NEUROCHEMICAL INVOLVEMENT OF METHAMPHETAMINE SEEKING IN MICE

小鼠寻找甲基苯丙胺的神经化学参与

• 批准号: 7469488
• 负责人: GREGORY P MARK
• 金额: $ 17.81万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7469488
• 关键词: Abstinence; Acetylcholine; Acute; Address; Adrenergic Agents; Adrenergic Antagonists; Affect; Affinity; Amygdaloid structure; Animal Model; Animals; Arousal; Attenuated; Autoreceptors; Behavior; Behavioral Genetics; Brain; Brain region; Breeding; Cannulas; Catecholamines; Cell Nucleus; Cells; Choline; Choline O-Acetyltransferase; Cholinergic Agents; Cholinergic Agonists; Cholinergic Receptors; Chromosome Pairing; Classification; Clinical; Corpus striatum structure; Data; Deoxyglucose; Detection; Development; Dopamine; Drug Addiction; Drug Exposure; Drug usage; Enzymes; Event; Exposure to; Extinction (Psychology); FOS gene; Fiber; Goals; Hippocampus (Brain); Image; Immunohistochemistry; Implant; Incidence; Injection of therapeutic agent; Label; Lead; Limbic System; Link; Maintenance; Measures; Mecamylamine; Medial; Mediating; Metabolic; Methamphetamine; Methods; Microdialysis; Microinjections; Modeling; Molecular; Motivation; Mus; Muscarinic Agonists; Muscarinic Antagonists; Muscarinics; Neurobiology; Neurons; Nicotine; Nicotinic Receptors; Nucleus Accumbens; Pathway interactions; Pharmaceutical Preparations; Pharmacotherapy; Pilot Projects; Play; Pontine structure; Prefrontal Cortex; Principal Investigator; Rattus; Research; Role; Self Administration; Self-Administered; Signal Transduction; Site; Smoke; Stimulus; Stress; Structure; Synapses; System; Testing; Training; Ventral Tegmental Area; Week; Work; acetylcholine transporter; addiction; base; carvedilol; cholinergic; cholinergic neuron; day; drinking; drug addict; drug reward; indexing; inhibitor/antagonist; intraperitoneal; methamphetamine exposure; neurochemistry; neuronal cell body; noradrenergic; programs; research study; response; stressor; transcription factor; transmission process; uptake

In recent years a dramatic rise in use of methamphetamine (MA) has prompted a serious research effort to identify the neurobiological substrates that underlie the development of MA addiction. Despite substantial progress, an understanding of the neurochemical systems that mediate the motivational aspects of drugseeking remains incomplete. A key example is our lack of information on the role of acetylcholine (ACh) receptors in MA addiction. A large proportion of MA addicts also self-administer the cholinergic agonist nicotine by smoking but we have only a rudimentary understanding of the role nicotinic receptors might play on the maintenance of MA addiction. To expand this understanding, we need to know how MA-seeking affects the release of ACh and conversely, how manipulations of the cholinergic system affect MA-seeking behaviors. To accomplish the first goal we will use microdialysis to measure ACh in the nucleus accumbens, dorsolateral striatum, hippocampus and prefrontal cortex of B6D2F1 mice that are trained to press a lever to self-administer MA through chronically implanted ICV cannulae. The results from these mice will be compared to matched controls that will receive equal amounts of MA (or vehicle) in a yoked fashion. This project will provide neurochemical data on structures relevant to drug-seeking for use in other components of this research center. The second aim will be to study the induction of transcription factors (ITF's) in cholinergic cells, identified by co-labeling for ChAT, and terminal fields after active and passive MA administration inB6D2Fl mice and in mice selectively bred in Scientific Component 6 for differences in MA drinking and MA-induced locomotor sensitization. In addition to regional changes in molecular signaling events such as ITF levels, we will measure the effect of active and passive MA on the choline uptake and vesicular ACh transporters. Finally, a third set of experiments will study the impact of brain-site specific microinjections of nicotinic and muscarinic drugs on the reinstatement of MA-seeking behavior in response to a stressful stimulus. These studies will address the issue of "stressor responsivity" and the findings will be directly relevant to work being done in the clinical and the behavioral genetic components of the center.

近年来，甲基苯丙胺（MA）的使用急剧增加，促使了认真的研究工作 确定基于MA成瘾发展的神经生物学底物。尽管很大 进步，对介导吸毒动机方面的神经化学系统的理解 仍然不完整。一个关键的例子是我们缺乏有关乙酰胆碱作用（ACH）的信息 MA成瘾中的受体。大部分的MA瘾君子也自助胆碱能激动剂 尼古丁通过吸烟，但我们只对烟碱受体可能扮演的角色有基本的了解 关于MA成瘾的维持。为了扩展这种理解，我们需要知道如何寻求言论 影响ACH的释放，而相反，胆碱能系统的操纵如何影响MA-seeking 行为。为了实现第一个目标，我们将使用微透析来测量伏隔核的ACH， B6D2F1小鼠的背外侧纹状体，海马和前额叶皮层，这些小鼠经过训练以按杠杆为 通过长期植入的ICV插管进行自我管理的MA。这些小鼠的结果将是 与匹配的对照相比，将以轭的方式接收等同数量的MA（或车辆）。这 项目将提供与寻求药物有关的结构的神经化学数据，以用于其他组件 这个研究中心。第二个目的是研究转录因子（ITF）的诱导 胆碱能细胞，通过共同标记进行聊天，在主动和被动MA之后识别末端场 在科学成分6中有选择地繁殖了MA的差异 饮酒和MA引起的运动敏化。除了分子信号的区域变化 诸如ITF级别之类的事件，我们将衡量主动和被动MA对胆碱摄取的影响以及 囊泡ACH转运蛋白。最后，第三组实验将研究脑位点特异性的影响 烟碱和毒蕈碱药物对恢复Ma-seeking行为的显微注射，以应对 压力刺激。这些研究将解决“压力响应性”的问题，发现将是 与在中心的临床和行为遗传成分中所做的工作直接相关。