Nicotinic Receptor Modulation of Alcohol Effects on Brain Synaptic Activity

说明(申请人提供)：习惯性使用烟草和酒精会导致相互依赖，滥用这些药物对我们的社会造成了重大的健康风险。因此，迫切需要有效的治疗方法。由于大多数酒精依赖者也是尼古丁依赖者，这种相互依赖似乎使戒酒变得更加困难。在正在进行的确定尼古丁(烟草中的主要成瘾成分)和酒精的大脑作用机制的研究中，我们使用电生理技术研究了小鼠海马脑组织中急性神经元功能和这两种药物可能的神经元相互作用。海马区是一个重要的大脑区域，它通过直接(通过谷氨酸能兴奋系统)和间接(通过GABA能抑制系统)机制来调节动机行为，包括奖赏和药物成瘾。已知酒精可以改变兴奋性谷氨酸能(NMDA和AMPA)和抑制性GABA能(GABAA)受体的活性。相比之下，尼古丁通过大脑中的烟碱型乙酰胆碱受体(NAChRs)发挥作用，增加神经传递。NAChR的17个亚型受酒精抑制，而1422个nAChR亚型被酒精增强。我们的数据显示，在海马区，尼古丁增加了兴奋性和抑制性神经元之间的化学交流(神经传递)，但急性酒精应用增加了抑制性，减少了兴奋性神经传递。因此，当这两种药物一起使用时，会产生复杂的相互作用来改变神经传递。重要的是，我们发现抑制性GABA能神经传递受17和1422亚型的调节，而兴奋性谷氨酸能神经传递主要受CA1区神经元17亚型的调控。尼古丁和酒精的联合使用会导致这一大脑区域抑制性突触神经传递的特定增加。习惯性饮酒会导致脑神经传递失调，我们假设当两种药物联合使用时，这种失调可能会恶化。我们建议研究尼古丁受体对酒精对长期酒精或尼古丁治疗的小鼠GABA能和谷氨酸能神经传递的影响。具体目标1旨在确定尼古丁诱导酒精处理小鼠神经元中谷氨酸和GABA能活动的机制。特定目的2旨在研究长期尼古丁自我给药如何调节酒精对谷氨酸和GABA能功能的影响。揭示慢性尼古丁和酒精对大脑神经传递的影响机制可能有助于确定治疗酒精和尼古丁依赖的药物开发的特定部位。

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.