immunohistochemical techniques. Dopamine-beta-hydroxylase-immunopositive neurons of different shapes could be observed in normal pancreas. The neurons had either spindle or oval shapes. In the transplanted tissue, DBH-positive neuronal profiles were found in the stroma. In some cases DBH-immunopositive cells appeared as a cluster of cells around pancreatic ducts and blood vessels or as solitary cells. The wall of pancreatic ducts in the transplants also contained DBH-immunopositive nerve profiles.
    背景与目标: 使用免疫组织化学技术在正常和胰腺组织碎片中分别注入多巴胺-β-羟化酶(DBH)阳性神经和胰腺组织,分别植入22天和32天。在正常胰腺中可以观察到不同形状的多巴胺-β-羟化酶免疫阳性神经元。神经元具有纺锤形或椭圆形。在移植的组织中,在基质中发现了DBH阳性的神经元特征。在某些情况下,DBH免疫阳性细胞表现为胰管和血管周围的细胞簇或单细胞。移植物中的胰管壁也含有DBH免疫阳性神经特征。
  • 【多巴胺D2和腺苷A2A受体通过A2A-D2受体异聚来调节伏隔神经元中NMDA介导的兴奋。】 复制标题 收藏 收藏
    DOI:10.1038/npp.2008.144 复制DOI
    作者列表:Azdad K,Gall D,Woods AS,Ledent C,Ferré S,Schiffmann SN
    BACKGROUND & AIMS: :Bursting activity of striatal medium spiny neurons results from membrane potential oscillations between a down- and an upstate that could be regulated by G-protein-coupled receptors. Among these, dopamine D(2) and adenosine A(2A) receptors are highly enriched in striatal neurons and exhibit strong interactions whose physiological significance and molecular mechanisms remain partially unclear. More particularly, respective involvements of common intracellular signaling cascades and A(2A)-D(2) receptor heteromerization remain unknown. Here we show, by performing perforated-patch-clamp recordings on brain slices and loading competitive peptides, that D(2) and A(2A) receptors regulate the induction by N-methyl-D-aspartate of a depolarized membrane potential plateau through mechanisms relying upon specific protein-protein interactions. Indeed, D(2) receptor activation abolished transitions between a hyperpolarized resting potential and a depolarized plateau potential by regulating the Ca(V)1.3a calcium channel activity through interactions with scaffold proteins Shank1/3. Noticeably, A(2A) receptor activation had no effect per se but fully reversed the effects of D(2) receptor activation through a mechanism in which A(2A)-D(2) receptors heteromerization is strictly mandatory, demonstrating therefore a first direct physiological relevance of these heteromers. Our results show that membrane potential transitions and firing patterns in striatal neurons are tightly controlled by D(2) and A(2A) receptors through specific protein-protein interactions including A(2A)-D(2) receptors heteromerization.
