• 【纹状体中多巴胺和谷氨酸之间的突触可塑性和生理相互作用。】 复制标题 收藏 收藏
    DOI:10.1016/s0149-7634(96)00029-2 复制DOI
    作者列表:Calabresi P,Pisani A,Centonze D,Bernardi G
    BACKGROUND & AIMS: Several electrophysiological studies have addressed the interaction between glutamate and dopamine within the striatum. Although the results obtained from these studies were often conflicting, more recently the characterization of new forms of synaptic plasticity in the basal ganglia provided a possible integrative explanation of the different electrophysiological data regarding the interaction between these transmitters. In this review we will try to summarize and discuss the available data concerning the possible impact of the functional role of D1 and D2 receptor activation on the modulation of the glutamatergic corticostriatal pathway. Moreover, we will also describe the function of the striatum in the integration of glutamatergic and dopaminergic inputs to produce long-term changes of synaptic efficacy (long-term depression, long-term potentiation). Finally, we will consider the implication of the interaction between dopamine and glutamate in the regulation of energetic metabolism whose failure is responsible for neuronal death.

    背景与目标: 几项电生理研究已经解决了纹状体内谷氨酸和多巴胺之间的相互作用。尽管从这些研究中获得的结果常常是矛盾的,但是最近在基底神经节中新形式的突触可塑性的表征为有关这些发射器之间相互作用的不同电生理数据提供了可能的综合解释。在这篇综述中,我们将尝试总结和讨论有关D1和D2受体激活的功能作用对谷氨酸能皮质皮质激素途径调节可能产生的影响的可用数据。此外,我们还将描述纹状体在谷氨酸能和多巴胺能输入的整合中的功能,以产生突触效力的长期变化(长期抑制,长期增强)。最后,我们将考虑多巴胺和谷氨酸之间相互作用对能量代谢的调节的意义,能量代谢的失败是神经元死亡的原因。
  • 【大剂量辛伐他汀对SD大鼠多巴胺水平及其在额叶前额叶皮层和纹状体中再摄取的影响。】 复制标题 收藏 收藏
    DOI:10.1016/j.neulet.2006.09.009 复制DOI
    作者列表:Wang Q,Tang XN,Wang L,Yenari MA,Ying W,Goh BC,Lee HS,Wilder-Smith EP,Wong PT
    BACKGROUND & AIMS: :Statins are increasingly being used for the treatment of a variety of conditions beyond their original indication for cholesterol lowering. We previously reported that simvastatin increased dopamine receptors in the rat prefrontal cortex [Q. Wang, W.L. Ting, H. Yang, P.T. Wong, High doses of simvastatin upregulate dopamine D(1) and D(2) receptor expression in the rat prefrontal cortex: possible involvement of endothelial nitric oxide synthase, Br. J. Pharmacol. 144 (2005) 933-939] and restored its downregulation in a model of Parkinson's disease (PD) [Q. Wang, P.H. Wang, C. McLachlan, P.T. Wong, Simvastatin reverses the downregulation of dopamine D1 and D2 receptor expression in the prefrontal cortex of 6-hydroxydopamine-induced Parkinsonian rats, Brain Res. 1045 (2005) 229-233]. Here we explore the effects of simvastatin treatment on tissue dopamine content and reuptake. Sprague-Dawley rats were given simvastatin (1 and 10 mg kg(-1)day(-1), p.o.) for 4 weeks. Brain tissue from prefrontal cortex and striatum were taken out for dopamine content and its reuptake. Using high-performance liquid chromatographic-mass spectrometer (HPLC-MS), simvastatin (10 mg kg(-1)day(-1)) was found to increase dopamine content by 110% in the striatum but decreased by 76% in the prefrontal cortex compared with the saline treated group. Dopamine (DA) reuptake was unchanged in both brain regions. These results suggest that chronic treatment with high dose of simvastatin may affect DA tissue level in prefrontal cortex and striatum without changing on DA reuptake. This may have important clinical implications in psychiatric and striatal dopaminergic disorders.
