Basic brain mechanisms underlying drug addiction, craving, and relapse

药物成瘾、渴望和复发的基本大脑机制

• 批准号: 7593286
• 负责人: ELIOT L GARDNER
• 金额: $ 37万
• 依托单位: NATIONAL INSTITUTE ON DRUG ABUSE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7593286
• 关键词: Acute; Addictive Behavior; Adolescent; Adult; Amphetamines; Amygdaloid structure; Animal Model; Animals; Attenuated; Behavior; Bilateral; Biochemical; Biological Assay; Biological Models; Brain; Cannabinoids; Cerebellum; Condition; Corpus striatum structure; Cues; Development; Dopamine; Drug Addiction; Electrical Stimulation of the Brain; Exposure to; Fluorine; Goals; High Pressure Liquid Chromatography; Image; Immunoblotting; Injection of therapeutic agent; Intravenous; Laboratory Animals; Laboratory Personnel; Laboratory Rat; Literature; Medicine; Metabolism; Methamphetamine; Microdialysis; Motor Cortex; Opioid; Pain management; Pharmaceutical Preparations; Polymerase Chain Reaction; Positron-Emission Tomography; Proteins; Psychological reinforcement; Psychostimulant dependence; RNA; Raclopride; Range; Relapse; Reporting; Research; Research Project Grants; Resources; Reverse Transcription; Rewards; Risk; Sampling; Scanning; Self Administration; Stress; Techniques; Temporal Lobe; Thalamic structure; Vigabatrin; Western Blotting; Work; addiction; craving; day; dopamine D3 receptor; enantiomer; fluorodeoxyglucose; gamma-Aminobutyric Acid; in vivo; insight; interest; mature animal; median forebrain bundle; neuroimaging; novel; pre-clinical; preference; sensory cortex; uptake

Due to diversion of laboratory personnel and resources to the dopamine D3 receptor, GABA, and cannabinoid research projects during the reporting period (01 Oct 06 to 30 Sept 07), only limited progress was made on this research project. During the reporting period, we used small animal positron emission tomography (PET) neuroimaging in combination with 11C-raclopride and fluorine-18 fluorodeoxyglucose (FDG) to examine methamphetamine-induced alterations in brain dopamine and metabolism. Adolescent laboratory rats (30 days old) received baseline microPET scans. The animals then received an injection of methamphetamine, followed by another set of microPET scans. Methamphetamine significantly increased striatal dopamine by approximately 22% and increased FDG uptake cortically, subcortically, and in the cerebellum. There were no effects of methamphetamine on occipital FDG uptake. Acute pretreatment with S-(+)-gamma-vinyl-GABA completely abolished these increases. This constitutes the first finding that racemic gamma-vinyl-GABA's effects on brain mechanisms may be due to actions of the S-(+)-gamma-vinyl-GABA enantiomer. As adults (>90 days old), the animals received another methamphetamine injection followed by microPET scanning. Adolescent exposure to S-(+)-gamma-vinyl-GABA attenuated methamphetamine-induced changes in FDG uptake in these adult animals. We also used a unqiue serial imaging strategy to obtain FDG microPET images both prior to and during the expression of methamphetamine-induced conditioned place preferences. We studied animals during both "forced exposure" and "free choice exposure" to the environmental cues previously associated with methamphetamine administration. We found that both types of exposure to amphetamine-paired environmental cues produced significant bilateral activations of motor cortex, temporal cortex, cerebellum, and thalamus. However, "free choice exposure" preferentially activated the medial forebrain bundle and striatum, while "forced exposure" preferentially activated the amygdala and sensory cortex. We also contributed 3 major review articles to the addiction medicine literature during this this reporting period - one on the "risk" of addiction during pain management with opioid medications, one on hypotheis-driven medication discovery for the treatment of psychostimulant addiction, and one on animal models of addiction.

由于在本报告所述期间(2006年10月1日至2007年9月30日)，实验室人员和资源被转用于多巴胺D3受体、GABA和大麻素研究项目，这一研究项目的进展有限。在报告期间，我们使用小动物正电子发射断层扫描(PET)神经成像结合11C-拉氯普利和氟-18氟脱氧葡萄糖(FDG)来检测甲基苯丙胺诱导的脑多巴胺和代谢的变化。青春期实验大鼠(30日龄)接受基线microPET扫描。然后，这些动物接受了甲基苯丙胺的注射，随后进行了另一组微型PET扫描。甲基苯丙胺显著增加纹状体多巴胺约22%，并增加皮质、皮质下和小脑的FDG摄取。甲基苯丙胺对枕骨FDG摄取无影响。S-(+)-γ-乙烯基-氨基丁酸急性预处理可完全消除上述升高。这是首次发现外消旋γ-乙烯基-氨基丁酸对脑机制的影响可能是由于S-(+)-γ-乙烯基-氨基丁酸对映体的作用。成年后(90天大)，动物接受另一次甲基苯丙胺注射，然后进行微型正电子发射计算机断层扫描。青春期暴露于S-(+)-γ-乙烯基氨基丁酸可减弱甲基苯丙胺对这些成年动物摄取FDG的影响。我们还使用了一种独特的序列成像策略，在甲基苯丙胺诱导的条件性位置偏爱表达之前和期间都获得了FDG microPET图像。我们研究了动物在“强迫暴露”和“自由选择暴露”期间对先前与甲基苯丙胺给药相关的环境线索的影响。我们发现，两种类型的苯丙胺配对环境线索都能显著激活运动皮质、颞叶皮质、小脑和丘脑。然而，“自由选择暴露”优先激活内侧前脑束和纹状体，而“强迫暴露”优先激活杏仁核和感觉皮质。在本报告所述期间，我们还为成瘾医学文献贡献了3篇主要综述文章-一篇关于阿片类药物治疗疼痛期间成瘾的“风险”，一篇关于治疗精神刺激性成瘾的假说驱动的药物发现，以及一篇关于成瘾的动物模型。