CHARACTERIZATION OF NICOTINE RECEPTORS: ROLE IN TOLERANCE AND DEPENDENCE

尼古丁的高成瘾倾向是众所周知的，事实上，戒烟策略，包括 行为矫正和药物治疗的成功率很低。了解生物学基础 如果我们要开发新的治疗策略，尼古丁依赖的治疗是必不可少的。巨大进步 关于尼古丁对离子门控胆碱能受体（nA）的作用， ChR）。在大量可能的nAChR亚型中，o 402和<x7受体接受的最多。 尼古丁的作用范围很广，包括奖赏、认知和疼痛。 重要的是，尼古丁成瘾已经在小鼠中建模，在条件位置偏好（CPP）中， 奖励效应和通过微型泵长期输注尼古丁，以诱导 治疗结束时的身体依赖性。有证据表明，奖励和身体依赖是 通过不同的烟碱受体亚型介导，并且可能涉及由Δ J5和CT Δ亚基组成的受体。 尼古丁还可以操纵内源性大麻素的水平，THC可以钝化一些尼古丁 方面的影响.我们的前提是，选择性烟碱受体激活内源性大麻素系统 这反过来又会导致尼古丁依赖。我们的第一个目标是确定a4 p2和ct 7 受体，以及含有α 5或α 7亚基的受体，在发育和表达中起作用。 与尼古丁依赖相关的奖励和戒断症状。我们将在小鼠中检查尼古丁CPP 缺乏或过度表达A402和A？受体以及具有A5缺失的小鼠。互补 实验将在野生型小鼠中进行，通过用这些选择性激动剂建立CPP， 受体亚型或使用选择性拮抗剂（特别是α 6拮抗剂）来阻断尼古丁的作用。 基因修饰小鼠将长期输注尼古丁，以评估 戒毒此外，在停药期间，我们将用受体选择性抗体激发野生型动物。 激动剂和拮抗剂以评估它们对躯体和情感体征的作用。我们亦会评估 伐尼克兰是一种A4 P2受体的部分激动剂，目前正在进行戒烟的临床试验， CPP和慢性输注范例。其次，我们将继续我们的前提，即CB 1大麻素 受体和内源性大麻素有助于尼古丁奖励效应，并可能导致情感戒断 信号装置.我们将在缺乏CB 1受体的小鼠和那些 缺乏脂肪酸酰胺水解酶，该酶是内源性大麻素anandamide失活所必需的。 我们将通过在野生型小鼠中进行相同的实验来补充这些研究， 与CB 1受体拮抗剂或脂肪酸酰胺水解酶抑制剂联用。花生四烯酸和2- 将研究在尼古丁CPP和戒断期间大脑奖励区域中的花生四烯酸甘油。

Nicotine's high addiction liability is well recognized, as is the fact that smoking cessation strategies, including behavioral modification and pharmacotherapies, have low success rates. Understanding the biological basis of nicotine dependence is essential if we are to develop new treatment strategies. Tremendous progress has been made in the past decade regarding the actions of nicotine at ion-gated cholinergic receptors (nA ChR). Of the large number of possible nAChR subtypes, o402 and <x7 receptors have received the most attention and have been implicated in a wide range of nicotine's effects, including reward, cognition and pain. Importantly, nicotine addiction has been modeled in mice, in conditioned place preference (CPP) for rewarding effects and chronic infusion of nicotine via minipumps to induce somatic and affective signs of physical dependence upon treatment end. Evidence is emerging that reward and physical dependence are mediated through different nicotinic receptor subtypes and may involve receptors made of aj5 and ct¿ subunits. Nicotine can also manipulate levels of endogenous cannabinoids and THC can blunt some nicotine effects. It is our premise that activation of selective nicotinic receptors activates the endocannabinoid system that in turn contributes to nicotine dependence. Our first goal is to determine what role a4p2 and ct7 receptors, and receptors that contain either a5 or a(J subunits, play in development and expression of rewarding and withdrawal signs associated with nicotine dependence. We will examine nicotine CPP in mice lacking or overexpressing a402 and a? receptors as well as mice with an a5 deletion. Complementary experiments will be conducted in wild-type mice by establishing CPP with selective agonists for these receptor subtypes or using selective antagonists (in particular a6 antagonists) to block nicotine's effects. Genetically modified mice will be chronically infused with nicotine to assess somatic and affective signs upon drug withdrawal. Additionally, during withdrawal, we will challenge wild-type animals with receptor selective agonists and antagonists to assess their effects on somatic and affective signs. We will also assess the effects of varenicline, a partial agonist for a4p2 receptors now in clinical trials for smoking cessation, in the CPP and chronic infusion paradigms. Secondly, we will pursue our premise that the CB1 cannabinoid receptor and endocannabinoids contribute to nicotine rewarding effects and possibly to affective withdrawal signs. We will study nicotine CPP and nicotine withdrawal in mice lacking the CB1 receptor and in those lacking fatty acid amidohydrolase, the enzyme necessary for inactivation of the endocannabinoid anandamide. We will complement these studies by conducting the same experiments in wild type mice challenged with CB1 receptor antagonist or inhibitors of the fatty acid amidohydrolase. Levels of anandamide and 2- arachidonoylglycerol in brain areas of reward during times of nicotine CPP and withdrawal will be studied.