Opioid Modulation of Excitatory Synapses

药物成瘾是一种神经和心理障碍，其特征是强迫性摄入、渴望和寻求具有负面影响的药物，这些药物对药物滥用者的生活产生不利影响。成瘾最近被认为是学习和记忆的一种病理形式，需要神经回路的长期变化。与这一建议相一致，我们最近的研究表明，阿片类药物的长期治疗改变了培养的解离神经元树突棘的稳定性。我科学生涯的最终目标是在系统和细胞水平上显著提高我们对药物成瘾的综合理解。我的研究的科学目标是确定树突棘的阿片类药物调制的细胞机制。本研究由美国国家药物滥用研究所（NIDA）R01基金（DA020582）资助，主要目的有三：（1）进一步研究MORs及其内化在树突棘突触后调节中的作用。(2)鉴定和确定Rho GT3介导阿片样物质对树突棘的调节。(3)鉴定和确定介导阿片类药物调节树突棘的蛋白激酶。这个K02奖将使我能够大大减少我的教学时间，使我可以把更多的精力投入到研究（从50%增加到75%的总努力）。我将用额外的25%的努力来加强和扩大R01项目在两个方面：（1）加强具体目标1和3与新提出的实验使用脑切片制备的不同区域的大脑，包括纹状体，腹侧被盖区（VTA），额叶新皮层和海马：我们最近出乎意料的结果表明，MORs可以存在于突触前或突触后位点，这取决于神经元的类型和大脑的区域。因此，为了更好地了解药物成瘾，我们将研究阿片类药物如何调节大脑不同区域的兴奋性突触传递。(2)学习和使用双光子显微镜技术研究慢性阿片类药物暴露期间AMPA受体的运输：吗啡的慢性治疗降低了微型EPSC的振幅，表明突触后AMPA受体的清除。这种方法的目的是为下一个未来的研究计划奠定坚实的基础时，我资助的R01赠款是竞争性的更新。下一步的研究计划是阐明阿片类药物暴露期间AMPA受体贩运的细胞机制。此外，这个K02奖也将让我投入额外的努力，我在阿片类药物药理学的培训。我将参加明尼苏达大学神经科学系和NIDA资助的药物滥用分子和细胞生物学基础中心的研讨会和会议。我将定期参加在冷泉港的NIDA资助的暑期课程，并参加国家和国际神经科学和药理学的科学会议。

DESCRIPTION (provided by applicant): Drug addiction is a neurological and psychological disorder characterized by compulsive intake, craving and seeking of drugs with negative impacts that adversely affect the lives of the drug abusers. Addiction has recently been proposed to be a pathological form of learning and memory, which requires long-term changes of neural circuits. Consistent with this proposal, our recent studies reveal that chronic treatment with opioids alters the stability of dendritic spines in cultured dissociated neurons. The ultimate goal of my scientific career is to significantly advance our integrated understanding of drug addiction at both system and cellular levels. The scientific objective of my research is to determine the cellular mechanism underlying opioid modulation of dendritic spines. My present research is funded by a National Institute on Drug Abuse (NIDA) R01 grant (DA020582) which contains three Specific Aims: (1) to further characterize the roles of MORs and their internalization in postsynaptic modulation of dendritic spines. (2) To identify and determine the Rho GTPase that mediates opioid modulation of dendritic spines. (3) To identify and determine the protein kinase(s) that mediate opioid modulation of dendritic spines. This K02 award will allow me to significantly reduce my teaching hours so that I can devote more of my effort to research (increased from 50% to 75% of total effort). I will use the extra 25% effort to strengthen and broaden the R01 project in two ways: (1) enhancing the Specific Aims 1 and 3 with newly proposed experiments using brain slices prepared from different regions of the brain including the striatum, ventral tegmental area (VTA), frontal neocortex and hippocampus: Our recent unexpected results reveal that MORs could exist in either pre or post-synaptic sites depending upon the types of neurons and the region of the brain. Therefore, to better understand drug addiction, we will investigate how opioids modulate excitatory synaptic transmissions in different regions of the brain. (2) Learning and using the two-photon microscopic technique to investigate AMPA receptor trafficking during chronic opioid exposure: Chronic treatment of morphine decreases the amplitude of miniature EPSCs, suggesting a removal of post-synaptic AMPA receptors. The objective of this approach is to lay a solid foundation for the next future research plan when my funded R01 grant is up for competitive renewal. This next future research plan is to clarify the cellular mechanism underlying the trafficking of AMPA receptors during opioid exposure. In addition, this K02 award will also allow me to devote extra effort to my training in opioid pharmacology. I will attend seminars and meetings in the Department of Neuroscience and the NIDA funded Basic Center for Molecular and Cellular Biology of Drug Abuse at the University of Minnesota. I will regularly attend the NIDA funded summer courses at Cold Spring Harbor and participate in national and international scientific meetings of neuroscience and pharmacology.