Central Cholinergic Involvement in Cocaine Addiction

可卡因成瘾中枢胆碱能的参与

• 批准号: 7493715
• 负责人: GREGORY P MARK
• 金额: $ 4.7万
• 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/7493715
• 关键词: Abstinence; Acetylcholine; Addictive Behavior; Affect; Amphetamines; Amygdaloid structure; Animal Model; Animals; Area; Behavior; Behavioral; Behavioral Model; Body Regions; Brain; Catheters; Characteristics; Cholinergic Agents; Cholinergic Antagonists; Cholinergic Receptors; Classification; Clinical Research; Cocaine; Cocaine Dependence; Complex; Condition; Cues; Daily; Development; Developmental Process; Dopamine; Dopamine Agonists; Drug Exposure; Esthesia; Exposure to; Extinction (Psychology); Health; Human; Injection of therapeutic agent; Intake; Measures; Mecamylamine; Medial; Mediating; Methods; Microdialysis; Microinjections; Modeling; Morphine; Neurobiology; Nicotine; Nicotinic Antagonists; Nicotinic Receptors; Nucleus Accumbens; Numbers; Pathway interactions; Pharmaceutical Preparations; Prefrontal Cortex; Psychophysiology; Rate; Rattus; Receptor Activation; Relapse; Relative (related person); Research; Risk; Role; Saline; Schedule; Self Administration; Self-Administered; Site; Staging; Stimulus; System; Testing; Training; Ventral Tegmental Area; Week; Work; addiction; behavior measurement; cholinergic; craving; day; desire; drug addict; drug craving; drug seeking behavior; experience; indexing; neurochemistry; neuronal cell body; paired stimuli; prevent; reinforced behavior; research study; response

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 cholinergicsystems 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-administrationon 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.

强迫性使用可卡因造成的巨大健康风险促使人们进行认真的研究工作 确定导致对该药物成瘾的神经生物学底物。尽管 实质性进展，对介导动机方面的神经化学系统的理解 寻求毒品和渴望毒品的行为仍然不完整。为了扩大这种理解，本提案将审查 四个离散的胆碱能系统参与了强迫性可卡因摄入和可卡因- 寻找老鼠的行为。实验将集中于烟碱乙酰胆碱（ACh）受体的激活 成瘾行为的发展和表达。第一个具体目标是确定不断升级的影响 可卡因自我给药对杏仁核复合体（AmC）、腹侧被盖区（VTA）中乙酰胆碱释放的影响 伏隔核 (NAc) 和前额皮质 (PFC)。老鼠将被训练按下杠杆进行自我管理 通过留置颈静脉导管吸食可卡因。可卡因的供应将从每天 1 小时增加到 6 小时 （已被证明会增加每日可卡因摄入量），微透析将在之前和之后测量乙酰胆碱的释放 可卡因摄入量增加后。第二个实验将检查脑内显微注射的影响 尼古丁或烟碱拮抗剂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 VTA、NAc、PFC 或 AmC 中的尼古丁注射是否会启动非强化杠杆按压 可卡因成瘾大鼠的行为。在测试之前，大鼠将接受尼古丁或盐水的全身注射 在自我注射可卡因 2 周之前。在测试日，大鼠将被给予脑内尼古丁和非尼古丁注射剂。 强化反应将作为可卡因渴望指数来衡量。本研究的第三个目的是 确定 AmC、VTA、NAc 和 PFC ACh 系统在药物相关刺激能力中的作用 控制非强化反应。在呈现可卡因相关线索期间将测量乙酰胆碱 以及将烟碱类药物显微注射到体内后由可卡因条件刺激引起的反应 AmC、VTA、NAc 和 PFC。在这四个区域注射烟碱拮抗剂有望降低杠杆- 对二阶刺激的呈现做出反应的新闻行为。希望这些研究的结果 将进一步了解可卡因强化中枢胆碱能机制的参与 行为和药物渴望以及尼古丁对可卡因成瘾和复吸的大脑特定位点的影响。