OPIOID PEPTIDES AND COCAINE ABUSE

阿片肽和可卡因滥用

• 批准号: 6294632
• 负责人: Heinz Steiner
• 金额: $ 11.81万
• 依托单位: ROSALIND FRANKLIN UNIV OF MEDICINE & SCI
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-09-30 至 2003-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6294632
• 关键词: behavioral /social science research tag; behavioral habituation /sensitization; cocaine; developmental genetics; developmental neurobiology; dopamine receptor; dynorphins; enzyme activity; gene induction /repression; glutamate decarboxylase; laboratory rat; neurogenesis; neurogenetics; neuropharmacology; opioid receptor; pharmacogenetics; psychopharmacology; receptor expression; regulatory gene; somatostatin

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.

描述：申请人的摘要 本研究计划的长期目标是确定功能 基底神经节神经元基因表达变化的后果 经过可卡因等精神运动兴奋剂的长期治疗后。 此类滥用药物的强化作用被认为是由以下因素介导的： 前脑中的多巴胺神经传递。 证据已 表明这种过度刺激多巴胺受体 药物导致多巴胺感受神经元的神经适应性变化 包括基因表达的变化。 这种神经元的改变可能会起到 在长期使用可卡因期间发生的行为变化中的作用 使用/治疗。 动物模型研究和人类大脑研究 可卡因成瘾者已经表明，可卡因引起的基因调控发生变化 可卡因包括增加阿片肽强啡肽的表达 投射到基底神经节输出核的纹状体神经元 （例如，黑质）。 我们之前的结果表明，这种增加 强啡肽水平的作用是减少或减弱纹状体黑质的多巴胺输入 神经元。 拟议的研究将调查增加的功能后果 强啡肽在不同水平上的表达。 (1) 我们将确定是否 强啡肽/κ阿片受体激动剂可以在纹状体中发挥作用，抑制 多巴胺受体反应（即立即早期基因的诱导） 纹状体黑质神经元。 (2) 我们的研究还将确定是否重复 可卡因治疗影响目标神经元的基因表达 纹状体黑质通路，以及这种变化是否与增加的 强啡肽表达。 (3) 在这些研究中，基因调控的变化将 与重复使用可卡因期间发生的行为变化相关 治疗，以确定改变强啡肽功能的贡献 长期可卡因治疗的行为影响。 基因表达的变化 将通过定量原位杂交组织化学进行评估。 这项工作将为阿片类药物和多巴胺的机制提供新的见解 受体调节基底神经节功能。 此外，通过展示如何 长期可卡因治疗期间强啡肽功能的改变会影响 纹状体黑质通路和行为，这项工作可能有助于建立一个 治疗可卡因滥用新方法的细胞基础。