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：(申请人提供) 强制使用可卡因带来的巨大健康风险促使 一项严肃的研究工作，以确定神经生物学底物 是对这种药物上瘾的基础。尽管有大量的 进展，对神经化学系统的理解 毒品寻觅和渴求的动机方面仍然不完整。要扩大规模 了解到这一点，这项建议将审查四个离散的参与 胆碱能系统在强迫性可卡因摄入和发展中的作用 大鼠的可卡因寻找行为。实验将集中在尼古丁上 乙酰胆碱(ACh)受体激活在血管紧张素转换酶的发生和表达中的作用 上瘾的行为。第一个具体目标是确定 递增可卡因自身给药对杏仁核ACh释放的影响 复合体(AMC)、腹侧被盖区(VTA)、伏隔核(NAC)和 前额叶皮质(PFC)老鼠将被训练按下杠杆以 通过留置颈静脉导管自我注射可卡因。的可用性 可卡因将从每天1小时增加到6小时(已表明 增加每日可卡因摄入量)和微透析将测量ACh的释放 可卡因摄入量增加前后。第二个实验将检验 脑内微量注射尼古丁或尼古丁拮抗剂的影响 甲戊胺对可卡因摄入量上升的影响。这样做的第二个目的是 建议确定在VTA、NAC、PFC或AMC注射尼古丁是否会 可卡因成瘾大鼠最佳非强化杠杆式按压行为。在.之前 测试中，大鼠将接受全身注射尼古丁或生理盐水，然后 自我注射可卡因2周。在考试日，将给老鼠 脑内尼古丁和非强化反应将被测量为 可卡因渴求指数。这项研究的第三个目标是确定 AMC、VTA、NAC和PFC ACh系统在药物关联能力中的作用 控制非强化反应的刺激。将在测试期间测量ACH 与可卡因相关的线索的呈现以及由 向AMC微量注射尼古丁药物后的可卡因条件刺激， VTA、NAC和PFC。在这四个区域注射尼古丁拮抗剂是 预计将减少杠杆按压行为，以响应 二阶刺激。希望这些研究的结果将 进一步认识中枢胆碱能机制的参与 在可卡因强化的行为、药物渴求和大脑部位特异性 尼古丁对可卡因成瘾和复发的影响。