PET AND SPECT IMAGING IN ALCOHOLIC SMOKERS

此MRSDA K01应用程序请求支持，以促进候选人发展为将正电子发射断层扫描(PET)和单光子发射断层扫描(SPECT)神经成像方法应用于酒精和尼古丁依赖的神经化学的独立研究员。候选人提出的职业发展和研究计划将通过与斯蒂芬妮·奥马利博士和罗伯特·B·因尼斯博士的持续指导关系来促进，这两位资深科学家分别在酒精依赖的临床神经精神药理学以及PET和SPECT成像方面取得了国际公认的成就。一份全面的五年职业发展计划将为应聘者提供所需的多学科技能，最终领导一项关于物质依赖的脑成像的独立和高产出的研究计划。该计划经过精心设计，以满足以下主要领域的特定职业发展需求：L)酒精中毒的临床研究方法；2)放射性同位素在人体中的使用；3)成像仪器和分析；4)放射性示踪剂开发、药代动力学和示踪剂动力学建模；以及5)定量技能和生物统计学。这些高度专业化领域的正规培训将通过密集的研讨会、教程、校外教学和研究课程来实现。我们提出了三个具体的目标，旨在评估主动依赖的酒精吸烟者和非吸烟者以及非酒精吸烟者和非吸烟者中关键的多巴胺和5-羟色胺能突触标志物的状态。我们建议L)确定酒精依赖者纹状体DA转运体是否减少，并使用[123I]β-CIT通过SPECT评估尼古丁在酒精依赖者和非酒精依赖者中的作用；2)确定脑干5-羟色胺转运体是否在过度依赖的酒精者中增加，并区分尼古丁在酒精依赖者和非酒精依赖者中的影响，如通过SPECT使用[123I]β-CIT评估的那样；3)确定皮质5HT2A受体在积极依赖的酒精吸烟者和酒精非吸烟者中是否存在差异调节，如通过PET使用[18F]deuroaltanserin评估的那样。这些研究的发现将为深入了解与酒精和尼古丁双重依赖有关的神经化学变化提供指导，可能会指导开发更有效的药物疗法来治疗这些毁灭性的大脑疾病。

This MRSDA K0l application requests support to promote the candidate's development into an independent investigator in the application of positron emission tomography (PET) and single photon emission tomography (SPECT) neuroimaging methods to the neurochemistry of alcohol and nicotine dependence. The candidate's proposed Career Development and Research Plans will be facilitated by ongoing mentoring relationships with Drs. Stephanie O'Malley and Robert B Innis, established senior scientists with internationally recognized accomplishments in clinical neuropsychopharmacology of alcohol dependence and PET and SPECT imaging, respectively. A comprehensive five-year Career Development Plan will provide the candidate with the multi- disciplinary skills required to ultimately lead an independent and highly productive research program in brain imaging of substance dependence. This plan has been carefully devised to satisfy specific career development needs in the following major areas: l) clinical research methods in alcoholism; 2) use of radioisotopes in humans; 3) imaging instrumentation and analysis; 4) radiotracer development, pharmacokinetic and tracer kinetic modeling; and 5) quantitative skills and biostatistics. Formal training in these highly specialized areas will be achieved through an intensive curriculum of seminars, tutorials, extramural didactics, and research studies. Three specific aims are proposed which seek to assess the status of key dopaminergic and serotonergic synaptic markers in actively dependent alcoholic smokers and nonsmokers and nonalcoholic smokers and nonsmokers. We propose l) to determine if striatal DA transporters are decreased in alcoholics and to delineate the effects of nicotine in the alcoholic and nonalcoholic populations as assessed via SPECT using [123I]beta-CIT; 2) To determine if brainstem 5-HT transporters are elevated in actively dependent alcoholics and to distinguish the effects of nicotine in alcoholic and nonalcoholic populations, as assessed via SPECT using [123I]beta-CIT and 3) To determine if cortical 5HT2A receptors are differentially regulated in actively dependent alcoholic smokers and alcoholic nonsmokers as assessed via PET using [18F]deuteroaltanserin. The findings from these studies will offer insight into the neurochemical alterations associated with dual alcohol and nicotine dependence which may guide the development of more effective pharmacotherapies for these devastating brain disorders.