Ethanol modulation of nicotinic receptors

描述（由申请人提供）：乙醇（EtOH）和尼古丁可能是美国最广泛滥用的药物。除了它的奖励作用，EtOH还具有深刻的镇静作用，这些作用可以通过尼古丁的共同施用而部分减少。我们发现，低的、生理上相关的EtOH浓度深刻抑制17亚型的烟碱乙酰胆碱受体（nAChRs）在外侧背被盖核（LDTg）。脑干边缘区、基底神经节和丘脑的被盖层投射影响许多行为，包括奖励、觉醒、运动控制和对滥用药物的敏感。已知EtOH可以调节cAMP/PKA信号，我们假设17个nAChRs对低EtOH浓度的显著敏感性是通过对PKA通路的影响介导的。17个nachr在尼古丁诱导的腹侧被盖区（VTA）多巴胺（DA）神经元的可塑性中发挥作用，同时滥用EtOH和尼古丁可能会改变这些作用。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介导急性系统性EtOH的部分运动损伤。因此，我们假设低量EtOH对运动损伤的影响是由EtOH与17个nachr的相互作用介导的，而尼古丁抵消了这种影响。除了EtOH对17个nachr的影响外，我们的数据显示，EtOH在侧LDTg中增强了非17个nachr。由于大量LDTg神经元向VTA发送兴奋性投射，这种增强可能是EtOH奖励的一种机制。LDTg中非17 nAChRs和17 nAChRs的增强和抑制也可能解释了在相对低浓度的EtOH下EtOH奖励和运动障碍的共同发生。研究EtOH与尼古丁胆碱能系统之间相互作用的机制可能会导致更有效的治疗酒精和尼古丁成瘾。

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.