NOVEL MODES OF ACTIONS OF ABUSED DRUGS

该应用程序描述了针对六个不同组的实验 有明确的目标。第一个实验涉及识别 孕期暴露对大鼠和孕妇的神经毒性影响 安非他命或可卡因的使用。神经解剖学技术 以前广泛使用，如酪氨酸羟基酶 将在以下时间对母亲及其后代进行免疫细胞化学评估 解剖学发展的不同阶段。初步证据表明 每天两次15毫克/公斤的可卡因剂量足以导致 多巴胺能黑质纹状体神经毒性的解剖学证据 大鼠的系统以及其他神经解剖学和神经化学 对母亲和后代都有影响。我们将使用三个 从连续光学和电子显微照片到三维重建 评估多巴胺能轴突的形态及其形成的突触 新纹状体。此外，我们将使用相同的三维 评价纹状体(斑块)形态的重建方法 和异质新纹状体的基质隔室和 不同生化鉴定的中间神经元在大脑皮层的分布 猴子和人脑的尸检。最后，我们将研究 多巴胺能和皮质传入对尾状核的兴奋性 这一因变量在麻醉大鼠的脑核中受 谷氨酸激动剂和拮抗剂、多巴胺激动剂和拮抗剂 以及使用末端方法的5-羟色胺能激动剂和拮抗剂 兴奋性测试由本实验室自行开发。我们发现 对大脑皮层传入的强直刺激导致了一种长期的变化 在皮层终末兴奋性中，这可能形成突触前基础 详细描述了海马区、大脑皮层的长时程增强 大脑皮层和其他特征明确的通路。这种形式的长期投资 可塑性可能在长期行为增敏中起作用 安非他明给药。

The application describes experiments which address six different groups of specific aims. The first experiment concerns the identifying the neurotoxic consequences after prenatal exposure of rats and the pregnant dams to amphetamine or cocaine administration. Neuroanatomical techniques used previously and extensively such as tyrosine hydroxylase immunocytochemistry will be assessed in the mothers and their offspring at various stages of anatomical development. Preliminary evidence suggests that doses of cocaine of 15 mg/kg twice per day are sufficient to lead to anatomical evidence of neurotoxicity to the dopaminergic nigrostriatal system in the rat as well as other neuroanatomical and neurochemical consequences in both mothers and offspring. We will be using three dimensional reconstruction from serial light and electron micrographs to assess the form of the dopaminergic axon and the synapses that it makes in the neostriatum. Further we will be using the same three dimensional reconstruction methods to assess the morphology of the striosomal (patch) and matrix compartments of the heterogeneous neostriatum and the distributions of different biochemically identified interneurons in the monkey and human brain postmortem. Finally, we will be studying the excitability of dopaminergic as well as cortical afferents to the caudate nucleus in the anesthetized rat as this dependent variable is affected by glutamate agonists and antagonists, dopamine agonists and antagonists as well as serotonergic agonists and antagonists using a method of terminal excitability testing as developed in our laboratory. We have discovered that tetanic stimulation of cortical afferents leads to a long-term change in cortical terminal excitability which may form a presynaptic basis for the long term potentiation described in detail for hippocampus, cerebral cortex and other well characterized pathways. Such forms of long term plasticiy may play a role in the behavioral ensitization to long term amphetamine administration.