    背景与目标: :纹状体中棘神经元的爆发活动是由膜下电位和膜上电位之间的膜电位振荡引起的,该膜电位振荡可以由G蛋白偶联受体调节。其中,多巴胺D(2)和腺苷A(2A)受体在纹状体神经元中高度富集,并显示出强烈的相互作用,其生理学意义和分子机制仍不清楚。更特别地,常见的细胞内信号传导级联和A(2A)-D(2)受体异源化的各自参与仍然未知。在这里我们显示,通过在脑片上执行穿孔膜片钳记录并加载竞争性肽,D(2)和A(2A)受体通过机制调节N-甲基-D-天冬氨酸对去极化膜电位平台的诱导依赖特定的蛋白质-蛋白质相互作用。确实,D(2)受体激活通过与支架蛋白Shank1 / 3的相互作用来调节Ca(V)1.3a钙通道活性,从而消除了超极化的静息电位和去极化的高原电位之间的过渡。值得注意的是,A(2A)受体激活本身没有任何作用,但通过严格强制A(2A)-D(2)受体异构化的机制完全逆转了D(2)受体激活的作用,因此证明了第一个直接的方法这些异聚体的生理相关性。我们的研究结果表明,纹状体神经元中的膜电位转变和放电模式受D(2)和A(2A)受体通过包括A(2A)-D(2)受体异源化的特定蛋白质-蛋白质相互作用严格控制。
  • 【帕金森氏病患者的褪黑激素和多巴胺血清水平与运动,认知和睡眠功能障碍的关系:一项横断面研究。】 复制标题 收藏 收藏
    DOI:10.3233/NRE-203075 复制DOI
    作者列表:Hadoush H,Lababneh T,Banihani SA,Al-Jarrah M,Jamous M
    BACKGROUND & AIMS: BACKGROUND:Parkinson's disease (PD) is a multisystem-progressive neurodegenerative disease characterized by dopaminergic neurons, however, the role of the non-dopaminergic system (such as melatonin hormone) in the pathogenesis of PD is now emerging. OBJECTIVE:To identify any potential correlation between the dopamine and melatonin serum levels, and motor, cognitive, and sleep dysfunctions in patients with PD. METHOD:Cross-sectional piloting study conducted with a sample of 34 patients with PD (aged 50-72 yrs old). Correlation tests performed to identify any potential correlations between the biomarkers' serum levels and motor, cognitive, and sleep dysfunctional levels in "on-medication" status. RESULTS:Spearman's test showed significant correlations between the melatonin serum level and sleep dysfunctions including overall sleep quality (P = 0.010) and subjective sleep quality sub-score (P = 0.001). On the other hand, spearman's test showed significant correlations between the dopamine serum level and motor dysfunctions including Berg Balance Scale (P = 0.026), 10-Meter Walk Test (P = 0.016), and Fear of Falling Index (P = 0.007), as well as comparisons between the dopamine serum level and cognitive dysfunction (P = 0.048). CONCLUSIONS:Melatonin serum level would serve as a potential biomarker in understanding the PD pathogenesis, and the melatonin serum level should be considered in future studies related to PD besides the dopamine serum level.
    背景与目标: 背景:帕金森氏病(PD)是一种以多巴胺能神经元为特征的多系统进展性神经退行性疾病,然而,非多巴胺能系统(例如褪黑激素)在PD的发病机理中的作用正在出现。
    目的:确定PD患者多巴胺和褪黑激素血清水平与运动,认知和睡眠功能障碍之间的潜在关系。
    方法:采用横断面试验研究,对34例PD(年龄在50-72岁之间)的PD患者进行了抽样研究。进行相关性测试以鉴定生物标记物的血清水平与“服药”状态下运动,认知和睡眠功能障碍水平之间的任何潜在相关性。
    结果:Spearman检验显示褪黑激素血清水平与睡眠功能障碍之间存在显着相关性,包括总体睡眠质量(P = 0.010)和主观睡眠质量亚评分(P = 0.001)。另一方面,spearman检验显示多巴胺血清水平与运动功能障碍之间存在显着相关性,其中包括Berg平衡量表(P = 0.026),10米步行测试(P = 160.016)和恐惧落体指数(P = 0.007),以及多巴胺血清水平与认知功能障碍之间的比较(P = 0.048)。
    结论:褪黑激素血清水平可能是了解PD发病机理的潜在生物标志物,除多巴胺血清水平外,未来与PD相关的研究应考虑褪黑激素血清水平。
  • 【多巴胺-β-羟化酶和血浆肾素活性在二十名高血压受试者中。】 复制标题 收藏 收藏
    DOI:10.3109/03009737509178986 复制DOI
    作者列表:Aberg H,Hedstrand H,Wetterberg L,Ross SB
    BACKGROUND & AIMS: :Dopamine-beta-hydroxylase (DBH), the enzyme responsible for the biosynthesis of noradrenalin from dopamine, was assayed in the blood plasma of 20 men with primary hypertension. At the same time plasma was taken for measurement of plasma renin activity. Renin release as well as the plasma level of DBH is dependent upon the activity of the sympathetic nervous system, at least to some extent. A possible relationship between the two enzymes was therefore investigated. However, no relationship could be found in this series of 20 hypertensive patients. Another aim was to study the levels of DBH in venous and arterial blood simultaneously. No difference in the DBH level was found in venous and in arterial blood in 11 patients undergoing heart catheterization.
