Dopaminergic Mechanisms of Kappa Opioid Receptor-Induced Potentiation of Cocaine

描述（由申请方提供）：人类κ阿片受体（KOR）的药理学激活引起烦躁不安的报告，啮齿动物中激动剂或应激诱发的强啡肽释放引起的KOR激活引起厌恶。KOR激活的这些焦虑/厌恶效应已显示出增加可卡因的奖励效应，增加药物自我给药，并恢复熄灭的药物寻求行为。负责KOR依赖性厌恶和可卡因奖赏增强的细胞和分子机制尚未完全了解，但更好的理解可能会提出新的治疗方法来治疗和预防与压力有关的疾病，包括某些形式的药物成瘾。证据强烈支持KOR依赖性抑制多巴胺（DA）释放的作用，在丘脑核（NAc）和KOR诱导的p38丝裂原活化蛋白激酶（MAPK）的激活。我们建议了解如何KOR激活和KOR诱导的p38 MAPK激活，无论是通过应激诱导的强啡肽释放在腹侧被盖区（VTA）和NAc或全身给药的选择性KOR激动剂，结果在增强可卡因的奖励作用。为了实现这些目标，我们提出：1）比较KOR诱导的可卡因条件性位置偏爱增强的信号转导途径使用快速扫描循环伏安法（FSCV）测量KOR（可卡因-CPP）对KOR激活和随后给予可卡因对NAc中刺激的DA释放的影响，和2）测量KOR诱导的可卡因-CPP的增强和KOR介导的与可卡因-CPP的相互作用。在动物中使用FSCV诱导DA释放的改变，其中功能性KOR活性已经选择性地恢复到KOR敲除（KO）动物的VTA。 公共卫生相关性：虽然压力反应通常是保护性的，但反复和不可控制的压力暴露会增加情绪障碍和药物成瘾的风险。在开发出更好的治疗压力相关疾病的方法之前，需要了解这些不良反应的机制。大脑中强啡肽/κ阿片系统的激活已被证明编码应激的烦躁效应。拟议的研究将测试这一假设，即通过激活KOR和KOR诱导的p38 MAPK激活来调节多巴胺释放有助于应激诱导的成瘾性药物的奖励性质的增强。

DESCRIPTION (provided by applicant): Pharmacological activation of kappa opioid receptors (KOR) in humans elicits reports of dysphoria, and KOR activation by agonists or by stress-evoked dynorphin release in rodents produces aversion. These dysphoric/aversive effects of KOR activation have been shown to increase the rewarding effects of cocaine, increase drug self-administration, and reinstate extinguished drug seeking behaviors. The cellular and molecular mechanisms responsible for KOR-dependent aversion and potentiation of cocaine reward are not fully understood, but a better understanding may suggest new therapeutic approaches to the treatment and prevention of stress-related diseases including some forms of drug addiction. Evidence strongly supports a role for KOR-dependent inhibition of dopamine (DA) release in the nucleus accumbens (NAc) and KOR-induced activation of p38 mitogen-activated protein kinase (MAPK). We propose to understand how KOR activation and KOR-induced activation of p38 MAPK, either by stress-induced dynorphin release in the ventral tegmental area (VTA) and NAc or by systemic administration of a selective KOR agonist, results in potentiation of the rewarding effects of cocaine. To accomplish these aims we propose 1) to compare the signal transduction pathways underlying KOR-induced potentiation of cocaine-conditioned place preference (cocaine-CPP) to the effects of KOR activation and subsequent administration of cocaine on stimulated DA release in the NAc using fast-scan cyclic voltammetry (FSCV) and 2) to measure KOR-induced potentiation of cocaine-CPP and KOR- mediated interactions with cocaine-induced alterations of DA release using FSCV in animals in which functional KOR activity has been selectively restored to the VTA of KOR knockout (KO) animals. PUBLIC HEALTH RELEVANCE: Although the stress response is generally protective, repeated and uncontrollable stress exposure can increase the risks of mood disorders and drug addiction. The mechanisms underlying these adverse effects need to be understood before better treatments for stress-related diseases can be developed. Activation of the dynorphin/kappa opioid systems in brain has been shown to encode the dysphoric effects of stress. The proposed studies would test the hypothesis that regulation of dopamine release by activation of KOR and KOR-induced activation of p38 MAPK contributes to the stress-induced potentiation of the rewarding properties of addictive drugs.