Neurobehavioral Mechanisms of Decisions to Smoke Marijuana and Cocaine in Humans

描述(由申请人提供)：近年来，在对目标导向决策的神经生物学的理解方面取得了实质性的进展。有证据表明，这样的决策产生了特定的神经激活模式，假想是为了反映主观或目标值(GV)的编码，GV被定义为可用期权的预测回报价值，在14，15号决策时以共同货币计算。这些知识的许多增长是从神经经济学学科中产生的。尽管这些发现与药物依赖有明显的相关性，可以说是决策的病理学16，22但人们对吸毒者做出的与临床最相关的决定的神经行为机制知之甚少：获得和使用药物的决定。本申请提出了两项平行的受试者内研究，考察了经常使用MJ和COC的人在选择金钱和大麻(MJ研究1)、可卡因(COC研究2)和可口食物(这两项研究)时GV的神经编码，以及线索暴露对这些过程的影响。结合人类行为药理学、先进的功能磁共振成像方法和神经经济学方法，我们的目标是帮助理解在常规吸毒者中决定使用药物和非药物奖励的神经行为机制，这些知识最终可能在开发干预措施以防止这些决定方面发挥核心作用。定期不寻求治疗的MJ(e4x/周~N=20)和COC(e2x/周~N=20)吸烟者将完成为期4天的住院方案，包括4种随机条件：1)中性提示后的药物选择与金钱选择~2)药物提示后的药物选择与金钱选择~3)中性提示后的食物选择与金钱选择~和4)食物提示后的食物选择与金钱选择。在fMRI任务中，将在药物/食物和金钱之间做出一系列选择，之后将随机选择一个进行实施，并相应地管理MJ、COC或食物。我们的目标是1)表征提供的药物或食物的数量与所做的决定之间的关系的神经中介；2)调查药物选择与食物选择之间的行为和神经GV信号的差异；3)比较药物和食物线索对药物和食物选择的行为和GV信号的影响。我们预计，腹内侧额前皮质(VmPFC)和纹状体中的信号将调节所有三种控制力提供的数量和做出的决定之间的关系。我们进一步假设，与药物相关的决定，以及在药物但不是食物线索之后的决定，将涉及vmPFC和纹状体中数量上更大的GV信号，这被认为是灵长类大脑14，15的最终评估地点。这些研究的执行将与全面的培训计划相结合，其中包括讲授MatLab编程、高级fMRI分析和神经经济学、人类行为药理学和fMRI方法的指导读物，以及由国际公认的人类行为药理学(Haney博士和Foltin博士)、高级fMRI分析(Lindquist博士)和决策神经生物学(Glimcher博士)专家组成的团队的监督和监督。因此，拟议的完善的培训计划将为首席调查员吉尔·贝迪博士提供这些领域的高级技能，以启动独立的研究计划，利用人类行为药理学和先进的功能磁共振技术来调查与药物成瘾有关的临床重要问题。贝迪博士接受了临床心理学的研究生培训和人类行为药理学的博士后培训，其中包括在非临床但不是吸毒人群中进行的非法药物挑战研究。作为一名早期职业调查员，她有着良好的出版记录，并在2011年获得了R03和R21奖，证明了有能力通过小额赠款获得NIH的资助。虽然这一新兴的研究轨迹预示着她有能力发展成为一名富有创造力和生产力的独立研究人员，但在她职业生涯的这个关头，根据K23奖项提供的受保护的时间、培训和指导的研究经验是至关重要的，使她能够完成向完全独立的过渡，成为一名以患者为导向的研究人员。贝迪博士的近期目标是发展人类行为药理学和功能磁共振成像分析方面的高级技能，这将使她能够获得独立的R01资金。她的长期目标是在纽约州精神病学研究所和哥伦比亚精神病学的物质使用研究中心内开发一条使用这些方法的程序性研究路线。支持贝迪博士成为研究人员的机构环境是世界上最好的之一，包括随时可以联系到国际知名的高级教职员工，年轻研究人员成功发展的成熟历史，世界一流的设施，包括支持涉及大麻和可卡因吸烟的自我管理研究的医疗设施，以及位于NYSPI磁共振中心的3T专门用于研究的GE MR扫描仪。因此，本申请提出了一个具有重大影响的创新项目。它结合了专家指导和全面的培训，以促进早期职业研究人员的过渡，以及有希望的新兴出版轨道和少量NIH赠款资金，以完全独立为一名以患者为导向的研究人员。

DESCRIPTION (provided by applicant): Recent years have seen substantial advances in understanding of the neurobiology of goal-directed decision making. There is evidence that such decisions produce specific neural activation patterns hypothesized to reflect encoding of subjective or goal values (GVs), defined as the predicted reward value of available options, calculated in a 'common currency' at the time of decision14,15. Many of these gains in knowledge are emerging from the discipline of neuroeconomics. Despite the clear relevance of these findings for drug dependence, arguably pathology of decision-making16, 22, little is known about the neurobehavioral mechanisms of the most clinically-relevant decisions made by drug users: decisions to obtain and use drugs. This application proposes two parallel within-subjects studies examining the neural encoding of GVs during choices between money and marijuana (MJ~ Study 1), cocaine (COC~ Study 2) and palatable food (both studies) in regular MJ and COC users, and the impact of cue exposure on these processes. Employing a combination of human behavioral pharmacology, advanced fMRI methods, and neuroeconomic approaches, we aim to contribute an understanding of the neurobehavioral mechanisms underlying decisions to use drugs versus non-drug rewards in regular drug users, knowledge that could ultimately play a central role in developing interventions to prevent these decisions. Regular non-treatment-seeking MJ (e4x/week~ N=20) and COC (e2x/week~ N=20) smokers will complete a 4-day inpatient protocol including 4 randomized conditions: 1) Drug versus money choices after neutral cues~ 2) Drug versus money choices after drug cues~ 3) Food versus money choices after neutral cues~ and 4) Food versus money choices after food cues. A range of choices between drug/food and money will be made in an fMRI task, after which one