Ultrastructure of Mesolimbic Transmitter Interactions

过去九年荣获优异奖的研究 中脑边缘多巴胺能神经元的突触传入 伏核腹侧被盖区及其靶点 (NAC)对精神刺激剂和抗精神病药物至关重要 行为。最重要的是，结果显示这些神经元接收到 含有神经降压素或5-羟色胺的终末的单突触传入 (5-羟色胺)和兴奋性前额叶皮质传入。突触 然而，传递取决于囊泡包装和质膜。 单胺的再摄取及其对功能相关蛋白激活的影响 受体，其亚细胞分布很大程度上是未知的。至 确定这些地点，提出了三项研究，使用定量 电子显微镜免疫细胞化学定位研究 新近克隆的序列特异性抗肽抗血清 转运体和受体。这些将在脑组织中进行检查 正常成年大鼠和接受慢性药物治疗的动物 氟哌啶醇，一种典型的抗精神病药物，阻断多巴胺D2 感受器。研究I将检验以下假设：(1) 囊泡单胺转运体(VMAT2)和多巴胺转运体(DAT) 中脑边缘和中皮质多巴胺能神经元的树突不同， 提示它们对树突状多巴胺能的能力存在差异 变速箱。神经降压素和神经降压素的潜在功能部位 多巴胺D3受体的激活也将被检查与 含有多巴胺、D2受体或γ-氨基丁酸的神经元 (GABA)，存在于非多巴胺能神经元中的神经递质。 VTA和NAC的多巴胺能终末的大多数靶点。研究报告II 将测试5-HT2A受体的假设，它是主要的结合 某些非典型抗精神病药物的位置存在于树突中 在NAc的VTA和/或GABA能神经元中的多巴胺能神经元。这个 5-羟色胺转运体(SERT)的定位将在 确定NAC的边缘壳和电机核心是否有 可能影响细胞外局部可利用性的区域差异 血清素。研究III将确定多巴胺D2和/或D3 受体存在于来自前额叶的轴突终末 NAC的大脑皮层或其突触后靶点。这项研究还将 检验假设(1)N-甲基-D-天冬氨酸(NMDA)谷氨酸 受体和D2受体存在于相同的树突棘中，并且 (2)氟哌啶醇的慢性治疗会产生选择性的改变 运动纹状体内含有GABA能神经元的NMDA。 总之，这些结果将有助于我们理解 运动多动障碍的病理生理学及治疗 精神分裂症。

Studies conducted over the past nine years of the MERIT award established synaptic inputs to mesolimbic dopaminergic neurons in the ventral tegmental area (VTA) and their targets in the nucleus accumbens (NAc) that are critical for psychostimulant and antipsychotic drug actions. Most importantly, the results show that these neurons receive monosynaptic input from terminals containing neurotensin or serotonin (5-HT) and from excitatory prefrontal cortical afferents. Synaptic transmission depends, however, on vesicular packaging and plasmalemmal reuptake of monoamines and on the activation of functionally relevant receptors, whose subcellular distributions are largely unknown. To determine these sites, three studies are proposed using quantitative electron microscopic immunocytochemistry for the localization of sequence-specific antipeptide antisera against recently cloned transporters and receptors. These will be examined in brain tissue from normal adult rats and from animals receiving chronic treatment with haloperidol, a typical antipsychotic drug that blocks dopamine D2 receptors. Study I will test the hypotheses that (1) the levels of the vesicular monoamine transporter (VMAT2) and dopamine transporter (DAT) differ in dendrites of mesolimbic and mesocortical dopaminergic neurons, suggesting differences in their capacity for dendritic dopaminergic transmission. The potential functional sites for neurotensin and dopamine D3 receptor activation also will be examined in relation to neurons that contain dopamine, D2 receptors or gamma-aminobutyric acid (GABA), the neurotransmitter present in non-dopaminergic neurons in the VTA and in most targets of dopaminergic terminals in the NAc. Study II will test the hypothesis that 5-HT2A receptors, which are major binding sites for certain atypical antipsychotic drugs, are present in dendrites of dopaminergic neurons in the VTA and/or GABAergic neurons in NAc. The localization of the serotonin transporter (SERT) will be examined in the limbic shell and motor core of the NAc to determine whether there are regional variations that may affect local availability of extracellular serotonin. Study III will determine whether dopamine D2 and/or D3 receptors are present in axon terminals derived from the prefrontal cortex or their postsynaptic targets in the NAc. This study will also test the hypotheses that (1) N-methyl-D-aspartate (NMDA) glutamate receptors and D2 receptors are present in the same dendritic spines, and (2) chronic treatment with haloperidol produces selective changes in NMDA containing spines of GABAergic neurons in the motor striatum. Together, the results will contribute to our understanding of the pathophysiology and treatment of hyperkinetic movement disorders and schizophrenia.