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了认真的研究， 确定这种药物成瘾发展的神经生物学基础。尽管 实质性的进展，对神经化学系统的理解，介导的动机方面， 寻求毒品和渴望毒品的行为仍然不完整。为了扩大这一理解，本提案将审查 参与四个离散的胆碱能系统在发展中的强迫性可卡因摄入和可卡因- 在老鼠身上寻找行为。实验将集中在烟碱乙酰胆碱（ACh）受体的激活， 成瘾行为的发展和表现。第一个具体目标是确定不断升级的 可卡因自身给药对杏仁复合体（AmC）、腹侧被盖区（VTA） 前额叶皮层（PFC）。老鼠将被训练按下杠杆进行自我管理 通过颈静脉导管注射可卡因可卡因的供应将从每天1小时增加到6小时 （已显示每日可卡因摄入量增加）和微透析将测量ACh释放之前， 可卡因摄入量增加后第二个实验将研究脑内微量注射 尼古丁或尼古丁拮抗剂美加明对可卡因摄入量增加的影响。第二个目的是 一项建议是确定VTA、NAc、PFC或AmC中的尼古丁注射是否会引发非增强型压迫 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 在服用可卡因前两周在测试日，将向大鼠脑内给予尼古丁和非尼古丁。 增强的反应将被测量为可卡因渴望的指数。本研究的第三个目的是 确定AmC，VTA，NAc和PFC ACh系统在药物相关刺激的能力中的作用， 控制非强化反应。乙酰胆碱将在可卡因相关线索的呈现期间测量 沿着可卡因条件刺激引起的反应， 在这四个区域注射烟碱拮抗剂有望降低水平， 对二阶刺激呈现的按压行为。希望这些研究的结果 这将进一步加深我们对可卡因增强的中枢胆碱能机制参与的理解。 行为和药物渴望以及尼古丁对可卡因成瘾和复发的大脑部位特异性影响。