Central Cholinergic Involvement in Cocaine Addiction

可卡因成瘾中枢胆碱能的参与

• 批准号: 6523371
• 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 2006-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6523371
• 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：（由申请人提供） 强迫性使用可卡因造成的巨大健康风险促使 一项认真的研究工作，以确定神经生物学底物 是这种药物成瘾的基础。尽管实质性 进步，对介导神经化学系统的理解 寻求毒品和渴望毒品的动机方面仍然不完整。扩大 根据这种理解，本提案将审查四个离散的参与情况 胆碱能系统在强迫性可卡因摄入和发展中的作用 老鼠寻求可卡因的行为。实验将集中于烟碱 乙酰胆碱 (ACh) 受体激活在发育和表达中的作用 成瘾行为。第一个具体目标是确定影响 增加可卡因自我给药对杏仁核中乙酰胆碱释放的影响 复合体 (AmC)、腹侧被盖区 (VTA)、伏隔核 (NAc) 和 前额皮质（PFC）。老鼠将被训练按下杠杆 通过留置颈静脉导管自行注射可卡因。可用性 可卡因将从每天 1 小时增加到 6 小时（已被证明 增加每日可卡因摄入量），微透析将测量乙酰胆碱释放 可卡因摄入量增加之前和之后。第二个实验将检查 脑内显微注射尼古丁或烟碱拮抗剂的影响 美加明对可卡因摄入量增加的影响。本次活动的第二个目的 建议确定在 VTA、NAc、PFC 或 AmC 中注射尼古丁是否会 可卡因成瘾大鼠的主要非强化杠杆按压行为。之前 测试前，大鼠将接受尼古丁或盐水的全身注射 自我注射可卡因两周。在测试日，将给予大鼠 脑内尼古丁和非强化反应将被测量为 可卡因渴望指数。本研究的第三个目的是确定 AmC、VTA、NAc 和 PFC ACh 系统在药物相关能力中的作用 控制非强化反应的刺激。 ACh 将在 呈现与可卡因相关的线索以及由可卡因引起的反应 将烟碱类药物显微注射到 AmC 后可卡因条件刺激， VTA、NAc 和 PFC。在这四个部位注射烟碱拮抗剂是 预计会减少杠杆按下行为以响应呈现 二阶刺激。希望这些研究的结果能够 进一步我们对中枢胆碱能机制参与的理解 可卡因强化行为和药物渴望以及大脑特定部位 尼古丁对可卡因成瘾和复吸的影响。