Nicotinic Receptor Modulation of Alcohol Effects on Brain Synaptic Activity

酒精烟碱受体调节对大脑突触活动的影响

基本信息

批准号：
7666977
负责人：
WILLIAM R PROCTOR
金额：
$ 18.2万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-08-01 至 2012-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7666977
关键词：
Acute Affect Alcohol consumption Alcohol dependence Alcohol withdrawal syndrome Alcohols Animals Area Attention Attenuated Behavior Behavioral Brain Chemicals Chronic Communication Complex Data Dependence Drug Addiction Drug usage Ethanol Glutamates Health Hippocampus (Brain)Human Inbred C57BL Mice Individual Lead Mediating Mus N-Methyl-D-Aspartate Receptors N-Methylaspartate Neurons Nicotine Nicotine Dependence Nicotinic Agonists Nicotinic Receptors Pharmaceutical Preparations Process Receptor Activation Recovery Regulation Rewards Risk Seizures Self Administration Short-Term Memory Site Slice Smoke Smoker Societies Synapses Synaptic Transmission System Techniques Testing Tobacco Tobacco use alcohol abstinence alcohol effect attenuation brain tissue design drinking drug abuser drug development hippocampal pyramidal neuron motivated behavior neurotransmission nicotine abuse receptor reward processing sensory gating theories therapy development transmission process

项目摘要

DESCRIPTION (provided by applicant): Habitual use of tobacco and alcohol leads to co-dependence and misuse of these drugs has imposed significant health risks on our society. Thus, efficacious treatments are urgently needed. As the majority of alcohol-dependent individuals are also nicotine-dependent, this co-dependence seems to make abstaining from alcohol more difficult. In ongoing studies to identify brain mechanisms of actions for nicotine (the principal addictive ingredient in tobacco) and alcohol, we use electrophysiological techniques to study acute neuronal function and possible neuronal interactions of these two drugs in mouse hippocampal brain tissue. The hippocampus is an important brain area that is known to regulate motivational behaviors, including reward and drug addiction, by both direct (via glutamatergic excitatory systems) and indirect (via GABAergic inhibitory systems) mechanisms. Alcohol is known to modify activities of excitatory glutamatergic (NMDA and AMPA) and inhibitory GABAergic (GABAA) receptors. Nicotine, in contrast, exerts its actions through nicotinic acetylcholine receptors (nAChRs) in the brain to increase neurotransmission. The 17 subtype of nAChRs is inhibited by alcohol, whereas the 1422 nAChR subtype is enhanced by alcohol. Our data show that in the hippocampus, nicotine increases both excitatory and inhibitory chemical communication between neurons (neurotransmission), but that acute alcohol application increases inhibitory and decreases excitatory neurotransmission. Thus, when these two drugs are used together, complex interactions arise to alter neurotransmission. Importantly, we found that inhibitory GABAergic neurotransmission is regulated by both 17 and 1422 subtypes, while the excitatory glutamatergic neurotransmission is controlled primarily by the 17 subtype in CA1 hippocampal neurons. The combined use of nicotine and alcohol produces specific increases in inhibitory synaptic neurotransmission in this brain area. Habitual alcohol drinking can cause brain neurotransmission deregulation, and we hypothesize that this deregulation may worsen when both drugs are used together. We propose to investigate nicotinic receptor regulation on the effects of alcohol on GABAergic and glutamatergic neurotransmission in mice that are chronically treated with alcohol or nicotine. Specific Aim 1 is designed to identify mechanisms of nicotine-induced glutamatergic and GABAergic activity in neurons from alcohol-treated mice. Specific Aim 2 is designed to investigate how chronic nicotine self-administration may modulate alcohol effects in glutamatergic and GABAergic function. Uncovering the mechanisms of chronic nicotine and alcohol effects on neurotransmission in brain may help to identify specific sites for drug development to treat alcohol and nicotine dependence.

描述（由申请人提供）：习惯使用烟草和酒精会导致共同依赖和滥用这些药物对我们的社会施加了重大的健康风险。因此，迫切需要有效的治疗。由于大多数酒精依赖性个体也是尼古丁依赖性的，因此这种共同依赖性似乎使戒酒更加困难。在正在进行的研究中，鉴定尼古丁作用的大脑机制（烟草中的主要成瘾成分）和酒精，我们使用电生理技术研究急性神经元功能以及这两种药物在小鼠海马脑组织中的神经元相互作用。海马是一个重要的大脑区域，众所周知，通过直接（通过谷氨酸能兴奋系统）和间接（通过GABAergic抑制系统）机制来调节动机行为，包括奖励和药物成瘾。已知酒精会改变兴奋性谷氨酸能（NMDA和AMPA）和抑制性GABA能（GABAA）受体的活性。相反，尼古丁通过大脑中的烟碱乙酰胆碱受体（NACHR）发挥作用，以增加神经传递。 NACHR的17个亚型受酒精抑制，而1422 NACHR亚型则通过酒精增强。我们的数据表明，在海马中，尼古丁在神经元之间增加了兴奋性和抑制性化学交流（神经传递），但是急性酒精应用会增加抑制性并降低兴奋性神经传递。因此，当将这两种药物一起使用时，会出现复杂的相互作用以改变神经传递。重要的是，我们发现抑制性GABA能神经传递受17和1422亚型调节，而兴奋性谷氨酸能神经传递主要由CA1海马神经元中的17个亚型控制。尼古丁和酒精的综合使用会在该大脑区域中产生抑制性突触神经传递的特异性增加。习惯性饮酒会导致大脑神经传递的放松管制，我们假设当两种药物一起使用时，这种放松管制可能会恶化。我们建议研究烟碱受体调节对酒精和谷氨酸能神经传递在经长期接受酒精或尼古丁治疗的小鼠中的影响。特定的目标1旨在识别来自酒精治疗小鼠的神经元中尼古丁诱导的谷氨酸能和GABA能活性的机制。特定目标2旨在研究慢性尼古丁自我给药如何调节谷氨酸能和GABA能功能的酒精效应。揭示慢性尼古丁和酒精对大脑神经传递的作用的机制可能有助于确定药物开发的特定部位，以治疗酒精和尼古丁依赖性。