Ethanol modulation of nicotinic receptors

描述(申请人提供)：乙醇(乙醇)和尼古丁可能是美国最广泛的联合滥用药物。除了有益的效果，乙醇还具有深刻的镇静作用，这些作用可以通过联合服用尼古丁来部分减少。我们发现，与生理相关的低浓度乙醇能显著抑制被盖外侧背核(LDTg)17个亚型的烟碱型乙酰胆碱受体(NAChRs)。脑干被盖投射到边缘区域、基底节和丘脑，参与许多行为，包括奖赏、觉醒、运动控制和对滥用药物的敏化。已知乙醇可以调节cAMP/PKA信号，我们推测17nAChRs对低浓度乙醇的显著敏感性是通过对PKA途径的影响而实现的。17个nAChRs参与尼古丁诱导的腹侧被盖区(VTA)和多巴胺(DA)神经元的可塑性，而乙醇和尼古丁的共同滥用可能改变这种作用。17种nAChR抑制剂抑制运动和认知功能，我们的初步数据表明，LDTg中的17种nAChR介导了急性全身性乙醇所致的部分运动损伤。因此，我们假设，低量乙醇的运动损伤效应是由乙醇与17个nAChRs的相互作用所介导的，尼古丁抵消了这一效应。除了乙醇对17个nAChRs的影响外，我们的数据还表明，乙醇增强了外侧LDTg中的非17个nAChRs。由于大量的LDTg神经元向VTA发送兴奋性投射，这种增强可能是乙醇奖赏的一种机制。LDTg中非17个nAChRs和17个nAChRs的增强和抑制也可以解释较低浓度的Etoh奖赏和运动损伤共存的原因。研究乙醇和尼古丁胆碱能系统之间相互作用的机制可能会导致对酒精和尼古丁成瘾的更有效的治疗。 公共卫生相关性：这项研究试图解释尼古丁和酒精共同滥用的生物学基础。酒精损害了判断力和反应时间，这是与酒精有关的事故的一个主要因素，导致无数人丧生。酒精还会增加尼古丁的奖励作用，这也可能解释了在饮酒期间吸烟行为增加的原因。酒精的镇静和奖赏作用可能都是由大脑同一区域的尼古丁受体介导的。因此，这些受体和这个大脑区域可能代表着未来药物治疗的目标，以遏制吸烟和饮酒行为，同时减少酒精损伤造成的死亡。

DESCRIPTION (provided by applicant): Ethanol (EtOH) and nicotine are perhaps the most widely co-abused drugs in the US. Along with its rewarding effects, EtOH also has profound sedative effects and these can partially be reduced by co-administration of nicotine. We have found that low, physiologically relevant EtOH concentrations profoundly inhibit nicotinic acetylcholine receptors (nAChRs) of the 17 subtype in the lateral dorsal tegmental nucleus (LDTg). Brainstem tegmental projections to limbic areas, basal ganglia and the thalamus contribute to many behaviors including reward, arousal, motor control and sensitization to drugs of abuse. EtOH is known to modulate cAMP/PKA signaling, and we hypothesize that the remarkable sensitivity of 17 nAChRs to low EtOH concentrations is mediated through effects on the PKA pathway. 17 nAChRs play a role in nicotine induced plasticity in ventral tegmental area (VTA) dopamine (DA) neurons and co-abuse of EtOH and nicotine may alter these effects. 17 nAChR inhibitors suppress locomotion and cognitive functions and our preliminary data indicates that 17 nAChRs in the LDTg mediate some of the motor impairment by acute systemic EtOH. We therefore hypothesize that motor impairment effects of low amounts of EtOH are mediated by an interaction of EtOH with 17 nAChRs, and that nicotine offsets this effect. In addition to the effects of EtOH on 17 nAChRs, our data show that EtOH potentiates non-17 nAChRs in the lateral LDTg. As large numbers of LDTg neurons send excitatory projections to the VTA, this potentiation may be a mechanism for EtOH reward. Potentiation and inhibition of non-17 nAChRs and 17 nAChRs respectively in the LDTg may also explain the co-occurrence of EtOH reward and motor impairment at relatively low concentrations of EtOH. Examining the mechanisms underlying the interactions between EtOH and the nicotinic cholinergic system may lead to more effective treatments for alcohol and nicotine addiction. PUBLIC HEALTH RELEVANCE: This study seeks to explain the biological basis for the co-abuse of nicotine and alcohol. Alcohol impairs judgment and reaction times, a major factor in alcohol related accidents leading to an untold cost in lives lost. Alcohol also increases the rewarding effects of nicotine, this may also explain increased smoking behavior reported during alcohol consumption. Both sedative and rewarding effects of alcohol may be mediated by nicotine receptors in the same region of the brain. These receptors and this brain region may therefore represent a target for future drug therapies to curb smoking and drinking behaviors while at the same time reducing fatalities caused by alcohol impairment.