    背景与目标: 他汀类药物已被用于治疗多种疾病,这些症状超出了降低胆固醇的最初指标。我们先前曾报道辛伐他汀会增加大鼠前额叶皮层中的多巴胺受体[Q.王伟丁宏阳黄,辛伐他汀大剂量上调大鼠前额叶皮层中的多巴胺D(1)和D(2)受体表达:可能与内皮一氧化氮合酶Br有关。 J.Pharmacol。 144(2005)933-939],并在帕金森氏病(PD)模型中恢复了其下调[Q.王凤华Wang C.McLachlan,P.T. Wong,辛伐他汀逆转了6-羟基多巴胺诱导的帕金森病大鼠Brain Res的前额叶皮层中多巴胺D1和D2受体表达的下调。 1045(2005)229-233]。在这里,我们探讨辛伐他汀治疗对组织多巴胺含量和再摄取的影响。 Sprague-Dawley大鼠接受辛伐他汀(1和10 mg kg(-1)day(-1),口服)4周。取出前额叶皮层和纹状体的脑组织中的多巴胺含量并重新摄取。使用高效液相色谱质谱仪(HPLC-MS),发现辛伐他汀(10 mg kg(-1)day(-1))在纹状体中可使多巴胺含量增加110%,但在前额叶中减少76%皮层与生理盐水处理组相比。在两个大脑区域中,多巴胺(DA)的再摄取均未改变。这些结果表明,高剂量辛伐他汀的长期治疗可能会影响额叶前额叶皮层和纹状体中的DA组织水平,而不会改变DA的再摄取。这在精神病和纹状体多巴胺能障碍中可能具有重要的临床意义。
  • 【减轻可卡因对细胞外多巴胺影响的直接方法:靶向多巴胺转运蛋白。】 复制标题 收藏 收藏
    DOI:10.1002/(SICI)1098-2396(199708)26:4<423::AID-SYN10 复制DOI
    作者列表:Morgan AE,Porter SP,Clarkson FA,Volkow ND,Fowler JS,Dewey SL
    BACKGROUND & AIMS: Using in vivo microdialysis techniques, the effects of RTI-55 and/or cocaine on extracellular dopamine (DA) concentrations were measured in the nucleus accumbens (NACC) of freely moving rats. In control animals, cocaine (20 mg/kg) increased NACC DA approximately 458% 60 minutes following administration, returning to baseline values within 200 minutes. Similarly, RTI-55 administration (0.25 mg/kg) increased NACC DA levels approximately 347%. When combined, however, cocaine further increased NACC DA to 705% of baseline values when given 4 hours following RTI-55. This increase was significantly larger than cocaine alone (P < 0.05). In addition, chronic RTI-55 administration (5 days) further potentiated cocaine's ability to increase NACC DA (783%) but this did not reach statistical significance (P > 0.1) compared to acute RTI55/cocaine animals. These findings indicate that RTI-55, a drug that binds directly to the dopamine transporter (DAT) with higher affinity than cocaine, does not appear to be effective in attenuating cocaine's effects on NACC dopamine levels. In fact, acute RTI-55 potentiates cocaine's effects on NACC DA.