choice will be randomly selected for implementation, with MJ, COC or food administered accordingly. We aim to 1) characterize neural mediators of relationships between the amount of drug or food offered and the decisions made~ 2) Investigate differences in behavior and neural GV signals during choices about drug compared to choices about food~ and 3) Compare effects of drug and food cues on behavior and GV signals during choices about drugs relative to food. We anticipate that signaling in the ventromedial Prefrontal Cortex (vmPFC) and striatum will mediate relationships between the amount of all three rein forcers offered and decisions made. We further hypothesize that drug-related decisions, and decisions after drug but not food cues, will involve quantitatively greater GV signaling in vmPFC and striatum, thought to be the final seat of valuation in the primate brain14,15. Execution of these studies will be combined with a comprehensive training program that includes didactic training in Matlab programming, advanced fMRI analysis, and neuroeconomics, guided readings in human behavioral pharmacology and fMRI methods, and supervision and oversight by a team of internationally- recognized experts in human behavioral pharmacology (Drs. Haney and Foltin), advanced fMRI analysis (Dr. Lindquist), and the neurobiology of decision-making (Dr. Glimcher). The well developed training plan proposed will therefore provide the Principal Investigator, Dr. Gill Bedi, with the advanced-level skills in these areas to initiate an independent research program, using human behavioral pharmacology and advanced fMRI skills to investigate clinically-important questions about drug addiction. Dr. Bedi has graduate training in clinical psychology and postdoctoral training in human behavioral pharmacology involving illicit drug challenge studies in non-clinical, but not drug-using, populations. She has a strong track record of publication for an early career investigator, and has demonstrated capacity to obtain NIH funding for small grants, having been awarded an R03 and a R21 in 2011. While this emerging research track bodes extremely well for her capacity to develop into a creative and productive independent researcher, the protected time, training, and mentored research experience that would be provided under this K23 award are critical at this juncture of her career to allow her to complete the transition to full independence as a patient-oriented researcher. Dr. Bedi's immediate goal is to develop advanced skills in human behavioral pharmacology and fMRI analysis that would allow her to obtain independent R01 funding. Her longer-term goal is to develop a programmatic line of research employing these methods within the Substance Use Research Center in New York State Psychiatric Institute and Columbia Psychiatry. The Institutional environment available to support Dr. Bedi's development as a researcher is among the best in the world, combining ready access to internationally-renowned senior faculty, an established history of successful development of young researchers, and world-class facilities including medical facilities to support studies involving marijuana and cocaine smoked self-administration and a 3T research-dedicated GE MR scanner housed in the NYSPI MRI Center. Thus, this application proposes an innovative project with the potential for substantial impact. It combines expert mentorship and comprehensive training to facilitate the transition of an early career researcher with a promising emerging track of publication and small NIH grant funding to full independence as a patient-oriented researcher.