Dopaminergic Mechanisms of Kappa Opioid Receptor-Induced Potentiation of Cocaine

描述(申请人提供)：在人类中，kappa阿片受体(KOR)的药理激活会引起焦虑症的报道，而激动剂或应激诱发的强啡肽释放在啮齿类动物中激活KOR会产生厌恶情绪。KOR激活的这些焦虑感/厌恶效应已被证明增加了可卡因的奖赏效应，增加了药物自我给药，并恢复了已熄灭的药物寻找行为。KOR依赖的厌恶和增强可卡因奖励的细胞和分子机制尚不完全清楚，但更好的理解可能会为治疗和预防应激相关疾病，包括某些形式的药物成瘾提供新的治疗方法。有证据有力地支持KOR依赖抑制伏核(NAC)中多巴胺(DA)的释放以及KOR诱导的p38丝裂原活化蛋白激酶(MAPK)的激活。我们建议了解KOR激活和KOR诱导的p38MAPK激活，无论是通过应激诱导腹侧被盖区(VTA)和NAC的强啡肽释放，还是通过全身应用选择性KOR激动剂，导致增强可卡因的奖赏效应。为了达到这些目的，我们建议1)使用快速扫描循环伏安法(FSCV)比较KOR诱导的可卡因条件性位置偏爱(Cocaine-CPP)增强(Cocaine-CPP)的信号转导途径与KOR激活和随后给予可卡因对NAC中刺激的DA释放的影响。2)利用FSCV在KOR基因敲除(KO)动物的VTA中测量KOR诱导的可卡因-CPP的增强和KOR介导的与可卡因诱导的DA释放的变化。

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.