Basic brain mechanisms underlying drug addiction, craving, and relapse

在报告期内（2006年10月1日至2007年9月30日），由于实验室人员和资源被转移到多巴胺D3受体、GABA和大麻素研究项目上，该研究项目仅取得有限进展。在报告期间，我们使用小动物正电子发射断层扫描（PET）神经成像联合11c -氯氯pride和氟-18氟脱氧葡萄糖（FDG）来检查甲基苯丙胺诱导的脑多巴胺和代谢的改变。青春期实验室大鼠（30天大）接受基线微pet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、皮质下和小脑对FDG的摄取。甲基苯丙胺对枕部FDG摄取没有影响。S-(+)- γ -乙烯基- gaba急性预处理完全消除这些增加。这是首次发现外消旋γ -乙烯基- gaba对脑机制的影响可能是由于S-(+)- γ -乙烯基- gaba对映体的作用。成年后（0 ~ 90天），这些动物再次接受甲基苯丙胺注射，然后进行微pet扫描。在这些成年动物中，青少年暴露于S-(+)- γ -乙烯基- gaba可减弱甲基苯丙胺诱导的FDG摄取变化。我们还使用了一种独特的连续成像策略来获得甲基苯丙胺诱导的条件位置偏好表达之前和期间的FDG显微pet图像。我们研究了动物在“被迫暴露”和“自由选择暴露”两种情况下与甲基苯丙胺管理有关的环境线索。我们发现，两种暴露于安非他明配对环境线索的类型都产生了显著的双侧运动皮层、颞叶皮层、小脑和丘脑的激活。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层。在本报告期间，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”，一篇关于治疗精神兴奋剂成瘾的假设驱动药物发现，还有一篇关于成瘾的动物模型。

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.