Ultrastructure of Mesolimbic Transmitter Interactions

过去九年的MERIT奖研究 建立了对中脑边缘多巴胺能神经元的突触输入 腹侧被盖区（VTA）及其在延髓核的靶点 (NAc)对精神兴奋剂和抗精神病药物至关重要 行动 最重要的是，结果表明，这些神经元接受 来自含神经降压素或5-羟色胺的末梢的单突触输入 （5-HT）和兴奋性前额叶皮层传入。 突触 然而，传播依赖于囊泡包装和质膜， 再摄取的单胺和激活功能相关的 受体，其亚细胞分布在很大程度上是未知的。到 确定这些网站，三项研究提出了使用定量 电镜免疫细胞化学定位 序列特异性抗肽抗血清 转运蛋白和受体。 这些将在脑组织中进行检查， 正常成年大鼠和接受慢性治疗的动物 氟哌啶醇，一种典型的抑制多巴胺D2的抗精神病药物 受体。 研究I将检验以下假设：（1） 囊泡单胺转运体（VMAT 2）和多巴胺转运体（DAT） 不同之处在于中脑边缘和中皮层多巴胺能神经元的树突， 表明它们对树突状多巴胺能神经元 传输 神经降压素的潜在功能位点， 多巴胺D3受体激活也将被检查与 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中的大多数多巴胺能末梢靶点。 研究II 将测试假设，5-HT 2A受体，这是主要的结合 某些非典型抗精神病药物的位点存在于树突中 腹侧被盖区的多巴胺能神经元和/或NAc的GABA能神经元。 的 5-羟色胺转运蛋白（SERT）的定位将在 边缘壳和运动核心的NAc，以确定是否有 可能影响局部细胞外 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 皮质或其NAc中的突触后靶标。 本研究还将 测试假设，（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， (2)氟哌啶醇长期治疗可选择性改变 运动纹状体中GABA能神经元的含NMDA的棘。 总之，这些结果将有助于我们了解 多动性运动障碍的病理生理学和治疗， 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.