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的共同滥用药物。沿着奖励作用外，EtOH还具有深刻的镇静作用，这些作用可以通过与尼古丁共同给药而部分减少。我们已经发现，低的，生理相关的乙醇浓度深刻地抑制烟碱乙酰胆碱受体（nAChRs）的17个亚型在外侧背盖核（LDTg）。脑干被盖投射到边缘区、基底神经节和丘脑有助于许多行为，包括奖励、唤醒、运动控制和对滥用药物的敏感。已知乙醇可调节cAMP/PKA信号传导，我们假设17个nAChR对低乙醇浓度的显著敏感性是通过对PKA通路的影响介导的。17 nAChR在腹侧被盖区（VTA）多巴胺（DA）神经元中尼古丁诱导的可塑性中发挥作用，EtOH和尼古丁的共同滥用可能会改变这些作用。17 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 nAChR介导了急性全身性EtOH引起的一些运动障碍。因此，我们假设少量EtOH的运动障碍效应是由EtOH与17 nAChR的相互作用介导的，尼古丁抵消了这种效应。除了EtOH对17 nAChR的影响外，我们的数据显示EtOH增强了横向LDTg中的非17 nAChR。由于大量LDTg神经元向腹侧被盖区发送兴奋性投射，这种增强作用可能是EtOH奖励的机制。LDTg中非17 nAChR和17 nAChR的增强和抑制也可以解释在相对低浓度的EtOH下EtOH奖赏和运动损伤的共同发生。研究乙醇和烟碱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.