    背景与目标: 在20例原发性高血压患者的血浆中测定了多巴胺-β-羟化酶(DBH),该酶负责从多巴胺生物合成去甲肾上腺素。同时取血浆以测定血浆肾素活性。肾素的释放以及DBH的血浆水平至少在某种程度上取决于交感神经系统的活动。因此研究了两种酶之间的可能关系。但是,在这20例高血压患者中,没有发现任何关系。另一个目的是同时研究静脉和动脉血中DBH的水平。在11名接受心脏导管检查的患者中,静脉血和动脉血中的DBH水平没有差异。
  • 【kappa阿片受体激动剂在灵长类动物中引起的催乳素释放被多巴胺D(2)样受体激动剂阻滞。】 复制标题 收藏 收藏
    DOI:10.1016/s0014-2999(01)01121-9 复制DOI
    作者列表:Butelman ER,Kreek MJ
    BACKGROUND & AIMS: :Kappa-opioid receptor agonists may have pharmacotherapeutic potential in the management of psychostimulant abuse, due to their ability to modulate dopamine receptor systems involved in drug reinforcement. kappa-Opioid receptor agonists also modulate dopamine receptor function in the hypothalamic tuberoinfundibular system, which has inhibitory control over an anterior pituitary hormone, prolactin. Prolactin levels may thus be a "biomarker" for the ability of kappa-opioid receptor agonists (e.g., (+)-(5 alpha,7 alpha,8 beta)-N-methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro[4.5]dec-8-yl]-benzeneacetamide (U69,593)) to modulate a dopamine receptor system in vivo in primates. The effectiveness of dopamine D(2)-like receptor agonists (quinpirole and (+/-)-7-hydroxy-dipropylaminotetralin (7-OH-DPAT); 0.0032-0.1 mg/kg) in preventing U69,593-induced prolactin release was studied in intact female rhesus monkeys. Quinpirole and 7-OH-DPAT inhibited U69,593-induced prolactin release (ID(50) values: 0.013 and 0.0072 mg/kg, respectively). However, the dopamine D(1)-receptor agonist (+/-)-6-chloro-7,8-dihydroxy-3-allyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazapine (SKF 82958; 1 mg/kg) did not inhibit U69,593-induced prolactin release under the same conditions. In contrast, the largest doses of quinpirole or 7-OH-DPAT presently studied (0.1 mg/kg), did not decrease sedation caused by U69,593 (0.01, 0.032 mg/kg), a prominent effect of centrally penetrating kappa-opioid receptor agonists. The sedative effect of U69,593 (0.032 mg/kg) was prevented by naltrexone (0.32 mg/kg), consistent with kappa-opioid receptor mediation of this effect. These studies suggest that prolactin release is a valid biomarker for the ability of kappa-opioid receptor agonists to modulate dopamine D(2)-like receptor function, and may also be used to quantify dopamine D(2)-like receptor agonist potency in primates.
