Plasticity of Kappa Opioid Function in Reward Circuitry

描述(申请人提供)：在阐明阿片肽和受体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，大部分的重点都放在了Mu阿片(MOP)受体上，因为它是吗啡及其类似物强大的止痛和成瘾作用的靶标。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战略。 Kappa阿片(Kop)受体广泛分布于中枢神经系统，与MOP受体相似，包括与动机和奖赏相关的皮质下结构。KOP受体激动剂具有强大的行为效应，这通常与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滥用药物相关的行为，KOP受体的基因与成瘾行为有关。KOP受体似乎在奖赏回路中发挥调节作用，使其成为治疗成瘾的诱人靶点。最后，KOP系统是高度可塑性的：KOP受体及其内源性配体强啡肽在接触滥用药物后都会发生变化。事实上，这一系统的可塑性为成瘾的发展提供了一种看似合理的机制。这一证据表明，要完全理解阿片类药物在奖赏回路中的作用，取决于阐明强啡肽和Kop受体在奖赏回路中的作用。 尽管KOP受体具有医学意义，但它既是一种潜在的机制，也是治疗成瘾的可能靶点，关于KOP受体的基本功能以及这些功能是如何被滥用药物改变的，仍有许多需要了解。本研究旨在研究精神刺激剂对伏隔核(NAC)壳内kappa阿片受体功能的调节作用。具体地说，我们建议检验这一假设，即精神刺激剂暴露产生多巴胺依赖的NAC中强啡肽释放的增加，从而导致Kop受体介导的谷氨酸释放抑制的下调。特定的AIMS将测试这种效应背后的细胞外和细胞内机制，以及测试这种效应对谷氨酸释放的特异性。

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.