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，促使了一项严肃的研究努力