Plasticity of Kappa Opioid Function in Reward Circuitry

奖励回路中卡帕阿片类药物功能的可塑性

• 批准号: 7039153
• 负责人: GREGORY Olaf HJELMSTAD
• 金额: $ 23.76万
• 依托单位: ERNEST GALLO CLINIC AND RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-04-01 至 2008-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7039153
• 关键词: central nervous system stimulants; dopamine receptor; dynorphins; electrophysiology; glutamate transporter; laboratory rat; neural plasticity; neural transmission; neurotransmitter antagonist; nucleus accumbens; operant conditionings; opioid receptor; receptor expression; reinforcer; substance abuse related behavior; synapses; voltage /patch clamp

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.

描述（由申请人提供）：在阐明阿片类肽和受体家族的功能方面取得了广泛的进展。可以理解的是，迄今为止的许多重点都放在了阿片类药物（MOP）受体上，因为它是吗啡和IT同类物的强大镇痛和成瘾作用的目标。但是，我们对拖把的核心行为的广泛了解并未导致对吸毒成瘾的新策略。 Kappa阿片类药物（KOP）受体在整个中枢神经系统中具有广泛的分布，这在很大程度上与MOP受体（包括与动机和奖励相关的皮质下结构）相似。 KOP受体激动剂具有强大的行为效应，通常与MOP的行为影响相反。 例如，尽管拖把受体激动剂Damgo在大鼠中产生条件的位置偏好，但KOP受体激动剂U69593产生条件的位置厌恶。此外，KOP受体激动剂显然改变了与滥用药物相关的行为，而KOP受体的基因与成瘾行为有关。 KOP受体似乎在奖励电路中起着调节作用，使其成为诱人的成瘾治疗目标。最后，KOP系统是高度塑性的：在暴露于滥用药物后，KOP受体及其内源性配体都会改变。实际上，该系统的可塑性为成瘾发展提供了合理的机制。该证据表明，对奖励电路中阿片类动作的完全理解取决于阐明奖励电路中驱动器和KOP受体的作用。 尽管它具有医学意义，但作为基本机制，也是成瘾治疗的可能目标，但有关KOP受体的基本功能以及如何通过滥用药物来修饰这些功能仍有很多待理解。该提案旨在检查暴露于精神刺激剂后伏隔核（NAC）壳中的Kappa阿片受体功能的调节。具体而言，我们建议检验以下假设：NAC中精神刺激性暴露会导致多巴胺依赖性增长，这导致了KOP受体介导的谷氨酸释放抑制作用的下调。具体目的将测试这种作用的细胞外和细胞内机制，并测试对谷氨酸释放作用的特异性。