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; 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.

强迫使用可卡因带来的很大的健康风险促使人们进行了认真的研究工作，以 确定基于这种药物成瘾发展的神经生物学底物。尽管 实质性进步，对介导的神经化学系统的理解 寻求毒品和渴望仍然不完整。为了扩展这种理解，该建议将研究 四个离散胆碱能系统参与强迫性可卡因摄入和可卡因的发展 在老鼠中寻求行为。实验将集中于烟碱乙酰胆碱（ACH）受体激活 成瘾行为的发展和表达。第一个具体目的是确定升级的影响 可卡因自我管理，ACH在杏仁核复合物（AMC），腹侧盖区（VTA）中的释放， 伏隔核（NAC）和前额叶皮层（PFC）。大鼠将接受训练以压杆以自我管理 可卡因通过留置颈导管。可卡因的可用性将从每天1小时增加到6个小时 （已证明可以升级每天可卡因摄入量），微透析将测量ACH释放前后 升级可卡因摄入后。第二个实验将检查脑内显微注射的影响 尼古丁或可卡因摄入升级的尼古丁拮抗剂梅卡米胺。第二个目标 提案是确定VTA，NAC，PFC或AMC中的尼古丁注射是否会启用非增强杠杆压力 可卡因上瘾大鼠的行为。在测试之前，大鼠将接受全身注射尼古丁或盐水 在自我管理可卡因2周之前。在测试日，将给予大鼠脑尼古丁和非 - 加强响应将被衡量为可卡因渴望的指数。这项研究的第三个目标是 确定AMC，VTA，NAC和PFC ACH系统在药物相关刺激对与 控制非强化响应。 ACH将在与可卡因相关线索的介绍期间进行测量 以及对烟碱药显微注射后可卡因条件刺激引起的响应 AMC，VTA，NAC和PFC。预计在这四个地区对烟碱拮抗剂的注射将降低杠杆 响应二阶刺激的响应行为。希望这些研究的结果 将进一步理解中央胆碱能机制在可卡因增强中的参与 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。