COCAINE'S EFFECT ON NORADRENERGIC PHYSIOLOGY

申请者摘要：本研究的主要目的是探索 中枢去甲肾上腺素能系统生理学是否出现净功能障碍 发生在长期服用可卡因的范例之后。研究计划 将用于研究蓝斑(LC)功能的变化和 去甲肾上腺素(NE)在躯体感觉和神经调节中的作用 反复注射可卡因后的小脑皮质。首字母A 一系列的研究将检查LC生理学的几个参数 在自发LC发放率和活动模式方面，以及在 α2受体对激动剂和拮抗剂敏感性的变化 化合物。此外，研究还将调查 LC对感觉诱发放电的反应行为和 离子电泳法通过释放推定的 可能介导LC感官反应的神经递质 刺激。我们假设可卡因，因为它有能力 提高去甲肾上腺素突触水平或其他独立作用，可改变LC 神经元的活动，因此NE细胞的输入/输出关系。一个 第二系列研究将检查去甲肾上腺素调节作用的变化 LC的两个靶结构--躯体感觉皮质和小脑皮质 去甲肾上腺素能神经支配。微离子导入的实验研究 谷氨酸、氨基丁酸和乙酰胆碱类神经递质的应用 配合外周和中枢神经系统刺激程序 将被用来定量评估去甲肾上腺素对心脏的调节作用 上述大脑回路中的突触效能。目的 这些实验是为了确定去甲肾上腺素神经调节的可能变化 可能构成神经底物的一部分，负责 可卡因的精神刺激作用。最后，“体外”受体 将使用放射自显影技术来测量亲属 α-2受体在LC中的分布 这一控制正常LC生理的重要受体的变化。 总体而言，这种方法的目的是发展一种全面的理解 慢性可卡因对中枢去甲肾上腺素能神经系统的影响 可能构成可卡因成瘾的部分基础的生理学。

APPLICANT'S ABSTRACT: The major goal of this research is to explore whether a net dysfunction of the central noradrenergic system physiology occurs after a paradigm of chronic cocaine administration. A research plan will be developed to study changes in locus coeruleus (LC) function and norepinephrine (NE) neuromodulatory actions in the somatosensory and cerebellar cortices after repeated cocaine administration. An initial series of investigations will examine several parameters of LC physiology in terms of spontaneous LC firing rate and patterns of activity, and in changes in alpha-2-receptor sensitivity to agonists and antagonists compounds. In addition, studies will also investigate alterations in the behavior of LC responses to sensory evoked discharges and iontophoretically-induced excitation by the release of putative neurotransmitters that supposedly mediate LC reaction to sensory stimulation. We hypothesized that cocaine, by virtue of its ability to increase synaptic level of NE or other independent actions, can alter LC neuron activity and thus the input/output relationship of NE cells. A second series of studies will examine changes in NE modulatory actions in the somatosensory and cerebellar cortices, two target structures of LC noradrenergic innervation. Experiments using microiontophoresis application of putative neurotransmitters glutamate, GABA and acetylcholine together with peripheral and central nervous system stimulation procedures will be employed to quantitatively assess the NE modulatory actions on synaptic efficacy within the aforementioned brain circuits. The purpose of these experiments is to identify possible alterations in NE neuromodulatory actions which might form part of the neural substrates responsible for cocaine's psychostimulant effects. Finally, the "in vitro" receptor autoradiography technique will be employed to measure the relative distribution of alpha-2 receptors in the LC in an effort to observe any changes in this important receptor that control normal LC physiology. Overall, this approach is aimed at developing a comprehensive understanding of the effects of chronic cocaine administration on CNS noradrenergic physiology which might form part of the basis of cocaine's addiction.