Nicotine and Alcohol Co-Dependence

尼古丁和酒精的相互依赖

• 批准号: 8853839
• 负责人: Scott C Steffensen
• 金额: $ 39万
• 依托单位: BRIGHAM YOUNG UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-06-01 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8853839
• 关键词: Acute; Alcohol consumption; Alcohol dependence; Alcoholism; Alcohols; Aminobutyric Acids; Behavioral; Belief; Brain; Cell Line; Cholinergic Receptors; Chronic; Conotoxin; Consumption; Data; Dependence; Development; Disease; Dopamine; Dose; Drosophila acetylcholine receptor alpha-subunit; Drug Addiction; Electrophysiology (science); Epithelium; Ethanol; Ethanol dependence; Exposure to; Glutamates; Goals; Homeostasis; Human; In Vitro; Intervention; Investigation; Knock-in Mouse; Knockout Mice; Mediating; Midbrain structure; Molecular; Motor; Mus; Neurons; Nicotine; Nicotine Dependence; Nicotinic Receptors; Nucleus Accumbens; Oocytes; Performance; Pharmaceutical Preparations; Preparation; Procedures; Property; Proteins; Recombinants; Relapse; Research; Resources; Rewards; Risk Factors; Role; Scanning; Slice; Small Interfering RNA; Smoking; Societies; Synaptic Transmission; System; Techniques; Testing; Therapeutic Agents; Tobacco; Transcript; Ventral Tegmental Area; Withdrawal; addiction; alcohol effect; alcohol exposure; alcohol reward; base; dopaminergic neuron; drinking; drug of abuse; drug reward; drug seeking behavior; effective therapy; evidence base; in vivo; insight; mesolimbic system; motor impairment; multidisciplinary; neurochemistry; neurotransmission; patch clamp; postsynaptic; pre-clinical; preference; presynaptic; programs; public health relevance; relating to nervous system; research study; response; transmission process; treatment strategy; vapor

ABSTRACT The prevailing view is that enhancement of dopamine (DA) transmission in the mesocorticolimbic system underlies the rewarding properties of alcohol and nicotine (NIC). The mesolimbic DA system consists of DA neurons in the midbrain ventral tegmental area (VTA) that innervate the nucleus accumbens (NAc). Dopamine neurotransmission is regulated by inhibitory VTA GABA neurons, whose excitability is a net effect of glutamate (GLU) and GABA neurotransmission that are modulated by NIC cholinergic receptors (nAChRs) on afferent terminals. We have shown that these neurons are excited by low-dose ethanol (Steffensen et al., 2009), but inhibited by moderate to high-dose ethanol (Gallegos et al., 1999; Ludlow et al., 2009; Steffensen et al., 2009; Stobbs et al., 2004; Yang et al., 2010), and adapt to chronic ethanol (Gallegos et al., 1999), evincing marked hyperexcitability during withdrawal. Based on our previous studies and data presented here, we propose that VTA GABA neurons are a common substrate for the acute actions of ethanol and NIC. The core thesis underlying this proposal is that ¿6*-nAChRs on GABA terminals mediate acute ethanol inhibition of VTA GABA neurons and DA release in the NAc. In addition, VTA GABA neuron hyperexcitability during withdrawal from chronic ethanol results from adaptations in presynaptic ¿6*-nAChRs and postsynaptic GABA(A)R-mediated inhibitory synaptic transmission to these neurons, which contributes to the dysregulation of mesolimbic DA homeostasis that accompanies dependence on ethanol and co-dependence on NIC. We will study of the role of ¿6*-nAChRs in acute and chronic effects of ethanol on VTA GABA neurons and on DA release. Our proposed studies constitute a focused investigation into the role of ¿6*-nAChRs in mediating acute ethanol effects on these neurons and their adaptation with alcohol dependence. Our studies will test the following specific hypotheses: 1) Acute ethanol inhibition of VTA GABA neuron activity and phasic DA release results from enhancement of GABA release via ¿6*-nAChRs on GABA terminals; 2) Lack of ¿6*-nAChRs results in disrupted ethanol consumption and reward; and 3) Hyperexcitability of VTA GABA neurons during withdrawal from chronic ethanol results from adaptation of ¿6*-nAChRs and subsequent reduction of DA release at terminals in the NAc. To test these hypotheses, we propose three Specific Aims, which involve electrophysiological, behavioral, neurochemical and molecular experiments with acute and chronic ethanol exposure in GAD GFP knock-in mice, and in wild type (WT) and ¿6*-nAChR KO mice: 1) Define the role of ¿6*-nAChRs in acute ethanol actions on VTA neurons and dopamine release in the NAc; 2) Define the role of ¿6*-nAChRs in mediating ethanol consumption and reward; and 3) Define the role of ¿6-nAChRs in mediating the hyperexcitability of VTA GABA neurons and lowered dopamine release in the NAc during withdrawal from chronic ethanol. We will show preliminary evidence that ¿6*-nAChRs mediate ethanol enhancement of NIC currents in recombinant nAChRs expression systems,that ethanol enhancement of GABA inhibition to VTA GABA neurons and ethanol reduction in DA release in the NAc, and compromised ethanol reward in ¿6*- nAChR KO mice. The proposed studies constitute a thorough and systematic investigation into the role of VTA GABA neurons in mediating the acute effects of ethanol and NIC and the role of ¿6*-nAChR in modulating GABA neurotransmission to these neurons that critically regulate DA neurotransmission in the mesolimbic system implicated in alcohol reward and dependence. Results from this study could provide a preclinical pharmacologic rationale for considering drugs that act selectively on ¿6*-nAChR as putative therapeutic agents for the treatment of alcohol dependence and alcohol and NIC co-dependence.

