p38 MAPK Mechanisms of Kappa Opioid-Induced Aversion

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依赖厌恶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依赖性抑制伏核(NAC)多巴胺释放的作用，然而最近的证据进一步表明，5-羟色胺能中缝背核(DRN)中强啡肽激活p38MAPK也是KOR依赖性厌恶所必需的。由于5-羟色胺在调节情感状态中的互补作用似乎是可信的，我们建议理解刺激KOR是如何激活p38MAPK的，无论是应激诱导DRN中强啡肽的释放还是全身应用选择性KOR激动剂，都会导致条件性位置厌恶。为了实现这些目标，我们建议1)测量条件基因敲除(CKO)小鼠对由PET1启动子驱动的Cre重组酶切割的P38A MAPK的依赖KOR的厌恶，2)评估KOR激活P38A MAPK对游泳应激小鼠(具有正常或转基因强啡肽/KOR系统功能的突触体)5-羟色胺转运体再摄取效率的影响，以及3)使用快速循环扫描伏安法测量KOR依赖的p38 MAPK激活对电诱导体内和脑片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于5-羟色胺转运体的P38A MAPK激活导致NAC内5-羟色胺能和多巴胺能张力之间的平衡发生变化的结果。

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.