Central Cholinergic Involvement in Cocaine Addiction

可卡因成瘾中枢胆碱能的参与

• 批准号: 6926286
• 负责人: GREGORY P MARK
• 金额: $ 22.65万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-30 至 2008-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6926286
• 关键词: acetylcholine; amygdala; anticholinergic agent; behavioral extinction; cocaine; craving; drug addiction; drug addiction antagonist; drug interactions; enkephalins; high performance liquid chromatography; laboratory rat; mecamylamine; neuropharmacology; nicotine; nicotinic receptors; nucleus accumbens; prefrontal lobe /cortex; psychopharmacology; self medication; substance P; tegmentum

DESCRIPTION: (provided by applicant) The substantial health risk posed by the compulsive use of cocaine has prompted a serious research effort to identify the neurobiological substrates that underlie the development of addiction to this drug. Despite substantial progress, an understanding of the neurochemical systems that mediate the motivational aspects of drug seeking and craving remains incomplete. To expand this understanding, this proposal will examine the involvement of four discrete cholinergic systems in the development of compulsive cocaine intake and cocaine-seeking behaviors in rats. Experiments will focus on nicotinic acetylcholine (ACh) receptor activation in the development and expression of addictive behavior. The first specific aim is to identify the impact of escalating cocaine self-administration on the release of ACh in amygdaloid complex (AmC), ventral tegmental area (VTA), nucleus accumbens (NAc) and prefrontal cortex (PFC). Rats will be trained to press a lever to self-administer cocaine through indwelling jugular catheters. Availability of cocaine will be increased from 1 to 6 hr per day (which has been shown to escalate daily cocaine intake) and microdialysis will measure ACh release before and after escalated cocaine intake. A second experiment will examine the impact of intracerebral microinjections of nicotine or the nicotinic antagonist mecamylamine on the escalation of cocaine intake. The second aim of this proposal is to determine if nicotine injections in VTA, NAc, PFC or AmC will prime non-reinforced lever-press behavior in cocaine addicted rats. Prior to testing, rats will receive systemic injections of nicotine or saline before self-administering cocaine for 2 weeks. On test days, rats will be given intracerebral nicotine and non-reinforced responding will be measured as an index of cocaine craving. The third aim of this research is to determine the role of AmC, VTA, NAc and PFC ACh systems in the ability of drug-associated stimuli to control non-reinforced responding. ACh will be measured during the presentation of cocaine-associated cues along with responding elicited by a cocaine-conditioned stimulus after microinjection of nicotinic drugs into AmC, VTA, NAc and PFC. Injections of nicotinic antagonists in these four areas are expected to reduce lever-press behavior in response to presentation of second-order stimuli. It is hoped that the results of these studies will further our understanding of the involvement of central cholinergic mechanisms in cocaine-reinforced behavior and drug craving and the brain site-specific influence of nicotine on cocaine addiction and relapse.

描述：（申请人提供） 强迫使用可卡因带来的重大健康风险已提示 一项认真的研究工作，以识别神经生物学底物 是对这种药物成瘾的发展。尽管很大 进展，对介导的神经化学系统的理解 寻求药物和渴望的动机方面仍然不完整。扩展 这种理解，该建议将研究四个离散的参与 强迫可卡因摄入量的胆碱能系统和 大鼠寻求可卡因的行为。实验将集中于烟碱 乙酰胆碱（ACH）受体在发育和表达中的激活 上瘾的行为。第一个具体目的是确定 在ACH释放杏仁核的自我管理上不断升级 复合物（AMC），腹侧盖区（VTA），伏隔核（NAC）和 前额叶皮层（PFC）。大鼠将接受训练以压杆 通过留置颈导管的自我管理可卡因。可用性 可卡因将从每天1小时增加到6个小时（已证明 每日可卡因摄入量升级）和微透析将测量ACH释放 在升级可卡因摄入之前和之后。第二个实验将检查 尼古丁或烟碱拮抗剂的脑内显微注射的影响 可卡因摄入量升级的梅卡米胺。第二个目标 建议是确定VTA，NAC，PFC或AMC中的尼古丁注射是否会 可卡因上瘾大鼠的主要非增强杠杆式压力行为。之前 测试，大鼠将接受全身注射尼古丁或盐水 自我管理可卡因2周。在测试日，将给予大鼠 脑内尼古丁和非增强反应将被衡量 可卡因渴望的索引。这项研究的第三个目的是确定 AMC，VTA，NAC和PFC ACH系统在药物相关的能力中的作用 刺激以控制非增强反应。 ACH将在 呈现可卡因相关的提示，以及由a引起的响应 将烟碱药显微注射到AMC中后，可卡因条件的刺激 VTA，NAC和PFC。在这四个领域注射烟碱拮抗剂是 预计会响应于 二阶刺激。希望这些研究的结果能 进一步了解中央胆碱能机制的参与 在可卡因增强的行为和渴望和大脑特定于大脑部位的行为中 尼古丁对可卡因成瘾和复发的影响。