    背景与目标: 使用体内微透析技术,在自由移动的大鼠伏伏核(NACC)中测量了RTI-55和/或可卡因对细胞外多巴胺(DA)浓度的影响。在对照动物中,可卡因(20 mg / kg)在给药60分钟后可使NACC DA升高约458%,在200分钟内恢复至基线值。同样,RTI-55的给药(0.25 mg / kg)使NACC DA水平升高约347%。但是,当联合使用时,可卡因在RTI-55后4小时给予时,NACC DA进一步增加至基线值的705%。这一增加比单独使用可卡因要大得多(P <0.05)。此外,长期RTI-55给药(5天)进一步增强了可卡因增加NACC DA的能力(783%),但与急性RTI55 /可卡因动物相比,这没有统计学意义(P> 0.1)。这些发现表明,RTI-55是一种比可卡因具有更高亲和力的直接结合多巴胺转运蛋白(DAT)的药物,在减轻可卡因对NACC多巴胺水平的影响方面似乎并不有效。实际上,急性RTI-55增强了可卡因对NACC DA的作用。

  • 【多巴胺D1和NMDA受体之间的突触后相互作用通过腺苷释放促进大鼠伏隔核中的突触前抑制。】 复制标题 收藏 收藏
    DOI: 复制DOI
    作者列表:Harvey J,Lacey MG
    BACKGROUND & AIMS: :The mechanism underlying dopamine D1 receptor-mediated attenuation of glutamatergic synaptic input to nucleus accumbens (NAcc) neurons was investigated in slices of rat forebrain, using whole-cell patch-clamp recording. The depression by dopamine of EPSCs evoked by single-shock cortical stimulation was stimulus-dependent. Synaptic activation of NMDA-type glutamate receptors was critical for this effect, because dopamine-induced EPSC depressions were blocked by the competitive NMDA receptor antagonist D/L-2-amino-5-phosphonopentanoate (AP5). Application of NMDA also depressed the EPSC, and both this effect and the dopamine depressions were blocked by the A1 receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX), implicating adenosine release in the EPSC depression. A1 receptor agonists also depressed EPSCs by a presynaptic action, causing increased paired-pulse facilitation, but this was insensitive to AP5. Activation of D1 receptors enhanced both postsynaptic inward currents evoked by NMDA application and the isolated NMDA receptor-mediated component of synaptic transmission. The biochemical processes underlying the dopamine-induced EPSC depression did not involve either protein kinase A or the production of cAMP and its metabolites, because this effect was resistant to the protein kinase inhibitors H89 and H7 and the cAMP-specific phosphodiesterase inhibitor rolipram. We conclude that activation of postsynaptic D1 receptors enhances the synaptic activation of NMDA receptors in nucleus accumbens neurons, thereby promoting a transsynaptic feedback inhibition of glutamatergic synaptic transmission via release of adenosine. Unusually for D1 receptors, this phenomenon occurs independently of adenylyl cyclase stimulation. This process may contribute to the locomotor stimulant action of dopaminergic agents in the NAcc.
    背景与目标: :使用全细胞膜片钳记录技术,在大鼠前脑切片中研究了多巴胺D1受体介导的伏谷核(NAcc)神经元的谷氨酸能突触输入衰减的机制。单电刺激皮层刺激引起的EPSCs的多巴胺抑制与刺激有关。 NMDA型谷氨酸受体的突触激活对此效应至关重要,因为多巴胺诱导的EPSC抑制被竞争性NMDA受体拮抗剂D / L-2-氨基-5-膦基戊酸酯(AP5)阻止。 NMDA的应用也抑制了EPSC,这种作用和多巴胺抑制均被A1受体拮抗剂8-环戊基-1,3-二丙基黄嘌呤(DPCPX)阻断,这暗示了EPSC抑制中腺苷的释放。 A1受体激动剂也通过突触前作用抑制EPSC,导致成对脉冲促进作用增强,但这对AP5不敏感。 D1受体的激活增强了由NMDA引起的突触后内向电流和分离的NMDA受体介导的突触传递成分。多巴胺引起的EPSC抑郁症的生化过程既不涉及蛋白激酶A,也不涉及cAMP及其代谢产物的产生,因为这种作用对蛋白激酶抑制剂H89和H7以及cAMP特异性磷酸二酯酶抑制剂咯利普兰具有抵抗力。我们得出的结论是,突触后D1受体的激活增强伏隔核神经元中NMDA受体的突触激活,从而通过释放腺苷促进谷氨酸能突触传递的突触反馈抑制。对于D1受体,这种现象通常与腺苷酸环化酶的刺激无关地发生。该过程可能有助于NAcc中多巴胺能药物的运动刺激作用。
  • 【大鼠腹侧被盖区中的食欲素轴突很少突触到多巴胺和γ-氨基丁酸神经元上。】 复制标题 收藏 收藏
    DOI:10.1002/cne.21420 复制DOI
