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

总结 最近青少年尼古丁电子烟的增加可能会增加未来酒精使用障碍的发病率 （AUD）.流行病学和动物研究发现，青少年接触尼古丁会增加乙醇 成年后的消费乙醇消费的这种长期增长并没有在类似的 在成年期暴露于尼古丁，表明青春期是一个独特的脆弱时期。但 介导这种增加的脆弱性的机制尚不清楚。青少年尼古丁暴露的影响 一系列成年人的行为，包括越来越多的焦虑样行为和对物质使用的脆弱性， 这些行为变化可能表明特定的大脑区域受到尼古丁的影响 exposure.重要的是，焦虑样行为的增加可能直接导致酒精消费的增加 通过负强化（即酒精减少了由增加的 焦虑，因此焦虑增加会导致更多的酒精使用）。在这个奖项中，我们针对两个神经元 对焦虑和奖励相关行为都至关重要的回路：腹侧被盖区（VTA） 向延髓核芯（NAc）和蓝斑（LC）/孤束核的投射 (NTS)投射到终纹腹侧床核（vBNST）。我们有初步的 有证据表明，青少年，而不是成年人，尼古丁自我管理减少多巴胺的释放， NAc和增加vBNST中的儿茶酚胺释放（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给药改变了VTA-NAc的发育， LC/NTS-vBNST电路，这种失调，在一定程度上，驱动增加焦虑样行为， 易受过度饮酒的影响。我将用神经化学，神经生理学， 和光遗传学技术。 在目标I中，我将确定青少年饮酒和焦虑样行为的变化， 或成人尼古丁自我管理，并检查这些是否与多巴胺的变化有关， NAc和vBNST中的去甲肾上腺素释放。我将我们两个电和光遗传学离体快速扫描 循环伏安法与乙醇消耗行为测量和焦虑测量相关 将神经化学和行为变化联系起来 在目标2中，我将在体内测量NAc和vBNST投射中神经元活性的变化， 青少年或成人尼古丁暴露后的乙醇消耗和焦虑样行为。然后我将 在清醒的行为动物中使用光遗传学来使神经元活动正常化，并研究这如何影响 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.