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

药物会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药物治疗 影响，如容忍和依赖。对这一现象的持续研究 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 神经元和药物暴露的持续时间。 在过去的一年里，该实验室监测了细胞水平 神经肽mRNAs和可能改变的转录因子基因 表达这些mRNAs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， 突触对脑内前脑啡肽原表达的跨突触调节 马尾神经脊束核尾侧核的痛觉调制神经元 对三叉神经进行了详细的描述。以及AP-1和CREB家族 可以参与这一调控的转录因子有 已确认身份。转基因小鼠拥有特定部分的 前脑啡肽原启动子的产生，并且它们只对 注意到前脑啡肽原表达的某些跨突触激活物。 表达的微基因结构对男性生育能力的有趣影响 并观察睾丸功能。最后，直接 在大脑中修饰这些转录因子途径 实质内注射修饰的寡核苷酸是有效的。 这些方法允许理解对尝试很重要的机制 从治疗上操纵药物对基因表达的影响。 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为 这种靶向治疗的疗效。

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.