p38 MAPK Mechanisms of Kappa Opioid-Induced Aversion

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。证据强烈支持的作用，KOR依赖性抑制多巴胺释放的伏隔核（NAc），然而，最近的证据进一步表明，强啡肽激活p38 MAPK的中缝背核（DRN）的多巴胺能神经元依赖性厌恶也是必需的。由于5-羟色胺在调节情感状态的补充作用似乎是合理的，我们建议了解如何激活p38 MAPK的KOR刺激，无论是通过应激诱导的强啡肽释放在DRN或全身管理的选择性KOR激动剂，结果在条件性的地方厌恶。为了实现这些目标，我们提出1）测量具有由PET 1启动子驱动的Cre重组酶切除的floxed p38 a MAPK的条件性敲除（CKO）小鼠中的KOR依赖性厌恶，2）评估KOR激活的p38 a MAPK对从具有正常或遗传修饰的强啡肽/KOR系统功能的游泳应激小鼠制备的突触体中的5-羟色胺转运蛋白再摄取效率的影响，和3）使用快速扫描循环伏安法测量KOR依赖性p38 MAPK激活对在体和脑切片中电诱发的5-羟色胺和多巴胺释放的影响。我们的假设是，KOR激活的厌恶效应是由5-羟色胺转运体的p38 a MAPK激活引起的NAc中多巴胺能和多巴胺能张力之间平衡的转变的结果。

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 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 release in the nucleus Accumbens (NAc), however recent evidence further suggests that dynorphin activation of p38 MAPK in the serotonergic dorsal raphe nucleus (DRN) is also required for KOR-dependent aversion. Because a complementary role of serotonin in the regulation of affective state seems plausible, we propose to understand how activation of p38 MAPK by KOR stimulation, either by stress-induced dynorphin release in the DRN or systemic administration of a selective KOR agonist, results in conditioned place aversion. To accomplish these aims we propose 1) to measure KOR-dependent aversion in conditional knockout (CKO) mice having floxed p38a MAPK excised by PET1-promoter driven Cre recombinase, 2) to assess the effects of p38a MAPK activation by KOR on serotonin transporter reuptake efficiency in synaptosomes prepared from swim stressed mice having either normal or genetically modified dynorphin/KOR system function, and 3) to measure the effects of KOR- dependent p38 MAPK activation on electrically evoked release of serotonin and dopamine in vivo and in brain slices using fast scan cyclic voltammetry. Our hypothesis is that the aversive effects of KOR activation is a consequence of a shift in the balance between serotonergic and dopaminergic tone in the NAc caused by p38a MAPK activation of the serotonin transporter.