    作者列表:Balcita-Pedicino JJ,Sesack SR
    BACKGROUND & AIMS: :Cells in the ventral tegmental area (VTA) facilitate motivated behaviors, and the activity of VTA neurons is regulated by dense projections from the lateral hypothalamic area (LHA). Orexin (Orx) neurons in the lateral and perifornical hypothalamus play important roles in arousal, feeding, and energy metabolism. Orx cells contribute substantially to the LHA projection to the rat midbrain. However, the morphological features of Orx fibers in the VTA and whether they synapse onto dopamine (DA) or gamma-aminobutyric acid (GABA) neurons have not yet been investigated. We utilized immunoperoxidase and immunogold-silver staining to examine the morphological features and synaptic incidence of Orx-labeled axons in the VTA. We then combined immunoperoxidase labeling for Orx with immunogold-silver labeling for GABA or for tyrosine hydroxylase (TH) in DA neurons. Electron microscopic analysis revealed that most Orx-labeled axons in the VTA were passing fibers. The less common Orx varicosities were occasionally apposed to TH- or GABA-labeled dendrites without synapsing. Only a small proportion of Orx-positive axons synapsed onto dendrites or soma. The synapses included both asymmetric and symmetric types and targeted TH- and GABA-labeled profiles with equal frequency. These findings suggest that most Orx fibers in the VTA are axons passing to caudal brainstem structures. However, Orx does mediate some direct synaptic influence on VTA DA and GABA neurons. Additional nonsynaptic effects are suggested by the presence of numerous dense-cored vesicles. These studies have important implications for understanding the mechanisms whereby Orx can alter behavior through regulating VTA DA and GABA cell activity.
    背景与目标: :腹侧被盖区(VTA)中的细胞有助于激发行为,而VTA神经元的活动受下丘脑外侧区(LHA)的密集投射所调节。下丘脑外侧和下丘脑中的食欲素(Orx)神经元在唤醒,进食和能量代谢中起重要作用。 Orx细胞在很大程度上促进了LHA投射到大鼠中脑。但是,尚未研究VTA中Orx纤维的形态特征以及它们是否突触到多巴胺(DA)或γ-氨基丁酸(GABA)神经元上。我们利用免疫过氧化物酶和免疫金银染色来检查VTA中Orx标记的轴突的形态特征和突触发生率。然后,我们在DA神经元中结合了Orx的免疫过氧化物酶标记和GABA或酪氨酸羟化酶(TH)的免疫金银标记。电子显微镜分析显示,VTA中大多数Orx标记的轴突都通过了纤维。不太常见的Orx静脉曲张偶尔与TH或GABA标记的树突并置而不发生突触。只有一小部分的Orx阳性轴突突触到树突或躯体上。突触包括不对称和对称类型以及具有相同频率的靶向TH和GABA标记的图谱。这些发现表明,VTA中的大多数Orx纤维都是传递至尾脑干结构的轴突。但是,Orx确实介导了对VTA DA和GABA神经元的一些直接突触影响。由于存在许多致密囊泡,提示了其他非突触作用。这些研究对于理解Orx可以通过调节VTA DA和GABA细胞活性来改变行为的机制具有重要意义。
  • 【对多巴胺D2受体具有高度亲和力的新型噻氯必利的氟取代类似物。】 复制标题 收藏 收藏
    DOI:10.1248/cpb.39.3211 复制DOI
    作者列表:Watanabe K,Fukumura T,Sasaki S,Maeda M,Takehara S
    BACKGROUND & AIMS: :Aiming at the development of positron-emitting ligands with specific and high affinity toward dopamine D2 receptors in the central nervous system, we synthesized a new fluorinated eticlopride derivative. A fluorine atom was introduced at the C-4 position of the pyrrolidine ring of eticlopride, a dopamine D2 antagonist of the benzamide series. The in vitro binding affinity of this ligand toward the D2 receptor was found to be as potent as eticlopride, suggesting that the corresponding 18F-labelled compound may be useful as an in vivo radioligand for positron emission tomography.
