Dopaminergic Mechanisms of Kappa Opioid Receptor-Induced Potentiation of Cocaine

描述（由申请人提供）：人类kappa阿片受体（KOR）的药理激活引起烦躁不安的报告，在啮齿动物中，通过激动剂或应激诱发的运动啡释放激活KOR会产生厌恶。这些KOR激活的不安/厌恶效应已被证明可以增加可卡因的奖励效应，增加药物自我给药，并恢复已消失的药物寻求行为。目前尚不完全了解导致依赖于kors的厌恶和可卡因奖励增强的细胞和分子机制，但更好的理解可能为治疗和预防包括某些形式的药物成瘾在内的压力相关疾病提供新的治疗方法。证据强烈支持kor依赖性抑制伏隔核（NAc）多巴胺（DA）释放和kor诱导的p38丝裂原活化蛋白激酶（MAPK）活化的作用。我们提出了解KOR激活和KOR诱导的p38 MAPK激活，无论是通过应激诱导的腹侧被皮层（VTA）和NAc的dynorphin释放，还是通过选择性KOR激动剂的全身管理，都能增强可卡因的奖励作用。为了实现这些目标，我们提出：1)使用快速扫描循环伏安法（FSCV）比较KOR诱导的可卡因条件位置偏好（可卡因- cpp）增强的信号转导途径与KOR激活和随后给药可卡因对NAc中受刺激的DA释放的影响；2)在动物中使用FSCV测量KOR诱导的可卡因- cpp增强和KOR介导的相互作用与可卡因诱导的DA释放改变功能性KOR活性被选择性地恢复到KOR基因敲除（KO）动物的VTA。

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.