Role of sigma receptors in ethanol reinforcement

西格玛受体在乙醇强化中的作用

基本信息

批准号：
7324074
负责人：
VALENTINA SABINO
金额：
$ 7.76万
依托单位：
SCRIPPS RESEARCH INSTITUTE, THE
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-12-01 至 2009-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7324074
关键词：
Agonist Alcohol abuse Alcohol consumption Alcoholism Alcohols Animal Model Animals Area Attenuated Behavioral Behavioral Model Binding Sites Brain Brain region Chronic Cocaine Commit Communities Dependence Development Plans Disruption Drug abuse Ethanol Ethanol dependence Exposure to Genes Genetic Polymorphism Glutamates Human Intake Ligands Mental disorders Mentors Methamphetamine Methods Modeling Molecular Mus Neurosciences Neurotransmitters Numbers Personal Satisfaction Pharmaceutical Preparations Physiological Play Property Rattus Reporting Research Research Institute Rewards Role Self Administration Signal Transduction Pathway Specificity Structure System Techniques Therapeutic Wild Type Mouse alcohol effect alcohol exposure alcohol preferring rats alcohol reinforcement alcohol reward base career insight mutant mouse model noradrenergic novel post-doctoral training preference protein expression receptor receptor expression research study response sigma receptors tool vapor

项目摘要

Summary: The application proposes a career development plan for Dr. Valentina Sabino, a pharmacologically-trained post-doctoral fellow committed to a research career in ethanol addiction aimed towards understand its molecular basis. The applicant will be mentored by Dr. George Koob in behavioral neuroscience methods and animal models of alcoholism and co-mentored by Dr. Pietro Sanna in immunohistochemical and molecular techniques. The project, to be conducted at The Scripps Research Institute in the rich neuroscience community of San Diego, concerns sigma receptors, unique mammalian binding sites that modulate other neurotransmitter systems and which are richly expressed in limbic brain structures. Pharmacological studies indicate that sigma receptors modulate actions of cocaine and methamphetamine. Recently, sigma receptors also have been proposed to modulate motivating properties of ethanol, consistent with findings of sigma receptor polymorphisms in human alcoholism. Until very recently, however, the understanding of sigma receptor systems had been hampered by the unavailability of specific, subtype-selective ligands or of mutant mouse models that lack sigma receptor subtypes. Furthermore, the role of sigma receptors in voluntary intake or self-administration of ethanol are unknown. The present multipdisciplinary application uses behavioral, pharmacologic, and molecular techniques to determine the modulatory role of sigma receptorswith subtype specificity on ethanol reward and reinforcementin distinct models of excessive ethanol consumption. Two models of excess ethanol intake will be studied in Specific Aims 1 and 3 -- genetically selected alcohol-preferring rats and withdrawn outbred rats made dependent during chronic, intermittent exposure to ethanol vapor, emphasizing positive and negative reinforcing properties of ethanol, respectively. Ethanol self-administration will be pharmacologically modulated (in Specific Aim 1), through the administration of novel a receptor ligands, and molecularly (in Specific Aim 2), through the use of o-1 receptor KO mice. The impact of chronic exposure to ethanol and of innate preference for ethanol on o receptor protein expression in discrete limbic brain regions will be investigated in Specific Aim 3. Relevance: The project will define the physiologic and potential therapeutic relevance of an undercharacterized modulatory receptor system for alcohol abuse and dependence.

摘要：该申请提出了瓦伦蒂娜·萨比诺（Valentina Sabino）博士的职业发展计划受到药理训练的博士后研究员致力于乙醇成瘾研究职业要了解其分子基础。申请人将由乔治·科布（George Koob）博士在行为中指导神经科学方法和酒精中毒的动物模型，并由Pietro Sanna博士合作免疫组织化学和分子技术。该项目将在Scripps Research进行圣地亚哥丰富的神经科学社区的研究所，涉及Sigma受体，独特的哺乳动物调节其他神经递质系统并在边缘大脑中丰富表达的结合位点结构。药理学研究表明，Sigma受体调节可卡因和甲基苯丙胺。最近，还提出了Sigma受体来调节乙醇，与人类酒精中毒中Sigma受体多态性的发现一致。直到最近，然而，特定的特异性不可用，对Sigma受体系统的理解受到了阻碍亚型选择配体或缺乏Sigma受体亚型的突变小鼠模型。此外， Sigma受体在自愿摄入量或乙醇自我给药中的作用尚不清楚。现在多学科应用使用行为，药理学和分子技术来确定 Sigma受体与亚型特异性对乙醇奖励和增强素的调节作用过度乙醇消耗的模型。将研究两种过多的乙醇摄入量的模型目的1和3-基因选择的酒精挑选的大鼠和撤回的大鼠依赖于在慢性，间歇性暴露于乙醇蒸气期间，强调积极和阴性增强乙醇的特性。乙醇自我给药将受到药理调节（在特定目标1）通过给予新型A受体配体，并分子（在特定目标2中），通过使用O-1受体KO小鼠。长期暴露于乙醇和先天的影响在离散边缘脑区域中，对乙醇对O受体蛋白表达的偏爱将在中特定目的3。相关性：该项目将定义一个生理和潜在的治疗相关性酗酒和依赖性的特色调节受体系统不足。

项目成果

期刊论文数量（9）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

A modified adjusting delay task to assess impulsive choice between isocaloric reinforcers in non-deprived male rats: effects of 5-HT₂A/C and 5-HT₁A receptor agonists.

DOI：
10.1007/s00213-011-2517-8
发表时间：
2012-01
期刊：
PSYCHOPHARMACOLOGY
影响因子：
3.4
作者：
Blasio, Angelo;Narayan, Aditi R.;Kaminski, Barbara J.;Steardo, Luca;Sabino, Valentina;Cottone, Pietro
通讯作者：
Cottone, Pietro

Sigma receptor-induced heavy drinking in rats: Modulation by the opioid receptor system.

DOI：
10.1016/j.pbb.2020.172914
发表时间：
2020-05
期刊：
PHARMACOLOGY BIOCHEMISTRY AND BEHAVIOR
影响因子：
3.6
作者：
Valenza, Marta;Blasio, Angelo;DiLeo, Alyssa;Cottone, Pietro;Sabino, Valentina
通讯作者：
Sabino, Valentina

DOI：
10.1016/j.bbr.2015.10.013
发表时间：
2016-01-15
期刊：
Behavioural brain research
影响因子：
2.7
作者：
Valenza M;DiLeo A;Steardo L;Cottone P;Sabino V
通讯作者：
Sabino V

The inverse agonist of CB1 receptor SR141716 blocks compulsive eating of palatable food.

DOI：
10.1111/adb.12056
发表时间：
2014-09
期刊：
Addiction biology
影响因子：
3.4
作者：
Dore R;Valenza M;Wang X;Rice KC;Sabino V;Cottone P
通讯作者：
Cottone P

Sigma-1 receptor mediates acquisition of alcohol drinking and seeking behavior in alcohol-preferring rats.

DOI：
10.1016/j.bbr.2015.03.065
发表时间：
2015
期刊：
BEHAVIOURAL BRAIN RESEARCH
影响因子：
2.7
作者：
Blasio, Angelo;Valenza, Marta;Lyer, Malliga R.;Rice, Kenner C.;Steardo, Luca;Hayashi, T.;Cottone, Pietro;Sabino, Valentina
通讯作者：
Sabino, Valentina