OPIOID PEPTIDES AND COCAINE ABUSE

描述：申请者摘要 这项研究提案的长期目标是确定功能 基底节神经元基因表达改变的后果 在使用可卡因等精神运动兴奋剂进行长期治疗后。 这种滥用药物的强化作用被认为是由 前脑中的多巴胺神经传递。有证据表明 提出了过度刺激多巴胺受体所产生的 药物导致多巴胺受体神经元的神经适应性改变 包括基因表达的变化。这种神经元的改变可能会起到 在慢性可卡因期间发生的行为变化中的作用 使用/治疗。动物模型研究和人脑研究 可卡因成瘾者已经表明，基因调控的变化是由 可卡因包括阿片肽强啡肽的表达增加 投射到基底节输出核的纹状体神经元 (例如，黑质)。我们之前的结果表明，这样的增加 强啡肽水平可减少或减弱对纹状体的多巴胺输入 神经元。 拟议的研究将调查增加的功能后果 强啡肽在不同水平均有表达。(1)我们将决定是否 强啡肽/kappa阿片受体激动剂可作用于纹状体抑制 脑内多巴胺受体反应(即即刻早期基因的诱导) 纹状体黑质神经元。(2)我们的研究还将确定是否重复 可卡因处理对大鼠脑内靶神经元基因表达的影响 纹状体黑质通路，以及这种变化是否与 强啡肽的表达。(3)在这些研究中，基因调控的变化将 与反复吸食可卡因期间发生的行为变化相关 治疗，以确定改变的强啡肽功能对 慢性可卡因治疗对行为的影响。基因表达的变化 将用定量原位杂交组织化学方法进行评估。 这项工作将为阿片类药物和多巴胺的作用机制提供新的见解。 基底神经节功能的受体调节。此外，通过展示如何 慢性可卡因治疗期间强啡肽功能的改变影响 纹状体黑质通路和行为，这项工作可能有助于建立 治疗可卡因滥用的新方法的细胞学基础。

DESCRIPTION: Applicant's Abstract The long-term objective of this research proposal is to determine functional consequences of changed gene expression in neurons of the basal ganglia after chronic treatment with psychomotor stimulants such as cocaine. The reinforcing effects of such drugs of abuse are thought to be mediated by the dopamine neurotransmission in the forebrain. Evidence has been presented that excessive stimulation of dopamine receptors produced by such drugs results in neuroadaptive changes in dopamine-receptive neurons including changes in gene expression. Such neuronal alterations may play a role in the behavioral changes that occur during chronic cocaine use/treatment. Research in animal models and studies of brains of human cocaine addicts have shown that changes in gene regulation produced by cocaine include increased expression of the opioid peptide dynorphin in neurons of the striatum that project to the basal ganglia output nuclei (e.g., substantia nigra). Our previous results indicate that such increased dynorphin levels function to reduce or blunt dopamine input to striatonigral neurons. The proposed research will investigate functional consequences of increased dynorphin expression on different levels. (1) We will determine whether dynorphin/kappa opioid receptor agonists can act in the striatum to inhibit dopamine receptor responses (i.e., induction of immediate-early genes) in striatonigral neurons. (2) Our studies will also determine whether repeated cocaine treatment affects gene expression in target neurons of the striatonigral pathway, and whether such changes are related to the increased dynorphin expression. (3) In these studies, changes in gene regulation will be correlated with behavioral changes that occur during repeated cocaine treatment, to determine the contribution of changed dynorphin function to behavioral effects of chronic cocaine treatment. Changes in gene expression will be assessed with quantitative in situ hybridization histochemistry. This work will provide new insights into mechanisms of opioid and dopamine receptor regulation of basal ganglia function. Furthermore, by showing how altered dynorphin function during chronic cocaine treatment affects the striatonigral pathway and behavior, this work may help to establish a cellular basis for new approaches in the treatment of cocaine abuse.