NOVEL MODES OF ACTIONS OF ABUSED DRUGS

该申请描述了针对六个不同群体的实验 具体目标。第一个实验涉及识别 大鼠和孕妇产前暴露后的神经毒性后果 安非他明或可卡因给药。 神经解剖技术 如酪氨酸羟化酶 免疫细胞化学将在母亲及其后代中进行评估， 解剖学发展的各个阶段。初步证据表明 每天两次15 mg/kg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 系统以及其他神经解剖学和神经化学 对母亲和后代的影响。我们将使用三个 三维重建从系列光和电子显微照片， 评估多巴胺能轴突的形式和它在大脑中形成的突触， 新纹状体此外，我们将使用相同的三维 评估纹状体（斑块）形态的重建方法 和异质新纹状体的基质隔室以及 不同的生化鉴定的中间神经元的分布， 猴子和人类的大脑最后，我们将研究 多巴胺能神经和皮质传入神经的兴奋性 麻醉大鼠的核，因为这个因变量受到以下因素的影响 谷氨酸激动剂和拮抗剂，多巴胺激动剂和拮抗剂， 以及肾上腺素能激动剂和拮抗剂， 我们实验室开发的兴奋性测试。我们已经发现 大脑皮层传入神经的强直性刺激会导致长期的变化 在皮质末端兴奋性，这可能形成突触前基础， 详细描述了海马、大脑皮层和海马神经元的长时程增强， 皮质和其他特征明确的通路。这种形式的长期 可塑性可能在长期行为敏感化中起作用 安非他明管理。

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.