Neuropharmacological substrates of alcohol addiction

酒精成瘾的神经药理学底物

• 批准号: 8312087
• 负责人: Scott C Steffensen
• 金额: $ 6万
• 依托单位: BRIGHAM YOUNG UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-13 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8312087
• 关键词: Abbreviations; Acute; Adenylate Cyclase; Alcohol dependence; Aminobutyric Acids; Area; Brain; Cells; Chronic; Connexins; Coupling; Data; Dependence; Dopamine; Dopamine D2 Receptor; Dopamine Receptor; Dose; Ethanol; Ethanol dependence; Evaluation; Exposure to; Frequencies; Gap Junctions; Gene Expression; Glutamates; Heroin; Homeostasis; In Vitro; Injection of therapeutic agent; Internal Capsule; Intravenous; Lesion; Link; Mediating; Membrane; Midbrain structure; Molecular; N-Methylaspartate; Neurons; Neurotoxins; Nucleus Accumbens; Opioid; Physiological; Physiology; Play; Population; Prefrontal Cortex; Principal Investigator; Property; Psychological reinforcement; Rattus; Reporting; Reproducibility; Research Design; Reverse Transcriptase Polymerase Chain Reaction; Rewards; Role; Saline; Self Administration; Self Stimulation; Sensory; Slice; Stimulus; Synapses; Synaptic Transmission; Tegmentum Mesencephali; Testing; Tissues; Training; Ventral Tegmental Area; alcohol reinforcement; alcohol reward; connexin 36; gamma-Aminobutyric Acid; in vivo; intravenous injection; mu opioid receptors; neurotoxic; receptor; response; transmission process

DESCRIPTION (provided by applicant): We have identified a homogeneous population of y-aminobutyric acid (GABA) neurons in the ventral tegmental area (VTA) that undergo adaptation in association with ethanol dependence. We have recently reported that VTA GABA neurons form part of a larger electrical network of ventral brain GABA neurons linked by connexin-36 gap junctions whose electrical coupling is enhanced by dopamine via D2 receptor-mediated activation of adenylate cyclase, and sensitive to low-dose ethanol. We hypothesize that VTA GABA neurons, and the electrical network they form, may act as unique integrators of convergent information from sensory, cortical and limbic areas subserving ethanol addiction. The overall objective of this application is to extend our evaluation of the role of this specific class of mesocorticolimbic GABA neurons in mediating the intoxicating and rewarding properties of ethanol. The core thesis underlying this proposal is that VTA GABA neurons underlie ethanol self-administration and that adaptive changes in VTA GABA neuron excitability and electrical synaptic transmission result from repeated exposure to contingent and/or non-contingent ethanol and contribute to the dysregulation of mesolimbic homeostasis that accompanies alcohol addiction. Our proposed in vivo and in vitro studies are designed to test four major hypotheses: 1) That VTA GABA neuron activity correlates with ethanol self-administration; 2) That lesioning VTA GABA neurons disrupts ethanol self-administration; 3) That gap junction transmission between VTA GABA neurons, or glutamate (GLU), GABA, or DA synaptic modulation of VTA GABA neuron gap junctions, is sensitive to ethanol; and 4) That persistent alterations in the gene expression of NMD A, non-NMDA, GABA, DA receptors, or connexin-36 gap junction proteins parallels the plasticity in synaptic adaptation that underlies the physiological manifestations of alcohol reward and dependence.

