ORPHANIN SYSTEM--ROLE IN STRESS AND ADDICTION

这项建议的重点是研究新发现的孤啡肽/孤啡肽系统(OFQ系统)，这是一个新的肽能系统，在进化上与内源性阿片类药物有关，但具有不同的生化、解剖和功能特性。工作假设是，OFQ系统在调节应激反应的生物学、奖励机制的生物学以及压力和奖励机制之间的相互作用方面发挥作用，因为它们影响与药物相关的行为。这一假设是基于迄今为止收集到的几条解剖学和功能证据。然而，在探讨这些功能性问题之前，关于这个系统的一些基本特征仍有许多需要了解的地方。因此，这项应用建议确定应激(新颖性和限制性)是否调节OFQ或其相关受体ORL1，特别是大脑区域，并确定这些应激敏感区域中OFQ调节边缘-下丘脑-垂体-肾上腺(LHPA)轴的能力(目标I)。它探索了OFQ系统在中皮质边缘多巴胺能系统中的解剖学特征，在那里它似乎是高表达的，并解决了OFQ和ORL1是否存在于多巴胺能神经元中，以及它们是否位于调节多巴胺能传递(AIM II)的电路中。最后，在上述电路的背景下，它检查了在导致对这些药物敏感的条件下，长期给予鸦片类药物和精神刺激剂对该系统进行调节的方式。反过来，它询问OFQ是否能够在应激和非应激条件下改变药物敏化的过程(目标III)。将使用分子、解剖学和行为学工具的组合来解决这些问题。总之，这些研究不仅将阐明这一新的肽能系统的功能，而且还将为应激机制、多巴胺能机制和物质滥用之间的重要接口提供新的见解。

This proposal is focused on studying the newly discovered Orphanin/Nociceptin system (OFQ system), a new peptidergic system, evolutionarily related to the endogenous opioids but exhibiting distinct biochemical, anatomical and functional properties. The working hypothesis is that the OFQ systems plays a role in the regulation of the biology of stress responsiveness, the biology of reward mechanisms, and the interactions between stress and reward mechanisms as they impact on drug-related behavior. This hypothesis is based on several lines of anatomical and functional evidence gathered to date. However, much remains to be learned about some of the fundamental features of this system before pursuing these functional questions. Thus, this application proposes to determine whether stress (novelty and restraint) regulates OFQ or its associated receptor, ORL1, in particular brain regions, and to ascertain the ability of OFQ in these stress-sensitive regions to modulate the limbic- hypothalamo-pituitary-adrenal (LHPA) axis) (Aim I). It explores the anatomical features of the OFQ system in the context of the mesocorticolimbic dopaminergic system, where it appears to be highly expressed, and addresses the issue of whether or not OFQ and ORL1 are present within dopaminergic neurons, and whether they are located in circuits which could modulate dopaminergic transmission (Aim II). Finally, in the context of the above circuits, it examines the way this system is modulated by chronic administration of opiates and psychostimulants under conditions which lead to sensitization to these drugs. In turn, it asks whether OFQ is able to alter the course of drug sensitization in stressful and non-stressful conditions (Aim III). A combination of molecular, anatomical, and behavioral tools will be used to address these questions. Together, these studies will not only shed light on the functioning of this novel peptidergic system, but will also provide new insights on the important interface between stress mechanisms, dopaminergic mechanisms, and substance abuse.