    背景与目标: :针对对中枢神经系统中对多巴胺D2受体具有特异性和高亲和力的正电子发射配体的开发,我们合成了一种新的氟化噻氯必利衍生物。在苯乙酰胺系列的多巴胺D2拮抗剂艾替洛必利的吡咯烷环的C-4位引入氟原子。发现该配体对D2受体的体外结合亲和力与埃替普利德一样有效,表明相应的18F-标记的化合物可用作体内放射配体用于正电子发射断层摄影。
  • 【体树突状多巴胺传递中的物种差异决定了D2自体受体介导的腹侧被盖区神经元放电的抑制作用。】 复制标题 收藏 收藏
    DOI:10.1523/JNEUROSCI.2745-12.2012 复制DOI
    作者列表:Courtney NA,Mamaligas AA,Ford CP
    BACKGROUND & AIMS: :The somatodendritic release of dopamine within the ventral tegmental area (VTA) and substantia nigra pars compacta activates inhibitory postsynaptic D2-receptors on dopaminergic neurons. The proposed mechanisms that regulate this form of transmission differ between electrochemical studies using rats and guinea pigs and electrophysiological studies using mice. This study examines the release and resulting dopamine D2-autoreceptor-mediated IPSCs (D2-IPSCs) in the VTA of mouse, rat, and guinea pig. Robust D2-IPSCs were observed in all recordings from neurons in slices taken from mouse, whereas D2-IPSCs in rat and guinea pig were observed less frequently and were significantly smaller in amplitude. In slices taken from guinea pig, dopamine release was more persistent under conditions of reduced extracellular calcium. The decline in the concentration of dopamine was also prolonged and not as sensitive to inhibition of reuptake by cocaine. This resulted in an increased duration of D2-IPSCs in the guinea pig. Therefore, unlike the mouse or the rat, the time course of dopamine in the extracellular space of the guinea pig determined the duration the D2-IPSC. Functionally, differences in D2-IPSCs resulted in inhibition of dopamine neuron firing only in slices from mouse. The results suggest that the mechanisms and functional consequences of somatodendritic dopamine transmission in the VTA vary among species. This highlights the complexity that underlies dopamine-dependent transmission in one brain area. Differences in somatodendritic transmission would be expected in vivo to affect the downstream activity of the mesocorticolimbic dopamine system and subsequent terminal release.
    背景与目标: 多巴胺在腹侧被盖区(VTA)和黑质致密部中的体树突状释放可激活多巴胺能神经元上的抑制性突触后D2受体。在使用大鼠和豚鼠进行的电化学研究与使用小鼠进行的电生理研究之间,调节这种传输形式的拟议机制有所不同。这项研究检查了小鼠,大鼠和豚鼠的VTA中多巴胺D2自身受体介导的IPSC(D2-IPSC)的释放和产生。在从小鼠采集的切片中的神经元的所有记录中均观察到了健壮的D2-IPSC,而在大鼠和豚鼠中观察到的D2-IPSC频率较低,并且振幅明显较小。在豚鼠的切片中,在细胞外钙减少的条件下,多巴胺的释放更为持久。多巴胺浓度的下降也延长了,对可卡因抑制再摄取的敏感性不高。这导致豚鼠中D2-IPSC的持续时间增加。因此,与小鼠或大鼠不同,豚鼠细胞外空间中多巴胺的时程决定了D2-IPSC的持续时间。在功能上,D2-IPSC的差异仅导致小鼠切片中多巴胺神经元放电的抑制。结果表明,树突状多巴胺在VTA中传播的机制和功能后果因物种而异。这突显了在一个大脑区域中依赖多巴胺传播的基础的复杂性。预计体内树突状传递的差异会影响中皮层皮质多巴胺系统的下游活性和随后的末端释放。
  • 【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。

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