Plasticity of Kappa Opioid Function in Reward Circuitry

描述（由申请人提供）：在阐明肽和受体的阿片样物质家族的功能方面已经取得了广泛的进展。可以理解的是，到目前为止，大部分重点都放在μ阿片（MOP）受体上，因为它是吗啡及其同系物强大镇痛和成瘾作用的靶点。然而，我们对MOP的中心作用的广泛了解并没有导致治疗药物成瘾的新策略。 κ阿片样物质（KOP）受体在整个CNS中具有广泛的分布，这在很大程度上与MOP受体的分布相似，包括与动机和奖励相关的皮质下结构。KOP受体激动剂具有强大的行为效应，其通常与MOPs的行为效应相反。 例如，MOP受体激动剂DAMGO在大鼠中产生条件性位置偏爱，而KOP受体激动剂U69593产生条件性位置厌恶。此外，KOP受体激动剂明显改变与药物滥用相关的行为，并且KOP受体的基因与成瘾行为有关。KOP受体似乎在奖赏回路中起着调节作用，使其成为治疗成瘾的诱人目标。最后，KOP系统是高度可塑的：KOP受体及其内源性配体强啡肽在暴露于滥用药物后发生改变。事实上，这个系统的可塑性为成瘾的发展提供了一个合理的机制。这一证据表明，阿片类药物在奖赏回路中的作用的完整理解取决于阐明强啡肽和KOP受体在奖赏回路中的作用。 尽管它的医学意义，无论是作为一个潜在的机制，以及作为一个可能的目标，用于治疗成瘾，许多仍然是了解KOP受体的基本功能，以及这些功能是如何被滥用药物的修改。本研究的目的是探讨在暴露于精神兴奋剂后，κ阿片受体在丘脑核壳（NAc）的功能调节。具体而言，我们建议测试的假设，即精神兴奋剂暴露产生多巴胺依赖性增加强啡肽释放的NAC，这会导致下调的KOP受体介导的抑制谷氨酸释放。具体的目标将测试细胞外和细胞内的机制，这种影响，以及测试的特异性谷氨酸释放的影响。

DESCRIPTION (provided by applicant): There has been extensive progress on elucidating the function of the opioid family of peptides and receptors. Understandably, much of the emphasis to date has been on the mu opioid (MOP) receptor, since it is the target of the powerful analgesic and addictive effects of morphine and it congeners. However, our extensive knowledge of the central actions of MOP has not led to new strategies for the treatment of drug addiction. Kappa opioid (KOP) receptors have a wide distribution throughout the CNS that largely parallels that of MOP receptors including subcortical structures associated with motivation and reward. KOP receptor agonists have powerful behavioral effects, which are typically opposed to the behavioral effects of MOPs. For example, while the MOP receptor agonist DAMGO produces conditioned place preference in rats, the KOP receptor agonist U69593 produces conditioned place aversion. Moreover, KOP receptor agonists clearly alter behaviors associated with drugs of abuse and the gene for the KOP receptor has been linked to addictive behaviors. KOP receptors appear to play a regulatory role in reward circuitry, making them an inviting target for the treatment of addiction. Finally, the KOP system is highly plastic: both KOP receptors and its endogenous ligand, dynorphin are altered following exposure to drugs of abuse. In fact, the plasticity of this system provides a plausible mechanism for the development of addiction. This evidence suggests that a complete understanding of opioid actions in reward circuitry depends upon elucidating the action of dynorphin and KOP receptors in reward circuitry. Despite its medical significance, both as an underlying mechanism as well as being a possible target for the treatment of addiction, much remains to be understood about the KOP receptor's basic functions as well as how those functions are modified by drugs of abuse. This proposal aims to examine the regulation of kappa opioid receptor function in the nucleus accumbens (NAc) shell following exposure to psychostimulants. Specifically, we propose to test the hypothesis that psychostimulant exposure produces a dopamine dependent increase in dynorphin release in the NAc, which causes a down-regulation of the KOP receptor-mediated inhibition of glutamate release. Specific aims will test both the extracellular and intracellular mechanisms underlying this effect, as well as testing the specificity of the effect on glutamate release.