Inhibiting P13K p110B to block cocaine-induced habits and drug seeking

抑制 P13K p110B 以阻止可卡因诱发的习惯和药物寻求

基本信息

批准号：
10318954
负责人：
Shannon Leigh Gourley
金额：
$ 39.88万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-03-01 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10318954
关键词：
1-Phosphatidylinositol 3-Kinase Adolescence Adolescent Adult Anatomy Behavior Behavioral Catalytic Domain Clinical Cocaine Complex Corpus striatum structure Coupled Crystallization Decision Making Dendritic Spines Development Disinhibition Dopamine Dopamine D2 Receptor Dopamine Receptor Drug Experimentation Drug Use Disorder Environment Exposure to FRAP1 gene Family Fragile X Syndrome Gene Silencing Goals Guanosine Triphosphate Phosphohydrolases Habits Human Individual Infusion procedures Intraventricular Knowledge Learning Life Long-Term Depression Medial Mediating Membrane Memory Modeling Morphology N-Methyl-D-Aspartate Receptors Nature Neurobiology Neurons Outcome Pharmaceutical Preparations Pharmacotherapy Phosphatidylinositols Prefrontal Cortex Reporting Second Messenger Systems Signal Transduction Site Stimulus Structure Sum System Techniques Testing Viral base cell type cocaine exposure density drug of abuse excitatory neuron experimental study inhibitor knock-down neuron development novel strategies overexpression postnatal development psychostimulant receptor receptor-mediated signaling resilience response treatment strategy young adult

项目摘要

SUMMARY PI3-kinase (PI3K) is a membrane-associated signaling complex that phosphorylates phosphoinositides, second messengers that regulate neuronal development, survival, and plasticity. In 2002, Izzo et al. reported that intraventricular PI3K inhibition blocks the expression of cocaine-induced psychomotor sensitization (Nature Neurosci.). Subsequent studies indicated that repeated cocaine exposure can increase PI3K activity in the medial prefrontal cortex (mPFC). Nevertheless, causal relationships between mPFC PI3K and cocaine- induced behavioral sequelae remain unconfirmed. We will directly manipulate the PI3K subunit p110β to mitigate stimulus-elicited habits following cocaine. p110β is one of the four PI3K catalytic subunits, and it is highly expressed throughout postnatal development and in adulthood. We find that reduction of Pik3cb, encoding p110β, broadly throughout the mPFC blocks stimulus-elicited habits and locomotor sensitization following cocaine exposure during adolescence or young adulthood. These are periods of considerable drug experimentation in humans. In Aim 1, we will use viral-mediated gene silencing to identify specific mPFC subregions responsible for the “protective” consequences of Pik3cb inhibition. One widely-reported consequence of repeated cocaine exposure is an imbalance in dopamine receptor- mediated signaling, favoring D1-family Gs-coupled, at the expense of D2-family Gi-coupled, systems. D1 stimulation activates PI3K and is a likely mechanism by which psychostimulants strengthen habit-based behavior. Overexpression of Drd1 in the mPFC decreases D2 expression in the downstream striatum, suggesting that normalization of mPFC D1-mediated signaling following cocaine could engage striatal D2 systems. In Aim 2, we will test the hypothesis that Pik3cb inhibition in the mPFC creates a permissive environment for dorsomedial striatal D2-dependent goal-directed response strategies. Cocaine can induce activity-dependent dendritic spine proliferation in the mPFC. Meanwhile, inhibiting PI3K p110β can normalize aberrant dendritic spine proliferation in models of Fragile X Syndrome. Thus, inhibiting p110β could conceivably correct cocaine-induced spinogenesis. Further, PI3K p110δ and γ regulate RhoA GTPase-dependent neuronal contraction and NMDA receptor-dependent long-term depression, respectively. In Aim 3, we will test the hypothesis that inhibiting p110β and δ will correct dendritic spine densities and block habits following cocaine, while p110γ inhibition could exacerbate cocaine’s influence. Our findings indicate that p110β blockade confers certain behavioral resiliencies to cocaine. The proposed studies will crystallize anatomical mechanisms and cyto-structural consequences. Knowledge gained from these experiments could advance treatment strategies for drug use disorders, given that subunit-selective inhibitors may have more favorable clinical profiles than broad-spectrum PI3K blockade.

概括 PI3-激酶（PI3K）是一种与膜相关的信号传导复合物，可磷酸化磷酸化肌醇，，磷酸化肌醇，调节神经元发育，生存和可塑性的第二个使者。 2002年，Izzo等。报告脑室内PI3K抑制阻碍了可卡因诱导的心理敏感性敏感性的表达（自然神经）。随后的研究表明，重复可卡因暴露会增加PI3K活性中位前额叶皮层（MPFC）。然而，MPFC PI3K与可卡因之间的因果关系 - 诱导的行为后遗症仍未得到证实。我们将直接操纵PI3K亚基P110β至可卡因后减轻刺激引诱的习惯。 P110β是四个PI3K催化亚基之一，并且在产后均高度表达发展和成年。我们发现PIK3CB的降低，编码P110β，广泛地在整个过程中 MPFC在可卡因暴露期间可卡因暴露后的刺激引诱的习惯和运动敏感性青少年或成年。这些是人类中考虑药物实验的时期。目标 1，我们将使用病毒介导的基因沉默来确定负责该的特定MPFC子区域 PIK3CB抑制作用的“保护性”后果。重复可卡因暴露的一个广泛报告的结果是多巴胺受体的不平衡介导的信号传导，有利于D1家庭的GS耦合，以D2-family GI耦合为代价。 D1 刺激激活PI3K，是一种可能通过这种机制来加强基于习惯的机制行为。 MPFC中DRD1的过表达在下游纹状体中降低D2的表达，表明可卡因后MPFC D1介导的信号传导的归一化可以参与纹状体D2 系统。在AIM 2中，我们将检验以下假设：MPFC中的PIK3CB抑制作用会产生允许性背侧纹状体D2依赖性目标指导响应策略的环境。可卡因可以在MPFC中诱导活性依赖性树突状脊柱增殖。平均，抑制 PI3KP110β可以使易碎X综合征模型中的异常树突状脊柱增殖标准化。那，抑制p110β可以想象可以纠正可卡因诱导的旋转发生。此外，PI3KP110δ和γ调节 RhoA GTPase依赖性神经元收缩和NMDA接收器依赖性长期抑郁症，在AIM 3中，我们将测试以下假设：抑制p110β和δ将纠正树突状脊柱可卡因之后的密度和阻滞习惯，而p110γ的抑制作用可能加剧可卡因的影响。我们的发现表明，p110β封锁承认对可卡因的某些行为振态。提议研究将结晶解剖机制和细胞结构后果。从中获得的知识考虑到亚基选择性，这些实验可以提高药物使用障碍的治疗策略抑制剂可能比广谱PI3K封锁具有更有利的临床特征。