Dorsal striatal phosphodiesterase 10A and compulsive ethanol use

背侧纹状体磷酸二酯酶 10A 和强迫性乙醇使用

基本信息

批准号：
10329951
负责人：
ERIC P ZORRILLA
金额：
$ 39.94万
依托单位：
SCRIPPS RESEARCH INSTITUTE, THE
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-01-15 至 2025-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10329951
关键词：
Adenylate Cyclase Affective Affinity Chromatography Alcohol abuse Alcohol consumption American Behavior Behavioral Behavioral Genetics Chronic Corpus striatum structure Cyclic AMP Cyclic AMP-Dependent Protein Kinases Cyclic GMP Data Disease Dorsal Dose Enzymes Ethanol Extinction (Psychology)Gene Activation Genes Genetic Guanylate Cyclase Human Human Genetics Immediate-Early Genes Knock-out Light Link LoxP-flanked allele Membrane Mental disorders Modeling Molecular Motor Neurobiology Neurons Nucleus Accumbens Pathway interactions Persons Pharmacology Protein Isoforms RNA Splicing Rattus Relapse Resistance Ribosomes Role Self Administration Social Interaction Testing Therapeutic Tissues Translating Viral Work alcohol behavior alcohol use disorder cost differential expression drinking drinking behavior economic behavior economic evaluation genetic variant inhibitor insight knock-down lipophilicity loss of function motor behavior multidisciplinary new therapeutic target novel phosphoric diester hydrolase psychogenetics putamen reinforcer rumination small hairpin RNA vapor

Adenylate Cyclase Affective Affinity Chromatography Alcohol abuse Alcohol consumption American Behavior Behavioral Behavioral Genetics Chronic Corpus striatum structure Cyclic AMP Cyclic AMP-Dependent Protein Kinases Cyclic GMP Data Disease Dorsal Dose Enzymes Ethanol Extinction (Psychology)Gene Activation Genes Genetic Guanylate Cyclase Human Human Genetics Immediate-Early Genes Knock-out Light Link LoxP-flanked allele Membrane Mental disorders Modeling Molecular Motor Neurobiology Neurons Nucleus Accumbens Pathway interactions Persons Pharmacology Protein Isoforms RNA Splicing Rattus Relapse Resistance Ribosomes Role Self Administration Social Interaction Testing Therapeutic Tissues Translating Viral Work alcohol behavior alcohol use disorder cost differential expression drinking drinking behavior economic behavior economic evaluation genetic variant inhibitor insight knock-down lipophilicity loss of function motor behavior multidisciplinary new therapeutic target novel phosphoric diester hydrolase psychogenetics putamen reinforcer rumination small hairpin RNA vapor

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项目摘要

ABSTRACT Alcohol use disorder (AUD) is a chronic, relapsing disorder that afflicts 29% of Americans in their lifetime1,2, is disabling2 and increases mortality3. New drug targets and neurobiological insight for AUD are needed. Compulsive drinking putatively involves a transition to dorsal (vs. ventral) striatal control over drinking and a relative underactivity of indirect pathway MSNs (iMSNs) that enable adaptive behavioral selection in contrast to overactive direct pathway MSNs (dMSNs) that drive drinking behaviors. Compulsive drinking also involves a shift to dorsal (caudate-putamen) from ventromedial (nucleus accumbens) striatal control of ethanol-related behavior. Guided by novel preliminary data, this multidisciplinary project tests the overarching hypothesis that decreasing dorsal striatal phosphodiesterase 10A (PDE10A) type 2 activity in indirect medium spiny neurons (MSN) reduces compulsive drinking. In 4 Specific Aims, we seek to fill molecular, circuitry, pharmacological, behavioral and human genetic gaps in our understanding of the role of PDE10A isoforms in activation of distinct striatal MSN pathways and compulsive drinking. Aim 1 seeks to identify translatable PDE10A inhibitors that reduce compulsive-like ethanol self-administration, with consideration of enzyme off-rate, lipophilic efficiency and neuroactivational effects on distinct MSN circuits. Aim 2 will intersect Adora2a-Cre rats with expression of a floxed, validiated PDE10A shRNA to knockdown dorsal iMSN PDE10A in order to determine this the role of caudate-putamen PDE10A in iMSNs in escalated and aversion-resistant self- administration. Aim 3 seeks to determine the causal role of the striatal-restricted, membrane-associated PDE10A2 isoform in compulsive-like ethanol intake. Finally, Aim 4 seeks PDE10A gene variants that associate with problematic alcohol use as well as their functional, expression, and psychiatric genetic correlates. The collective work of our assembled, multidisciplinary collaborative team will shed light on the neurobiological and genetic role of PDE10A isoforms in distinct striatal circuits and compulsive drinking behaviors as well as the potential impact of novel translatable PDE10A inhibitors to treat AUD.

抽象的酒精使用障碍（AUD）是一种慢性复发障碍，在其一生中遭受29％的美国人的痛苦1,2，是禁用2并增加死亡率3。需要新的药物靶标和神经生物学见解。强迫性饮酒预定涉及向背侧（与腹侧）纹状体控制的过渡和间接途径MSN（IMSN）的相对不足，与适应性行为选择相比驱动饮酒行为的过度活动直接通路MSN（DMSN）。强迫性饮酒也涉及从乙醇相关的腹侧（伏隔核）纹状体对照转向背侧（尾状抗耐药型）行为。在新的初步数据的指导下，这个多学科项目检验了总体假设间接培养基神经元中降低背纹状体磷酸二酯酶10a（PDE10A）2型活性（MSN）减少强迫性饮酒。在4个特定目标中，我们寻求填充分子，电路，药理，行为和人类遗传差距在我们对PDE10A同工型在激活中的作用的理解中独特的纹状体MSN途径和强迫性饮酒。 AIM 1试图识别可翻译的PDE10A 减少强迫性乙醇自我给药的抑制剂，考虑到酶离速率，亲脂性效率和神经激活对不同MSN电路的影响。 AIM 2将与Adora2a-cre相交大鼠表达了flox的，受过验证的PDE10A shRNA以敲除背IMSN PDE10A 确定这一点在升级和抗厌恶的自我中，尾状毒剂pde10a在IMSN中的作用行政。 AIM 3旨在确定纹状体限制的膜相关的因果作用强迫性乙醇摄入中的PDE10A2同工型。最后，AIM 4寻求PDE10A基因变体与有问题的酒精使用以及它们的功能，表达和精神遗传相关。我们组装的多学科合作团队的集体工作将阐明 PDE10A同工型在不同的纹状体回路和强迫性饮酒中的神经生物学和遗传作用行为以及新型可翻译PDE10A抑制剂治疗AUD的潜在影响。