摘要 普遍的观点认为，中皮质边缘系统多巴胺（DA）传递的增强 酒精和尼古丁（NIC）的奖励属性的基础。中脑边缘DA系统由DA 中脑腹侧被盖区（VTA）神经元，支配丘脑核（NAc）。多巴胺 神经传递由抑制性VTA GABA神经元调节，其兴奋性是谷氨酸的净效应 (GLU)和GABA神经传递，由传入神经上的NIC胆碱能受体（nAChRs）调节 terminals.我们已经表明，这些神经元被低剂量乙醇兴奋（Steffensen等人，2009年），但 受到中剂量至高剂量乙醇的抑制（Gallegos等人，1999;卢德洛等人，2009; Steffensen等人，二○ ○九年; Stobbs等人，2004; Yang等人，2010），并适应慢性乙醇（Gallegos等人，1999），evincing标记 戒断时过度兴奋根据我们以前的研究和这里提供的数据，我们建议， VTA GABA神经元是乙醇和NIC急性作用的共同底物。核心论点 这一假设的基础是GABA末端上的<$6 *-nAChR介导VTA GABA的急性乙醇抑制 NAc内神经元和DA的释放。此外，VTA GABA神经元在戒断过程中过度兴奋， 慢性乙醇产生于突触前6*-nAChRs和突触后GABA（A）R介导的适应性 抑制突触传递到这些神经元，这有助于中脑边缘DA的失调 体内平衡伴随着对乙醇的依赖和对NIC的共同依赖。我们将研究 在急性和慢性乙醇对腹侧被盖区GABA神经元和DA释放的影响中，我们 拟议的研究构成了一个重点调查的作用，6*-nAChRs介导急性乙醇 对这些神经元的影响及其对酒精依赖的适应。我们的研究将测试以下内容 具体假设：1）急性乙醇抑制VTA GABA神经元活性和阶段性DA释放结果 通过GABA末端上的<$6 *-nAChR增强GABA释放; 2）缺乏<$6 *-nAChR导致 中断乙醇消耗和奖赏; 3）戒断过程中VTA GABA神经元的过度兴奋 从慢性乙醇的结果从适应的<$6 *-nAChRs和随后的减少DA释放， 在NAC的终端。为了验证这些假设，我们提出了三个具体目标，其中包括 急性和慢性乙醇的电生理学、行为学、神经化学和分子实验 GAD GFP敲入小鼠以及野生型（WT）和n6 *-nAChR KO小鼠中的暴露：1）定义 急性乙醇对腹侧被盖区神经元的作用和NAc中多巴胺的释放中的6*-nAChRs; 2）定义 <$6 *-nAChRs在介导乙醇消耗和奖励中的作用;以及3）定义<$6-nAChRs在介导 VTA GABA神经元的过度兴奋性和NAc中多巴胺释放的降低， 慢性乙醇我们将显示初步证据，6*-nAChRs介导乙醇增强NIC 在重组nAChRs表达系统中，乙醇增强GABA对VTA的抑制作用， GABA神经元和乙醇减少了NAc中DA的释放，并损害了6*- nAChR KO小鼠。拟议的研究构成了对VTA作用的全面和系统的调查 GABA神经元介导乙醇和NIC的急性效应以及<$6 *-nAChR在调节乙醇和NIC急性效应中的作用 GABA神经传递到这些神经元，这些神经元严格调节中脑边缘的DA神经传递 酒精奖励和依赖的系统。这项研究的结果可以提供临床前 考虑选择性作用于6*-nAChR的药物作为推定治疗药物的药理学原理 用于治疗酒精依赖和酒精与NIC共依赖的药剂。