GENES RELATED TO DRUG ABUSE--REGULATION OF OPIOID PEPTIDE GENES

药物改变大脑中许多重要基因的表达。 这些 基因表达的变化可能有助于长期的药物治疗。 影响，如宽容和依赖。继续研究 编码内源性吗啡样肽的基因表明， 药物诱导的基因调控依赖于连接到神经元的回路。 神经元和药物暴露的持续时间。 在过去的一年里，实验室监测了细胞水平， 神经肽mRNAs和转录因子基因，可能改变 这些mRNA的表达，以评估与功能相关的基因调控 这些神经元的活动。 在今年完成的研究中， 前脑啡肽原表达的跨突触调节 脊髓束尾侧核的痛觉调节神经元 详细描述了三叉神经。AP-1和CREB家族 可能参与这种调节的转录因子有 鉴定 转基因小鼠具有特定的部分， 前脑啡肽原启动子的产生，和他们的反应，只有 注意到前脑啡肽原表达的某些跨突触激活剂。 表达的小基因构建体对雄性育性的有趣影响 和睾丸功能。最后， 通过改变大脑中的这些转录因子通路， 经修饰的寡核苷酸的实质内注射是有效的。 这些方法有助于理解尝试的重要机制 to therapeutic治疗manipulating操纵drug药物influences影响on gene基因expression表达. 使用阿片类拮抗剂改变的人类研究的初步结果 这些阿片肽基因的表达提供了证据， 这种靶向治疗的效果。

Drugs alter the expression of many important genes in the brain. These changes in gene expression are likely to contribute to long-term drug effects, such as tolerance and dependence. Continuing studies of the genes encoding endogenous morphine-like peptides suggest that drug-induced gene regulation depends on the circuits connecting to the neuron and the duration of drug exposure. During the past year, the laboratory has monitored cellular levels of neuropeptide mRNAs and of the transcription factor genes that may alter expression of these mRNAs to assess gene regulation related to functional activity in these neurons. In studies completed during this year, transsynaptic regulation of preproenkephalin expression in pain-modulating neurons of the nucleus caudalis of the spinal tract of the trigeminal was described in detail. and the AP-1 and CREB family transcription factors that could participate in this regulation were identified. Transgenic mice possessing a specific portion of the preproenkephalin promoter were produced, and their responsiveness to only certain trans-synaptic activators of preproenkephalin expression noted. Interesting effects of expressed minigene constructs on male fertility and testicular function were found. Finally, approaches to directly modifying these transcription factor pathways in brain with intraparenchymal injection of modified oligonucleotides were validated. These approaches allow understanding of mechanisms important for attempts to therapeutically manipulate drug influences on gene expression. Preliminary results from a human study using opiate antagonists to change the expression of these opioid peptide genes provide evidence for the efficacy of such targeted therapies.