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

青少年自我服用尼古丁对神经化学、神经生理学和饮酒的影响

• 批准号: 9910620
• 负责人: Elizabeth G Pitts
• 金额: $ 6.11万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-10 至 2020-09-04
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9910620
• 关键词: Adolescence; Adolescent; Adult; Alcohol consumption; Alcohol or Other Drugs use; Alcohols; Amygdaloid structure; Animals; Anxiety; Award; Behavior; Behavioral; Brain; Brain region; Catecholamines; Consumption; Corpus striatum structure; Development; Dopamine; Emotions; Epidemiology; Ethanol; Fiber; Functional disorder; Future; Human; Lead; Learning; Limbic System; Link; Measures; Mediating; Motivation; Negative Reinforcements; Neurons; Neurotransmitters; Nicotine; Norepinephrine; Nucleus Accumbens; Nucleus solitarius; Outcome; Periodicity; Pharmaceutical Preparations; Photometry; Play; Population; Rattus; Research; Resistance; Rewards; Role; Scanning; Self Administration; Signal Transduction; Structure; Structure of terminal stria nuclei of preoptic region; Techniques; Testing; Ventral Tegmental Area; addiction; alcohol use disorder; anxiety-like behavior; awake; behavior measurement; drug of abuse; in vivo; locus ceruleus structure; mesolimbic system; negative affect; neurochemistry; neuronal circuitry; neurophysiology; nicotine exposure; nicotine use; novel; optogenetics; vaping

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.

概括 尼古丁的青少年烟雾蒸发的最近增加可能会提高未来的酒精使用障碍率 （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。在类似 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。但是， 介导这种增加脆弱性的机制尚不清楚。青春期尼古丁的暴露影响 一系列成人行为，包括增加焦虑症的行为和对药物使用的脆弱性， 这些行为变化可能表明受发育尼古丁影响的特定大脑区域 接触。重要的是，增加的焦虑症行为可能直接推动增加的酒精消耗量 通过负强化（即酒精会降低由增加的负面情感状态 焦虑，因此增加焦虑会驱动更多的酒精使用）。在这个奖项中，我们针对两个神经元 对于类似焦虑和奖励相关的行为至关重要的电路：腹侧段落区域（VTA） 对伏隔核（NAC）和基因座（LC）/核的投影 （NTS）投影到质末端的腹侧床核（VBNST）。我们有初步 青少年但不是成人的证据，尼古丁自我给药会减少多巴胺的释放 NAC并增加了VBNST中的儿茶酚胺释放（可能是去甲肾上腺素）。因此，我们的中心 假设是青少年尼古丁自我给药改变了VTA-NAC和 LC/NTS-VBNST电路，并且这种失调部分会驱动焦虑样行为，并且 过度使用酒精的脆弱性。我将使用神经化学，神经生理学， 和光遗传技术。 在AIM I中，我将确定青少年后饮酒和类似焦虑的行为的变化 或成人尼古丁自我给药，并检查它们是否与多巴胺和多巴胺的变化有关 NAC和VBNST中的去甲肾上腺素释放。我将我们既电气和光遗传学）快速扫描 与乙醇消耗和焦虑措施的行为度量有关的环状伏安法 将神经化学和行为变化相关联。 在AIM 2中，我将测量在NAC和NAC和VBNST投影中对神经元活动的体内变化 青少年或成人尼古丁暴露后的乙醇消耗和类似焦虑的行为。然后我会 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检查这如何影响 行为。