    背景与目标: Kappa-阿片受体激动剂可能具有调节精神兴奋剂滥用的药物治疗潜能,因为它们具有调节参与药物增强的多巴胺受体系统的能力。 κ阿片受体激动剂还调节下丘脑结核漏斗下腺系统中的多巴胺受体功能,该系统对垂体前叶激素催乳素具有抑制作用。催乳素水平因此可能是κ阿片受体激动剂(例如()-(5 alpha,7 alpha,8 beta)-N-甲基-N- [7-(1-吡咯烷基)- 1-oxaspiro [4.5] dec-8-基]-苯乙酰胺(U69,593))在灵长类动物体内调节多巴胺受体系统。多巴胺D(2)样受体激动剂(喹吡罗和(-)-7-羟基-二丙基氨基四氢萘(7-OH-DPAT); 0.0032-0.1 mg / kg)预防U69,593诱导的催乳素释放的有效性为在完整的雌性恒河猴中进行了研究。喹吡罗和7-OH-DPAT抑制U69,593诱导的催乳素释放(ID(50)值分别为0.013和0.0072 mg / kg)。然而,多巴胺D(1)-受体激动剂(/-)-6-chloro-7,8-dihydroxy-3-allyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazapine(在相同条件下,SKF 82958; 1 mg / kg)不会抑制U69,593诱导的催乳素释放。相反,目前研究的最大剂量喹吡罗或7-OH-DPAT(0.1 mg / kg)并未降低U69,593(0.01,0.032 mg / kg)引起的镇静作用,这是中央渗透性阿片类药物的显着作用受体激动剂。纳曲酮(0.32 mg / kg)阻止了U69,593(0.032 mg / kg)的镇静作用,与这种作用的κ阿片受体介导的作用一致。这些研究表明,催乳素释放是κ-阿片受体激动剂调节多巴胺D(2)-样受体功能的能力的有效生物标志物,也可用于量化灵长类动物中多巴胺D(2)-样受体激动剂的效力。 。
  • 【谷氨酸和多巴胺受体促进大鼠新皮质切片中癫痫样放电的横向扩散。】 复制标题 收藏 收藏
    DOI:10.1111/j.1528-1167.2007.01385.x 复制DOI
    作者列表:Goda M,Kovac S,Speckmann EJ,Gorji A
    BACKGROUND & AIMS: PURPOSE:The effects of AMPA-type glutamate receptor as well as dopamine D1 and D2 receptors on the lateral propagation of epileptiform field potentials (EFP) were studied across adjacent areas of rat neocortical tissues. METHODS:Epileptiform burst discharges were induced by superfusion of Mg(2+)-free artificial cerebrospinal fluid. Simultaneous field potential recordings of EFP were obtained from four microelectrodes placed 2-3 mm apart across coronal slices in the third layer of the neocortex. The effects of AMPA receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), dopamine D1 receptor agonist SKF 81297, and dopamine D2 receptor agonist quinpirole on lateral propagation of burst discharges were investigated. RESULTS:CNQX, applied focally between recording sites, blocked rapid propagation across treated areas and resulted in the emergence of spatially separate, independent pacemakers. Focal application of SKF 81297 between recording sites increased the repetition rate of EFP, but reduced the amplitude as well as the duration of epileptic discharges. However, addition of SKF 81297 to the bath medium abolished EFP. Both local and systemic applications of quinpirole irreversibly enhanced repetition rate of epileptiform burst discharges. CONCLUSIONS:The results indicate the prerequisite of AMPA synaptic transmission for synchronized lateral propagation of Mg(2+)-free ACSF-induced epileptic activity and the modulatory effects of dopamine D1 and D2 receptors on both EFP initiation and propagation in epileptic tissues.