描述（由申请人提供）：我们已经确定了在腹侧被盖区（VTA）中的γ-氨基丁酸（GABA）神经元的同质群体，其经历与乙醇依赖相关的适应。我们最近报道，腹侧被盖区GABA神经元形成一个更大的电网络的腹侧脑GABA神经元连接的连接蛋白36间隙连接，其电耦合增强多巴胺通过D2受体介导的腺苷酸环化酶的激活，和敏感的低剂量乙醇。我们推测，腹侧被盖区GABA神经元，和他们形成的电网络，可能作为独特的整合器的会聚信息从感觉，皮层和边缘系统领域subserving乙醇成瘾。本申请的总体目标是扩大我们的评估的作用，这类特定的mesocorticolimbic GABA神经元介导的酒精的醉人和奖励的属性。这一建议的核心论点是，腹侧被盖区GABA神经元乙醇自我管理的基础和适应性变化的腹侧被盖区GABA神经元兴奋性和电突触传递的结果反复暴露于特遣队和/或非特遣队乙醇和促进伴随酒精成瘾的中脑边缘稳态失调。我们提出的体内和体外研究旨在验证四个主要假设：1）VTA GABA神经元活动与乙醇自我给药相关; 2）损伤VTA GABA神经元破坏乙醇自我给药; 3）VTA GABA神经元之间的间隙连接传递或谷氨酸（GLU）、GABA或DA突触调制VTA GABA神经元间隙连接对乙醇敏感;和4）NMDA、非NMDA、GABA、DA受体或连接蛋白-36间隙连接蛋白的基因表达的持续改变与突触适应中的可塑性平行，突触适应是酒精奖赏和依赖的生理表现的基础。

项目成果

The peripheral dopamine 2 receptor antagonist domperidone attenuates ethanol enhancement of dopamine levels in the nucleus accumbens.

• DOI: 10.1111/acer.14775
• 发表时间: 2022-03
• 期刊: Alcoholism, clinical and experimental research
• 作者: Obray JD;Jang EY;Klomp AM;Small CA;Richardson AP;LeBaron JJ;Lee JG;Yorgason JT;Yang CH;Steffensen SC
• 通讯作者: Steffensen SC

Cocaine disinhibits dopamine neurons in the ventral tegmental area via use-dependent blockade of GABA neuron voltage-sensitive sodium channels.

• DOI: 10.1111/j.1460-9568.2008.06479.x
• 发表时间: 2008-11
• 期刊: The European journal of neuroscience
• 作者: Steffensen SC;Taylor SR;Horton ML;Barber EN;Lyle LT;Stobbs SH;Allison DW
• 通讯作者: Allison DW

Mefloquine effects on ventral tegmental area dopamine and GABA neuron inhibition: a physiologic role for connexin-36 GAP junctions.

• DOI: 10.1002/syn.20907
• 发表时间: 2011-08
• 期刊: SYNAPSE
• 影响因子: 2.3
• 作者: Allison, David W.;Wilcox, Rebecca S.;Ellefsen, Kyle L.;Askew, Caitlin E.;Hansen, David M.;Wilcox, Jeffrey D.;Sandoval, Stephanie S.;Eggett, Dennis L.;Yanagawa, Yuchio;Steffensen, Scott C.
• 通讯作者: Steffensen, Scott C.

Dehydroepiandrosterone sulfate and estrone sulfate reduce GABA-recurrent inhibition in the hippocampus via muscarinic acetylcholine receptors.

硫酸脱氢表雄酮和硫酸雌酮通过毒蕈碱乙酰胆碱受体减少海马中 GABA 的反复抑制。

• DOI: 10.1002/hipo.20232
• 发表时间: 2006
• 期刊: Hippocampus
• 影响因子: 3.5
• 作者: Steffensen,ScottC;Jones,MarcD;Hales,Kimberly;Allison,DavidW
• 通讯作者: Allison,DavidW

Contingent and non-contingent effects of low-dose ethanol on GABA neuron activity in the ventral tegmental area.

• DOI: 10.1016/j.pbb.2008.10.012
• 发表时间: 2009-03
• 期刊: PHARMACOLOGY BIOCHEMISTRY AND BEHAVIOR
• 影响因子: 3.6
• 作者: Steffensen, Scott C.;Walton, Christine H.;Hansen, David M.;Yorgason, Jordan T.;Gallegos, Roger A.;Criado, Jose R.
• 通讯作者: Criado, Jose R.