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Neural mechanisms underlying nicotine as a 'gateway' drug.

机译：尼古丁作为“门户”药物的神经机制。

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摘要

Epidemiological studies have established that drug use in adolescence is initiated with tobacco and alcohol and progresses to marijuana and other illicit drugs. These findings have led to the hypothesis that tobacco is a 'gateway' drug that sensitizes central reward pathways to the effects of illicit substances. Despite strong epidemiological evidence, few preclinical studies have examined whether there is a biological basis for this pattern of drug use and the underlying mechanism. This dissertation evaluated whether nicotine, the main psychoactive constituent of tobacco, during adolescence alters subsequent drug-reinforced behavior and the neural circuitry mediating this response.;In order to test the 'gateway' theory, I have developed a novel method to model the early, initiation phase of teenage smoking in rats. This exposure paradigm is brief, only 4 days, and delivers the equivalent nicotine in 2-4 cigarettes each day, and more closely mimics the pharmacokinetics of smoking. Using this model, I tested the 'gateway' hypothesis that adolescent nicotine treatment has unique effects on reward-related behavior.;Nicotine pretreatment increased self-administration of cocaine in adolescent, but not adult, rats. Enhanced acquisition of drug-taking behavior was also found for ethanol and methamphetamine. Furthermore, the enhanced responding is not generalized to natural reinforcers, since pretreatment had no effect on sucrose operant reponse. These experiments demonstrate that adolescent nicotine treatment sensitizes the brain to drugs of abuse.;When examining cocaine's locomotor activating properties, prior nicotine treatment did not alter acute cocaine-induced activity. However, adolescent nicotine pretreatment did enhance behavioral plasticity in response to repeated cocaine. Findings from these experiments demonstrate that adolescent nicotine exposure uniquely enhances cocaine-induced behavioral plasticity.;Neurochemical studies showed that forebrain monoamine systems are immature during adolescence, and nicotine exposure accelerates their development. To further demonstrate serotonin's role, the selective 5-HT1a receptor antagonist, WAY 100635, pretreatment was shown to block nicotine-induced enhancement of cocaine and methamphetamine self-administration, but had no effect on behavior in saline-pretreated controls. These findings suggest that nicotine-induced changes in serotonergic maturation may underlie enhancement of reward behavior. Together, this dissertation provides strong biological evidence for the 'gateway' hypothesis and identifies a potential neural mechanism.
机译：流行病学研究表明，青少年时期的毒品使用是从烟草和酒精开始的，并逐渐发展为大麻和其他非法药物。这些发现导致了这样的假设：烟草是一种“网关”药物，它使中央奖励途径对非法物质的影响敏感。尽管有强大的流行病学证据，但很少有临床前研究检查这种药物使用模式及其潜在机制是否具有生物学基础。这篇论文评估了青春期烟草的主要精神活性成分尼古丁是否会改变随后的药物强化行为以及介导这种反应的神经回路。为了测试“网关”理论，我开发了一种新颖的方法来模拟早期在大鼠中开始青少年吸烟的阶段。这种暴露模式是短暂的，只有4天，并且每天在2-4支香烟中提供等效的尼古丁，并且更类似于吸烟的药代动力学。使用这个模型，我测试了“网关”假设，即青少年尼古丁治疗对奖励相关行为具有独特的影响。尼古丁预处理增加了可卡因在青少年（而非成年）大鼠中的自我给药。还发现乙醇和甲基苯丙胺的吸毒行为获得增强。此外，由于预处理对蔗糖操作性反应没有影响，因此增强的反应并未推广至自然增强剂。这些实验表明，青少年尼古丁治疗会使大脑对滥用药物敏感。当检查可卡因的运动激活特性时，先前的尼古丁治疗并未改变可卡因诱导的急性活动。然而，青春期尼古丁预处理确实增加了对可卡因重复的行为可塑性。从这些实验中发现，青春期尼古丁暴露可独特地增强可卡因诱导的行为可塑性。神经化学研究表明，前脑单胺系统在青春期不成熟，而尼古丁暴露可促进其发育。为了进一步证明5-羟色胺的作用，选择性5-HT1a受体拮抗剂WAY 100635被证明可以阻止尼古丁引起的可卡因和甲基苯丙胺自我给药的增强，但对盐水预处理的对照组的行为没有影响。这些发现表明，尼古丁引起的血清素能成熟的变化可能是奖励行为增强的基础。总之，本论文为“网关”假说提供了有力的生物学证据，并确定了潜在的神经机制。

著录项

  • 作者

    McQuown, Susan C.;

  • 作者单位

    University of California, Irvine.;

  • 授予单位 University of California, Irvine.;
  • 学科 Biology Neuroscience.;Health Sciences Pharmacology.
  • 学位 Ph.D.
  • 年度 2009
  • 页码 150 p.
  • 总页数 150
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

  • 入库时间 2022-08-17 11:38:19

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