    背景与目标: 目的:研究了AMPA型谷氨酸受体以及多巴胺D1,D2受体对大鼠新皮层组织相邻区域癫痫样电位(EFP)横向传播的影响。
    方法:癫痫样突发放电是由无Mg(2)的人工脑脊髓液的灌注引起的。 EFP的同时场电势记录是通过在新皮层第三层中横跨冠状切片的2-3 mm处放置的四个微电极获得的。研究了AMPA受体拮抗剂6-氰基-7-硝基喹喔啉-2,3-二酮(CNQX),多巴胺D1受体激动剂SKF 81297和多巴胺D2受体激动剂喹吡罗对脉冲放电横向传播的影响。
    结果:CNQX集中应用于记录站点之间,阻止了在治疗区域之间的快速传播,并导致了空间上独立的独立起搏器的出现。在记录位点之间局部使用SKF 81297可以提高EFP的重复率,但可以降低幅度和癫痫放电的持续时间。但是,在浴液中添加SKF 81297取消了EFP。喹吡罗的局部和全身应用均不可逆地提高了癫痫样猝发放电的重复率。
    结论:结果表明,AMPA突触传递对于无Mg(2)的ACSF诱导的癫痫活动同步横向传播的先决条件,以及多巴胺D1和D2受体对EFP起始和在癫痫组织中传播的调节作用。
  • 【反射控制多巴胺β-羟化酶缺乏症的交感神经活动。】 复制标题 收藏 收藏
    DOI:10.1161/01.hyp.15.1.107 复制DOI
    作者列表:Rea RF,Biaggioni I,Robertson RM,Haile V,Robertson D
    BACKGROUND & AIMS: :Patients with autonomic failure secondary to dopamine beta-hydroxylase deficiency lack the enzyme activity necessary for the conversion of dopamine to norepinephrine in sympathetic nerve terminals and the adrenal medulla. These patients have virtually undetectable norepinephrine and epinephrine in plasma and cerebrospinal fluid. The presence of intact sympathetic nerve activity in these patients has been suggested by the enhanced release of dopamine (but not norepinephrine) in response to maneuvers that augment sympathetic outflow in normal subjects. In the present study, we recorded sympathetic nerve traffic by using microneurography in a patient with dopamine beta-hydroxylase deficiency and measured sympathetic neural responses to static exercise, the cold pressor test, and pharmacological alterations of blood pressure. At rest, sympathetic nerve activity was abundant and was modulated in a normal manner by handgrip (+278%), the cold pressor test (+169%), hypotension induced with isoproterenol (+102%), and hypertension induced with phenylephrine (-85%). These results provide the first electrophysiological evidence for intact regulation of sympathetic neural outflow in a patient with dopamine beta-hydroxylase deficiency and suggest that central norepinephrine and epinephrine pathways believed essential for the control of sympathetic neurotransmission in humans may be supplanted by alternative redundant mechanisms.
    背景与目标: 继发于多巴胺β-羟化酶缺乏症的自主神经衰竭患者缺乏在交感神经末梢和肾上腺髓质中将多巴胺转化为去甲肾上腺素所需的酶活性。这些患者的血浆和脑脊液中实际上没有检测到去甲肾上腺素和肾上腺素。多巴胺(而非去甲肾上腺素)的释放增加,提示在这些患者中存在完整的交感神经活动,这是由于在正常受试者中会增加交感神经的反应。在本研究中,我们通过使用微神经​​造影术记录了多巴胺β-羟化酶缺乏症患者的交感神经交通,并测量了对静态运动,冷压试验和血压药理学改变的交感神经反应。休息时,交感神经活动丰富,并通过握力(278%),冷压试验(169%),异丙肾上腺素引起的低血压(102%)和苯肾上腺素引起的高血压(-85%)正常调节。 。这些结果为多巴胺β-羟化酶缺乏症患者的交感神经流出的完整调节提供了首个电生理证据,并表明可能被认为是控制人交感神经传递必不可少的中枢去甲肾上腺素和肾上腺素途径可能被替代的冗余机制所取代。
  • 14 Suppression of Dopamine Neurons Mediates Reward. 复制标题 收藏 收藏

    【多巴胺神经元的抑制介导奖励。】 复制标题 收藏 收藏
    DOI:10.1371/journal.pbio.1002586 复制DOI
    作者列表:Yamagata N,Hiroi M,Kondo S,Abe A,Tanimoto H
    BACKGROUND & AIMS: :Massive activation of dopamine neurons is critical for natural reward and drug abuse. In contrast, the significance of their spontaneous activity remains elusive. In Drosophila melanogaster, depolarization of the protocerebral anterior medial (PAM) cluster dopamine neurons en masse signals reward to the mushroom body (MB) and drives appetitive memory. Focusing on the functional heterogeneity of PAM cluster neurons, we identified that a single class of PAM neurons, PAM-γ3, mediates sugar reward by suppressing their own activity. PAM-γ3 is selectively required for appetitive olfactory learning, while activation of these neurons in turn induces aversive memory. Ongoing activity of PAM-γ3 gets suppressed upon sugar ingestion. Strikingly, transient inactivation of basal PAM-γ3 activity can substitute for reward and induces appetitive memory. Furthermore, we identified the satiety-signaling neuropeptide Allatostatin A (AstA) as a key mediator that conveys inhibitory input onto PAM-γ3. Our results suggest the significance of basal dopamine release in reward signaling and reveal a circuit mechanism for negative regulation.
