The impact of adolescent nicotine self-administration on neurochemistry, neurophysiology, and alcohol consumption

摘要 最近青少年吸食尼古丁的增加可能会增加未来酒精使用障碍的发生率 (澳元)。流行病学和动物研究发现，青少年接触尼古丁会增加酒精含量 成年期的消费。这种乙醇消费的长期增长并没有发现类似的 成年期接触尼古丁，这表明青春期是一个独特的脆弱时期。然而， 调节这种脆弱性增加的机制尚不清楚。青少年尼古丁暴露的影响 一系列成人行为，包括焦虑样行为的增加和对药物使用的脆弱性， 这些行为变化可能表明特定的大脑区域受到发育中尼古丁的影响 曝光。重要的是，焦虑类行为的增加可能直接导致饮酒量的增加 通过消极强化(即酒精降低由增加的酒精引起的消极情绪状态 焦虑，所以焦虑增加会导致更多的饮酒)。在这个奖项中，我们的目标是两个神经元 对焦虑样行为和奖赏相关行为都至关重要的环路：腹侧被盖区(VTA) 向伏核(NAC)和蓝斑(LC)/孤束核的投射 (NTS)向终纹腹侧床核(VBNST)投射。我们有初步的 有证据表明，青少年尼古丁自我给药减少了多巴胺的释放，但不是成年人。 NAC并增加vBNST中儿茶酚胺的释放(可能是去甲肾上腺素)。因此，我们的中央 假设青少年尼古丁自我管理改变VTA-NAC的发展和 LC/NTS-vBNST回路，这种失调在一定程度上会导致焦虑样行为和 易受过度饮酒的影响。我将用神经化学、神经生理学、 以及光遗传技术。 在目标I中，我将确定青少年之后饮酒和类似焦虑的行为的变化 或成人尼古丁自我给药，并检查这些是否与多巴胺和 去甲肾上腺素在NAc和vBNST的释放。我会用电学和光生技术进行体外快速扫描 循环伏安法与酒精消费行为测量和焦虑测量的关系 将神经化学和行为变化联系起来。 在目标2中，我将测量在体内向NAC和vBNST投射的神经元活动的变化 青少年或成人尼古丁暴露后的酒精消费和焦虑样行为。那我会的 在清醒行为的动物中使用光遗传学来使神经元活动正常化并检查这是如何影响的 行为。

Summary The recent rise in adolescent vaping of nicotine could increase future rates of alcohol use disorder (AUD). Epidemiological and animal studies find that adolescent exposure to nicotine increases ethanol consumption in adulthood. This long-term increase in ethanol consumption is not found following similar exposure to nicotine in adulthood, indicating adolescence is a uniquely vulnerable period. However, the mechanisms mediating this increased vulnerability are not known. Adolescent nicotine exposure impacts a range of adult behaviors, including increasing anxiety-like behavior and vulnerability to substance use, and these behavioral changes may indicate specific brain regions impacted by developmental nicotine exposure. Importantly, increased anxiety-like behavior may directly drive increased alcohol consumption through negative reinforcement (i.e. alcohol decreases the negative affective state caused by increased anxiety, so increased anxiety drives greater alcohol use). In this award, we are targeting two neuronal circuits that are critical for both anxiety-like and reward-related behaviors: ventral tegmental area (VTA) projections to the nucleus accumbens core (NAc) and locus coeruleus (LC)/nucleus of the solitary tract (NTS) projections to the ventral bed nucleus of the stria terminalis (vBNST). We have preliminary evidence that adolescent, but not adult, nicotine self-administration decreases dopamine release in the NAc and increases catecholamine release (likely norepinephrine) in the vBNST. Therefore, our central hypothesis is that adolescent nicotine self-administration alters the development of VTA-NAc and LC/NTS-vBNST circuits, and this dysregulation, in part, drives increased anxiety-like behaviors and vulnerability to excessive alcohol use. I will test this hypothesis using neurochemical, neurophysiological, and optogenetic techniques. In Aim I, I will identify changes to alcohol consumption and anxiety-like behaviors following adolescent or adult nicotine self-administration and examine if these relate to changes in dopamine and norepinephrine release in the NAc and vBNST. I will us both electrical and optogenetic ex vivo fast scan cyclic voltammetry in connection with behavioral measures of ethanol consumption and anxiety measures to correlate neurochemical and behavioral changes. In Aim 2, I will measure in vivo changes to neuronal activity in projections to the NAc and vBNST during ethanol consumption and anxiety-like behaviors following adolescent or adult nicotine exposure. I will then use optogenetics in awake behaving animals to normalize neuronal activity and examine how this impacts behavior.