NICOTINE AND CENTRAL ALPHA 2 ADENOCEPTORS

尼古丁和中央 ALPHA 2 腺感受器

• 批准号: 6494800
• 负责人: YOUSEF TIZABI
• 金额: $ 13.19万
• 依托单位: HOWARD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-08-01 至 2002-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6494800
• 关键词: alpha adrenergic receptor; autoradiography; clonidine; drug abuse chemotherapy; drug interactions; drug withdrawal; gas chromatography mass spectrometry; gender difference; laboratory rat; nicotine; receptor binding; receptor sensitivity; smoking cessation; statistics /biometry; tobacco abuse

Nicotine, the primary psychoactive gent in tobacco, interacts with specific neurotransmitter systems including the noradrenergic system. Noradrenergic neurotransmission is mediated by several receptor subtypes including alpha2-adrenoceptors. Nicotine-alpha2-adrenoceptors interactions may not only be responsible for some of the beneficial effects of nicotine, but may also be involved in nicotine dependence and nicotine withdrawal symptoms. Indeed, smoking cessation may be facilitated by clonidine, an alpha2-adrenoceptor agonist. However, clonidine's adverse effects preclude its use as a first-line treatment in smoking cessation. Various subtypes of alpha-2 adrenoceptors with distinct central distribution have been identified. Chronic nicotine administration results in increased density of cortical alpha2-adrenoceptors. However, it is not know whether alpha2-adrenoceptors in other discrete brain regions are also affected by nicotine. More importantly, no information is available on interactions between nicotine and specific alpha2-adrenoceptor subtype(s). This information is critical in identifying specific alpha2-adrenoceptor subtypes as potential targets for the development of novel agents in treatment of nicotine dependence and/or withdrawal. Thus, we propose to establish the specificity, time-course, duration, and dose-response relationship between nicotine administration/withdrawal and central alpha 2-adrenoceptors. Furthermore, since gender differences in the effects of nicotine and clonidine have been observed, both male and females will be studied. Nicotine will be administered to rats by osmotic mini-pumps. Autoradiography will be used to quantify alpha2-adreneceptor subtypes plasma levels of nicotine and cotinine (a major nicotine metabolite) will be determined by gas chromatography/mass spectrography and will be correlated with receptor binding data. These studies will significantly enhance our understanding of nicotine-alpha2-adrenoceptor interactions in the brain and will set the stage for further characterization of this interaction which may lead to novel pharmacotherapy in smoking cessation.

尼古丁是烟草中主要的精神活性物质，它与 特定的神经递质系统，包括去甲肾上腺素能系统。 去甲肾上腺素能神经传递由几种受体亚型介导 包括α2-肾上腺素受体。尼古丁-α2-肾上腺素受体相互作用 可能不仅造成了一些有益的影响 尼古丁，但也可能与尼古丁依赖和尼古丁有关 戒断症状。事实上，戒烟可以通过 可乐定，一种α2-肾上腺素受体激动剂。然而，可乐定的不利 的影响使其无法用作戒烟的一线治疗方法。 α2 肾上腺素受体的各种亚型具有不同的中枢 分布已确定。长期尼古丁给药结果 皮质α2-肾上腺素受体密度增加。然而，它并不是 了解其他离散大脑区域中的 α2 肾上腺素受体是否也存在 受尼古丁影响。更重要的是，目前还没有任何相关信息 尼古丁和特定α2-肾上腺素受体亚型之间的相互作用。 该信息对于识别特定的 α2 肾上腺素受体至关重要 亚型作为开发新药物的潜在目标 治疗尼古丁依赖和/或戒断。因此，我们建议 确定特异性、时程、持续时间和剂量反应 尼古丁给药/戒断与中枢α之间的关系 2-肾上腺素受体。此外，由于性别影响的差异 已观察到尼古丁和可乐定，男性和女性都会 研究过。尼古丁将通过微型渗透泵给予大鼠。 放射自显影将用于量化 α2-肾上腺素受体亚型 尼古丁和可替宁（主要尼古丁代谢物）的血浆水平将 通过气相色谱/质谱法测定，并且将 与受体结合数据相关。这些研究将显着 增强我们对尼古丁-α2-肾上腺素受体相互作用的理解 大脑，并将为进一步表征这一点奠定基础 相互作用可能会导致新的戒烟药物疗法。