CONTINUOUS COCAINE--PERSISTING AFTEREFFECTS AND TOXICITY

安非他明（AMPH）和可卡因（COC）成瘾者都会出现狂欢模式， 其中药物在延长的时间段内频繁施用， 产生几乎连续的摄入方案。对于这两种药物，在这些 运行烦躁和偏执进行性增加。同样，AMPH 和COC，当连续给予动物时， 行为，最初的探索和刻板印象阶段， 发展为一个“晚期”，其特征是类似致幻剂的行为。 然而，这两种药物被发现是完全不同的许多人， 持续给药时对大脑产生的持续影响。 连续AMPH对尾状核多巴胺有选择性神经毒性作用 终端，而COC没有，和连续COC诱导持续 胆碱能和GABA受体的改变，特别是在尾状核， 而AMPH则没有。 在最近的研究中，连续性AMPH和 COC给药后，我们发现这两种药物类似地诱导 外侧缰核（LH）中轴突的高度特异性变性， 后屈束（FR）。我们现在建议进一步研究这一点 现象详细我们将进一步描述 变性，确定剂量和持续时间的药物所需的诱导 它，并试图澄清退化轴突的神经递质 以及它们细胞体的位置使用损伤技术，受体 阻断剂和直接激动剂，我们将试图确定哪些神经 通路和神经递质介导这种效应。 在行为研究中，我们将试图确定 这些退化的轴突，以及是否手术横断的主要 所涉及的通路改变了以下观察到的行为序列： 持续COC，特别是在重复的暴食期间，类似于 非常有毒瘾微透析技术将用于测试， 尾状核，重要的假设，即FR轴突退化介导 调节多巴胺释放的负反馈回路的一部分。这 将通过测量首次给药动物和COC预处理动物来完成 使由D1激动剂剂量诱导的多巴胺和GABA的水平沉淀 SKF38393。 在第二次实验中，我们还将进一步研究 海马体和海马旁的退化， 在持续服用苯环利定后发现，苯环利定是一种 第二个也是重要的精神病药物模型 该实验室处于进行这些研究的独特位置，因为 我们在缓释药物颗粒、退化模式和 行为

Both amphetamine (AMPH) and cocaine (COC) addicts develop binge patterns in which the drug is frequently administered over prolonged periods of time, producing a nearly continuous intake regimen. For both drugs, during these runs dysphoria and paranoia progressively increase. Similarly, both AMPH and COC, when administered continuously to animals, induce clear stages of behavior, with initial exploratory and stereotypy phases and the eventual development of a "late-stage" characterized by hallucinogen-like behaviors. Yet the two drugs have been found to be quite dissimilar many of the persisting effects on brain they produce when delivered continuously'. Continuous AMPH has a selective neurotoxic effect on caudate dopamine terminals, whereas COC does not, and continuous COC induces persisting alterations in cholinergic and GABA receptors, especially in caudate, whereas AMPH does not. In recent studies of degeneration patterns following continuous AMPH and COC administration we have discovered that both drugs similarly induce highly specific degeneration of axons in the lateral habenula (LH) and fasciculus retroflexus (FR). We now propose to further study this phenomenon in detail. We will further characterize pattern and extent of degeneration, determine the doses and duration of drugs necessary to induce it, and attempt to clarify the neurotransmitters of the degenerating axons and the location of their cell bodies. Using lesioning techniques, receptor blockers, and direct agonists we will attempt to determine what neural pathways and neurotransmitters mediate this effect. In behavioral studies, we will attempt to determine persisting effects of these degenerated axons and whether surgical transections of the principal pathways involved alter the sequence of behaviors observed following continuous COC, especially during repeated binges similar to those in the very chronic addict. Microdialysis techniques will be used to test, in caudate, the important hypothesis that FR axons which degenerate mediate part of the negative feedback circuitry regulating dopamine release. This will be done by measuring in drug-naive and animals pretreated with COC pellets the levels of dopamine and GABA induced by doses of the Dl agonist SKF38393. In secondary experiments we will also further study the pronounced degeneration in hippocampus and parahippocampus which we have recently found following continuous administration of phencyclidine, which is a second and important drug model of psychosis. This laboratory is in a unique position to conduct these studies because of our expertise in slowrelease drug pellets, degeneration patterns, and behavior.