    背景与目标: 多巴胺神经元的大量激活对于自然奖赏和药物滥用至关重要。相反,其自发活动的重要性仍然难以捉摸。在果蝇中,原脑前内侧(PAM)簇多巴胺神经元的去极化信号会向蘑菇体(MB)奖励并驱动食性记忆。着眼于PAM簇神经元的功能异质性,我们发现一类PAM神经元PAM-γ3通过抑制自身的活性来介导糖的奖励。选择性嗅觉学习需要PAM-γ3,而这些神经元的激活又会引起厌恶记忆。食糖会抑制PAM-γ3的持续活性。令人惊讶的是,基础PAM-γ3活性的瞬时失活可以代替奖赏并诱导食性记忆。此外,我们确定了饱食信号神经肽Allatostatin A(AstA)是将抑制性输入传达到PAM-γ3的关键介体。我们的结果表明基础多巴胺释放在奖励信号传导中的重要性,并揭示了负调节的电路机制。
  • 【氰吲哚衍生物作为高度选择性的多巴胺D(4)受体部分激动剂:固相合成,结合测定和功能实验。】 复制标题 收藏 收藏
    DOI:10.1021/jm0009989 复制DOI
    作者列表:Hübner H,Kraxner J,Gmeiner P
    BACKGROUND & AIMS: :Traceless linking of diethoxymethyl (DEM)-protected 5- and 6-cyanoindoles and subsequent incorporation of phenylpiperazine derivatives led to the 2- and 3-piperazinylmethyl-substituted cyanoindoles 3a-m. Dopamine receptor binding studies on the final products 3a-m clearly indicated strong and selective recognition of the D(4) subtype which is known as a promising target for the treatment of neuropsychiatric disorders. The most interesting binding properties were observed for the 2-aminomethyl-5-cyanoindoles FAUC 299 (3f) and FAUC 316 (3j) (K(i) = 0.52 and 1.0 nM, respectively) when the fluoro derivative 3j proved extraordinary selectivity over D(1), D(2long), D(2short), and D(3) (>8600). To determine ligand efficacy, mitogenesis experiments were performed indicating partial agonist effects for the test compounds 3f,j (35% and 30%, when compared to the full agonist quinpirole).
    背景与目标: :二乙氧基甲基(DEM)保护的5-和6-氰基吲哚的无规连接和随后苯基苯哌嗪衍生物的引入导致2-和3-哌嗪基甲基取代的氰基吲哚3a-m。对最终产品3a-m的多巴胺受体结合研究清楚地表明,D(4)亚型具有强大的选择性识别能力,该亚型被称为治疗神经精神疾病的有希望的靶标。当氟衍生物3j在D上表现出非凡的选择性时,观察到了最有趣的2-氨基甲基-5-氰基吲哚FAUC 299(3f)和FAUC 316(3j)的结合特性(K(i)分别为0.52和1.0 nM)。 (1),D(2long),D(2short)和D(3)(> 8600)。为了确定配体功效,进行了有丝分裂实验,表明测试化合物3f,j的部分激动剂作用(与完全激动剂喹吡罗比较时为35%和30%)。

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